database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! suggested reviewers: prof. anthony turner university of leeds a.j.turner@leeds.ac.uk dr. daniel lambert university of sheffield d.w.lambert@sheffield.ac.uk database connection failed! microsoft word stauduhar international journal of cancer therapy and oncology www.ijcto.org copyright © stauduhar et al. issn 2330-4049 are output measurements always necessary after ct tube  replacement?    paul j stauduhar, aaron kyle jones the university of texas m. d. anderson cancer center, houston, tx, usa. received march 19, 2014; published online april 08, 2014 [presented at the young investigator’s symposium at the 2014 annual meeting of southwest chapter of american association of physicists in medicine (aapm) in san antonio, texas, usa] conference proceeding abstract purpose: tx regulations and the acr require that ct radiation output be measured within 30 days of major service. the most common major service is tube replacement. we hypothesized that historical qc data could be used instead to determine if output measurements are necessary, reducing the need for costly output measurements. methods: we reviewed 66 records of tube replacements to determine with what frequency output falls outside specifications. we also conducted an experiment to verify that clinically significant output changes could be identified by comparing image noise in historical qc data with the same data after tube replacement. we used 30 days of historical qc data to establish a baseline noise level and 95% confidence interval (ci) for individual noise measurements. to simulate output changes, we acquired phantom images with our qc protocol while manually changing output (ma). we acquired 10 images using the baseline output and 10 images at each different “output”. we evaluated individual images and subsets of images at each “output” to determine if the system was within the manufacturer’s specifications. results: none of the 66 tube replacements resulted in an output change that exceeded specifications. analysis of 30 days of historic qc data for our experimental system indicated a mean noise of 5.4 hu with 95% ci of 5.1 ‒ 5.7 hu. when using the mean noise of 10 images acquired at each of the varying outputs, we were able to identify, with 100% accuracy, images acquired at outputs outside manufacturer’s specifications. conclusion: the results of our review of historical tube replacement data indicated the likelihood of output falling outside manufacturer’s specifications is low. considering this, it is likely that by using qc data from programs required by regulation and the acr physicists can reliably verify radiation output stability remotely instead of making physical measurements. ------------------------------------------------------------------ presenting author: paul j stauduhar; the university of texas m. d. anderson cancer center, houston, tx, usa. cite this article as: p stauduhar, a jones. are output measurements always necessary after ct tube replacement? int j cancer ther oncol 2014; 2(2):020238. doi: 10.14319/ijcto.0202.38 http://ijcto.org/index.php/ijcto/index http://dx.doi.org/10.14319/ijcto.0202.38 2 stauduhar et al. international journal of cancer therapy and oncology www.ijcto.org copyright © stauduhar et al. issn 2330-4049 fig.1: plot showing output after a ct xray tube change. output specifications (0%) and limits (red and green dashed lines) are from manufacturer technical specifications. the limit for siemens was +/-20%, ge publishes an expected variation of +/-15% and a maximum variation of +/40%. in the current study (66 instances), we found no records of x�ray tubes failing to meet manufacturer’s specifications when oem replacement tubes are used. *image noise is mean from 10 scans †15% output change corresponds to 3.9% change in image noise, 95% ci for image noise = [5.1, 5.7]. ci was calculated by using the ci for baseline noise and applying scaling factor to calculate ci at +/� 15% output deviation from baseline. the lower limit of the ci for �15% output and the upper limit of the ci for +15% output were used in the final ci. fig. 2: results of qc experiment demonstrate that it is possible to detect changes in post�replacement tube output using historical qc data. values in the top row highlighted green indicate output changes that are within +/-15% manufacturer limits, values highlighted in red fall outside limits. “pass” or “fail” values in bottom row indicate results of comparison of image noise between “post�change” images, simulated by changing ma, and “pre�change” historical qc data. one output value that was within specified limits (-15%) was indicated as failing by our analysis. it was noted that changes in image noise were larger than expected as output decreased, while changes were at the expected level as output was increased. one possible explanation for this result is increasing contribution of electronic noise as output was reduced. microsoft word mikell international journal of cancer therapy and oncology www.ijcto.org copyright © mikell et al. issn 2330-4049 characterization of tumor dose heterogeneity for 90y microsphere  therapies using voxel‐ based dosimetry    justin mikell1, firas mourtada2, armeen mahvash1, s cheenu kappadath1 1the university of texas m. d. anderson cancer center, houston, tx, usa. 2christiana care, newark, de, usa. received march 19, 2014; published online april 08, 2014 [presented at the young investigator’s symposium at the 2014 annual meeting of southwest chapter of american association of physicists in medicine (aapm) in san antonio, texas, usa] conference proceeding abstract purpose: dosimetry for 90y microsphere therapies (ymt) with standard (sm) and partition (pm) models provide only uniform dose estimates to tumor and liver. our objective is to calculate tumor dose heterogeneity, known to effect response, using voxel-based dosimetry and investigate the limitations of sm and pm. methods: voxel-based dosimetry was performed on 17 ymt patients using monte carlo dosxyznrc. 90y activity and tissue/density distributions were based on quantitative 90y bremsstrahlung spect/ct. tumors (n=31), liver, and treatment lobe/segments were segmented on diagnostic ct or mr. dose volume histograms (dvh) were created for tumors and normal liver. bland-altman analysis compared voxel-based mean absorbed doses to tumor and liver with sm and pm. tumor and normal liver absorbed dose heterogeneity were investigated through metrics: integral uniformity (iu), d10/d90, cov. correlations of heterogeneity with voxel-based mean doses and volumes were evaluated. results: heterogeneity metrics (mean ± 1σ) for tumor dose were cov = 0.48 ± 0.28, d10/d90 = 4.7 ± 3.9, and iu = 0.8 ± 0.18. heterogeneity metrics correlated with tumor volume (r > 0.58) but not tumor mean doses (r < 0.20). voxel-based tumor mean doses correlated with pm (r = 0.84) but not sm (r = 0.08). both yielded poor limits of agreement with of 83 ± 174 and -28 ± 181 gy, respectively. normal liver heterogeneity metrics (mean ± 1σ) were cov = 0.83 ± 0.29, d10/d90 = 12 ± 15, and iu = 0.97 ± 0.03. only d10/d90 (r = 0.49) correlated with mean normal liver absorbed dose. voxel-based normal liver/lobe mean doses correlated with pm (r = 0.96), but had poor limits of agreement (26 ± 29 gy). conclusion: tumor doses have high levels of heterogeneity that increase with volume but are independent of dose. voxel-based dvh and dose heterogeneity metrics will promote accurate characterization of tumor response following ymt. [research support: nih/nci r01 ca138986] ------------------------------------------------------- key results: fig. 1: this figure shows the tumor dose heterogeneity (max to min range of individual absorbed dose tumor estimates in beige shadow), together with the mean voxel-based tumor absorbed dose (red) and those for the pm (blue) and sm (green). high levels of heterogeneity are observed. the pm and sm are unable to encompass the heterogeneity which is represented as the shaded area for each tumor. the pm tracks the mean voxel-based dose better than the sm. unfortunately, the pm overestimates for 28/31 with a large mean difference of 83 ± 174 gy. presenting author: justin mikell; the university of texas m.d. anderson cancer center, houston, tx, usa. cite this article as: mikell j, mourtada f, mahvash a, kappadath sc. characterization of tumor dose heterogeneity for 90y microsphere therapies using voxelbased dosimetry. int j cancer ther oncol 2014; 2(2):020228. doi: 10.14319/ijcto.0202.28 http://ijcto.org/index.php/ijcto/index http://dx.doi.org/10.14319/ijcto.0202.28 2 mikell et al. : characterization of tumor dose heterogeneity international journal of cancer therapy and oncology www.ijcto.org copyright © mikell et al. issn 2330-4049 fig. 2: a plot of mean tumor voxel-based dose versus those from pm and sm showing that the pm is a better surrogate for true mean doses than the sm. no correlation between voxel-based and sm was found. voxel-based and pm were correlated, but notice that the pm overestimates the true mean dose by a factor of ~2. table 1: correlations of heterogeneity metrics with voxel-based mean absorbed doses. checkered cells indicate that no correlation was found. d10 and d90 are derived from cumulative dose volume histograms. d90 is the minimum dose in the hottest 90% of tumor volume. similarly, d10 is the minimum dose in the hottest 10% of the tumor volume. cov is the coefficient of variation (= standard deviation/mean). non uniformity metric linear fits of heterogeneity metrics (correlation coefficient) versus voxel-based mean dose (gy) versus volume (cc) tumor (n=31) y = mx + b (corr coef) normal liver (n=17) y = mx + b (corr coef) tumor (n=31) y = mx + b (corr coef) normal liver (n=17) y = mx + b (corr coef) cov 7.0e-4x + 0.34 (0.68) max/min 2.0e-1x + 15 (0.32) d10/d90 4.1e-1x – 3.6 (0.49) 9.4e-3x + 2.7 (0.64) -9.6e-3x + 25 (0.44) iu 4.0e-4x + 0.71 (0.59) table 2: bland altman analyses of dosimetry models with voxel-based mean absorbed dose as truth. biases calculated as pm or sm minus voxel-based mean absorbed dose. both sm and pm overestimate the normal liver dose compared to voxel-based means. bland altman analysis with voxel-based mean dose as truth tumor (n=31) bias ± 2σ (gy) normal liver (n=17) bias ± 2σ (gy) standard model -28.1 ± 180.7 40.1 ± 26.8 partition model 83.4 ± 174.4 25.7 ± 29.3 international journal of cancer therapy and oncology www.ijcto.org copyright © vasdev et al. issn 2330-4049 nikhil vasdev, ben lamb, tim lane, gregory boustead, james m adshead hertfordshire and south bedfordshire urological robotic centre, department of urology, lister hospital, stevenage, uk received september 03, 2013; accepted september 18, 2013; published online september 20, 2013 scientific note a radical cystectomy (rc) with pelvic lymph node dissection (plnd) is the gold standard for the management of the appropriately selected patient with muscle invasive bladder cancer (mibc) and non-muscle invasive bladder cancer (nmibc)/carcinoma in situ (cis) who fail appropriate intravesical therapy. in the last decade, robotic radical cystectomy (rrc) is being performed in a large number of international centre’s with the published advantages of decreased blood loss, improved post-operative convalescence and earlier initiation of adjuvant therapy1 when compared to open cystectomy (oc). current literature indicates that a rc is equivalent to oc from the oncological perspective. an oc is associated with high rates of morbidity (19-64%) or mortality (6-11%), although there is a wide variation in current literature.1-11 a rrc is perhaps just one modality in a raft of measures to try reducing mortality and morbidity of a cystectomy. to the robotic urological surgeon, a rrc comes with numerous specific challenges. questions that arise at the time of commencing a rrc include the learning curve of the procedure, learning steps to enhances ones speed to perform the procedure efficiently and safely, level of lymphnode dissection, whether one should embark of performing an intracorpealileal conduit or neobladder formation and the cost of commencing a rrc service. the patient’s postoperative management is the most important step to ensure that the post-operative complications are kept to a minimum using a multi-disciplinary team (mdt) approach. in current literature high volume centers with experienced surgeons have reported patient outcomes that are acceptable from the perspective of extended pelvic lymph node dissection, positive surgical margin rates and highlight that patients are not being compromised from the surgical perspective in undergoing a rc.2 the learning curve of a rrc is not as clearly defined in comparison to robotic radical prostatectomy (rrp). before commencing arrc it is important to be proficient and familiar with robotic pelvic surgery. most robotic surgeons are proficient in rrp before embarking on performing independent rrc. hayn et al.3 have indicated that an acceptable level of proficiency to perform a rrc is established after the 30th case by measuring post-operative parameters such as operative time, lymph node yield (lny), estimated blood loss (ebl), and margin positivity. at our center we commenced performing rc after performing 150 robotic rrp. we would strongly recommend that a robotic urological surgeon who is keen to commence robotic rc should be proficient in robotic rrp and in performing an extended pelvic lymph node dissection (eplnd). a well-trained robotic team consisting of the lead experience console surgeon, experienced assistant, nursing staff and an experience anesthetist is essential for the commencement of a rrc program. the techniques that a team needs to develop to aid in improving intra-operative times including a fast docking/ undocking time, piggyback techniques for ports and , the use of different specimen retrieval bags, use of laparoscopic staplers and new intraoperative hemostatic agents. whilst performing an adequate rrc involves the removal of the bladder, the importance of performing an eplnd cannot be understated. there is no defined lymph node dissection template for a rrc and some centers now perform an eplnd before performing the robotic cystectomy during a rrp.4 the anatomical landmark that we recommend to be followed is up to the level of the aortic bifurcation or the inferior mesenteric artery (ima), lymph node of cloquet distally, genitofemoral nerve laterally and perivesical tissue laterally. using this template the surgeon will be able to excise the external iliac, obturator, hyogastic and common corresponding author: nikhil vasdev, frcs (urol); hertfordshire and south bedfordshire urological robotic centre, department of urology, lister hospital, stevenage, uk. email: nikhilvasdev@doctors.org.uk cite this article as: vasdev n, lamb b, lane t, boustead g, adshead j. robotic cystectomy : important considerations before commencing the procedure independently. int j cancer ther oncol 2013;1(1):01017. doi: 10.14319/ijcto.0101.7 robotic cystectomy : important considerations before commencing the procedure independently http://dx.doi.org/10.14319/ijcto.0101.7 2 vasdev et al.: robotic cystectomy international journal of cancer therapy and oncology www.ijcto.org copyright © vasdev et al. issn 2330-4049 iliac. some authors5 recommend the excision of the presacrallymphnode as the excision of this lymph node group facilitates the transposition of the left ureter behind the sigmoid mesentery to aid in intracorporeal anastomosis. with an evolution in robotic systems there has been an increase in the number of patients undergoing intracorporeal ileal conduit and neobladder formation. the excellent technical description of the procedure has led to the adoption of these techniques worldwide.5 we have recently published the results of our initial patients.6 robotic surgeons must be proficient in the performing the cystectomy part of the rrc before embarking on either an intracorporeal ileal conduit or neobladders formation due the complications of keeping patients in the steep trendelenburg position for prolonged periods, which include compartment syndrome, neurological complications, intraocular complications, and rhabdomyolysis.7,8 recent evidence from high volume centres performing rrc and intracorporeal neobladders diversion confirm that initial results are comparable to contemporary open series with regards to complication rates, functional and oncological outcomes.9 we recommend that a surgeon should embark on performing an intracorporeal ileal conduit and neobladder formation only if the ablative part of rrc is less than 2.5 hours of total operative time. if the ablative times are longer we recommend performing a mini-laparotomy for excision of the cystectomy specimen and completing an extracorporeal ileal conduit or neobladders.6 the cost effectiveness of a rrc when compared to an open radical cystectomy (orc) has a disadvantage of being more expensive due to the initial high purchase and maintenance contract cost, although when the indirect costs of complications and extended hospital stay with orc are considered, rrc may be less expensive than the traditional open procedure. in order to accurately evaluate the cost effectiveness of rarc versus orc, prospective randomized trials between the two surgical techniques with long-term oncologic efficacy are needed.10 in conclusion, a rrc with intracorporeal ileal conduit or neobladders formation is a complex robotic procedure that should only be undertaken by an experienced robotic pelvic oncological surgeon who is completely competent at performing a rrp + eplnd. a carefully mentored approach and a well-trained robotic team are the two key components to make the procedure a success. competing interests the authors declare that they have no conflicts of interest. the authors alone are responsible for the content and writing of the paper. references 1. liss ma, kader ak. robotic-assisted laparoscopic radical cystectomy: history, techniques and outcomes. world j urol 2013 ; 31 :489-9. 2. khan ms, elhage o, challacombeet al b. long-term outcomes of robot-assisted radical cystectomy for bladder cancer. eur ur 3. hayn mh, hussain a, mansour am et al. the learning curve of robot-assisted radical cystectomy: results from the international robotic cystectomy consortium. eur urol 2010; 58: 197-202. 4. desai mm, berger ak, brandinarret al. robotic and laparoscopic high extended pelvic lymph node dissection during radical cystectomy: technique and outcomes. eur urol 2012; 61: 350-5. 5. pruthi rs, nix j, mcrackan d, et al. robotic-assisted laparoscopic intracorporeal urinary diversion. eur urol 2010; 57: 1013–21. 6. bishop c, vasdev n, boustead g, adshead jm. robotic intracorpealileal conduit formation – initial experience from a single uk centre. advances in urology [article in press]. 7. mattei a, di pierro gb, rafeld v, konrad c, beutler j, danuser h. positioning injury, rhabdomyolysis, and serum creatine kinase-concentration course in patients undergoing robot-assisted radical prostatectomy and extended pelvic lymph node dissection. j endourol 2013; 27: 45-5. 8. pandey r, garg r, darlong v, punj j, chandralekha, kumar a. unpredicted neurological complications after robotic laparoscopic radical cystectomy and ileal conduit formation in steep trendelenburg position: two case reports. actaanaesthesiol belg 2010; 61: 163-6. 9. tyritzis si, hosseini a, collins j, nyberg t, jonsson mn, laurin o, khazaeli d, adding c, schumacher m, wiklund np. oncologic, functional, and complications outcomes of robotic assisted radical cystectomywith totally intracorporeal neobladder diversion. eur urol 2013 (article in press). 10. mmeje co, martin ad, nunez-nateras r, parker as, thiel dd, castle ep. cost analysis of open radical cystectomy versus robot-assisted radical cystectomy. curr urol rep 2013;14: 26-3. 11. prentis jm, trenell mi, vasdev n, french r, dines g, thorpe a, snowden cp. impaired cardiopulmonary reserve in an elderly population is related to postoperative morbidity and length of hospital stay after radical cystectomy. bju int 2013; 112: e13-9. ol 2013; 64: 219–224. http://dx.doi.org/10.1007/s00345-013-1053-z http://dx.doi.org/10.1016/j.eururo.2013.01.006 http://dx.doi.org/10.1016/j.eururo.2013.01.006 http://dx.doi.org/10.1016/j.eururo.2010.04.024 http://dx.doi.org/10.1016/j.eururo.2011.09.011 http://dx.doi.org/10.1016/j.eururo.2009.12.028 http://dx.doi.org/10.1089/end.2012.0169 http://dx.doi.org/10.1089/end.2012.0169 http://dx.doi.org/10.1016/j.eururo.2013.05.050 http://dx.doi.org/10.1016/j.eururo.2013.05.050 http://dx.doi.org/10.1007/s11934-012-0292-7 http://dx.doi.org/10.1111/bju.12219 http://dx.doi.org/10.1111/bju.12219 international journal of cancer therapy and oncology www.ijcto.org corresponding author: carmen salvador-coloma; medical oncology department, university hospital la fe, valencia, spain. cite this article as: salvador-coloma c, montalar j, niño om, tormo a, aparicio j. long term survival after brain metastases from malignant melanoma. int j cancer ther oncol. 2016; 4(4):448. doi: 10.14319/ijcto.44.8 © salvador-coloma et al. issn 2330-4049 long term survival after brain metastases from malignant melanoma carmen salvador-coloma1, joaquín montalar1, óscar mauricio niño1, alejandro tormo2, jorge aparicio1 1medical oncology department, university hospital la fe, valencia, spain 2radiotherapy department, university hospital la fe, valencia, spainreceived august 25, 2016; revised december 13, 2016; accepted december 20, 2016; published online december 28, 2016 case report abstractwe present the case of a 32-year-old patient with malignant melanoma whorelapsed with an unresectable brain metastases (bm). he was managed with wholebrain radiotherapy (wbrt) and temozolomide chemotherapy. a metabolicpositron emission tomography (pet-scan) complete response was achieved. he isliving disease-free more than 6 years after the diagnosis of bm. he is now 51 yearsold and remains asymptomatic and free of disease since then. however, apronounced residual image still appears on magnetic resonance imaging (mri) antpet-scan. keywords: malignant melanoma, brain metastases, long-term survival,unresectable brain metastases 1. introductionmelanoma has a high propensity to metastasize thecentral nervous system (cns). after breast and lungcancer, it is the third most common neoplasm causingbrain metastases (bm).1-2 some characteristics ofmelanoma are associated with an increased risk ofsystemic disease and therefore bm: origin in mucosalsurfaces or skin of trunk, head and neck, male gender,ulcerated primary lesion, wide thickness invasion, acrallentiginous or nodular lesions, involvement of 3 or moreregional lymph nodes, and visceral metastases at thetime of diagnosis.1at 5 years, median survival for stage iv melanoma is6-10 months, but for melanoma with bm is 2-9 months.2long-term survival after bm is very unusual because ofpoor prognosis, regardless of cancer type. nevertheless,survival is different depending on the primaryneoplasm. patients with ovarian tumors have the highestsurvival rate (7.8%), which is only 2.3% for patientswith melanoma.3we present the case of a patient with malignantmelanoma who relapsed with an unresectable bm. he isliving disease-free more than 6 years after the diagnosisof bm. he was managed with whole brain radiotherapy(wbrt) and temozolomide chemotherapy. 2. case presentationa 32 year-old man, with medical history of hypertension,diabetes and dyslipidemia, was diagnosed with acutaneous malignant melanoma (stage ii-a), in his leftshoulder in 1997. he underwent wide surgery and wasrendered disease-free.in 2001, a physical exam revealed axillary lymph nodeenlargement. he was treated with surgery,complementary radiotherapy (40 gy) and adjuvantalpha 2b interferon therapy (20 mu/m2/dayintravenously (i.v) 5 days a week for 4 weeks, then 10mu/m2 subcutaneously (s.c) three times per week for 48weeks).however, in 2002, in transit skin metastases weredetected. he underwent salvage surgery plus adjuvantchemotherapy with 6 courses of dacarbazine (250mg/m2 × 5 days, every 4 weeks), that was welltolerated.he was disease-free until 2010, when an unresectablebm relapse (5 cm in diameter, intraaxial with satellitelesions) was noticed in the right frontal lobe (figure 1). http://www.ijcto.org/ http://dx.doi.org/10.14319/ijcto.44.8 2 salvador-coloma et al.: long term survival after brain metastases international journal of cancer therapy and oncology www.ijcto.org © salvador-coloma et al. issn 2330-4049 figure 1: magnetic resonance: melanoma metastatic lesion at diagnosis (2010). figure 2: magnetic resonance: post-treatment residual hemorrhagic injury (2016).the lesion was not studied by biopsy. he receivedconcomitant chemo-radiotherapy (temozolamide 75mg/m2 continuous during wbrt to a total dose of 30gy). after concomitant treatment, he received eighteencycles of temozolamide (200 mg/m2 days 1-5 of 28days). the clinical tolerance was acceptable, presentingonly grade 2-3 emesis, which was controlled withstandard antiemetic therapy. a metabolic positron emission tomography (pet-scan)complete response was achieved. he is now 51 years oldand remains asymptomatic and free of disease sincethen. however, a pronounced residual image stillappears on magnetic resonance imaging (mri) antpet-scan (figures 2 and 3). volume 4 • number 4 • 2016 international journal of cancer therapy and oncology 3 www.ijcto.org © salvador-coloma et al. issn 2330-4049 figure 3: pet-scan: complete response. 3. discussionmalignant melanomas tend to metastasize into the cns.4this specific dissemination has a negative effect onoverall survival and in most cases represents a terminalevent.5 patients with large (>4 cm), or numerous lesionsare difficult to treat and usually receive palliativetherapies. in contrast, smaller (<2 cm) and single lesionscan be treated more effectively.6 for patients with bm,some studies have shown favorable prognostic variablesfor extended survival: younger age, the presence of asingle lesion, surgical resection, chemotherapy andwbrt.3the treatment of choice for oligometastatic cns diseaseis surgical resection. it depends on the number oflesions, the size and locations of the tumor, the state ofsystemic disease and performance status.7 in this groupof patients surgery has been shown to improvesurvival.8 in 60-70% of patients, wbrt has shown asurvival improvement of 1-2 months and is effective inpalliating symptoms of bm.9 a series from the sydneymelanoma unit report outcome of 646 melanomapatients treated for bm. median survival was 8.7 monthsfor surgery versus 8.9 months for surgery andpostoperative wbrt and 3.4 months for patients treatedsolely with wbrt.10 stereotactic radiosurgery can treatsmaller metastatic lesions. the benefit is that it allowsfor treatment lesions that would otherwise beinoperable.11-12 a variety of cytotoxic drugs has beentested for the treatment of bm of melanoma, includingtemozolamide. most of the studies have shown betterresults for combination therapies as compared to wbrtalone.13-14for solitary bm, the recommended treatment is surgicalremoval of the lesion followed by wbrt or wbrt withstereotactic radiosurgery. the case reported here unde-rwent concomitant chemotherapy and radiotherapyfollowed by adjuvant chemotherapy. stereotacticradiosurgery or surgery was not administrated due to the lesion extension and its location. historically, bmwere treated with wbrt followed by stereotacticradiosurgery. in recent years, however, it is suggestedthat stereotactic radiosurgery of smaller lesionsprovides long-term control as exclusively treatment, andthat many patients did not appear to require additionaltreatment.15 there are some clinical trials includingpatients with one to three bm from different kind ofcancers that have shown local control with stereotacticradiosurgery is not improved by wbrt, but thedevelopment of new bm is decreased by the addition ofwbrt.12,16,17 4. conclusionsystemic treatment has not been shown to be effectivein melanoma bm, therefore it has uncommonly beenused as primary treatment.18 nowadays, thedevelopment of new therapeutic agents point out animportant improvement in management options forthese patients.19 the present case suggests thattreatment of melanoma bm remains an ongoingchallenge, and advances in treatment are providingbenefit for patients. nevertheless, we must continueinvestigating ways to develop an optimal treatment forthese patients. conflict of interestthe authors have no actual, potential, real or apparentinterest to declare and have no involvement that mightraise the question of bias in the work reported or in theconclusions, implications, or opinions stated. references1. ballo mt, ross mi, cormier jn, et al.combined-modality therapy for patients withregional nodal metastases from melanoma. int jradiat oncol biol phys. 2006;64:106-13. https://doi.org/10.1016/j.ijrobp.2005.06.030 4 salvador-coloma et al.: long term survival after brain metastases international journal of cancer therapy and oncology www.ijcto.org © salvador-coloma et al. issn 2330-4049 2. mahmood h, faheem m, asghar hussain asgharah, et al. long-term survivor of brainmetastases from malignant melanoma. j collphysicians surg pak. 2010;20(12):832-4.3. hall wa, djalilian hr, nussbaum es, et al.long-term survival with metastatic cancer tothe brain. med oncol. 2000;17(4):279-86.4. kotb s, detappe a, lux f, et al.gadolinium-based nanoparticles and radiationtherapy for multiple brain melanomametastases: proof of concept before phase itrial. theranostics. 2016;6(3):418-27.5. shapiro dg and samlowski w. management ofmelanoma brain metastases in the era oftargeted therapy. j skin cancer.2011;2011:845863.6. schellinger pd, meinck hm, thron a. diagnosticaccuracy of mri compared to cct in patientswith brain metastases. j neurooncol.1999;44(3):275-81.7. maher e, mckee a. neoplasms of the centralnervous system, in atlas of diagnosticoncology. 3rd ed. elsevier science, london, uk,2003.8. lee jy, lunsford ld, subach br, et al. brainsurgery with image guidance: currentrecommendations based on a 20-yearassessment. stereotact funct neurosurg.2000;75(1):35-48.9. solan mj, brady lw. skin cancer. principles andpractice of radiation oncology. philadelphia:lippincott williams & wilkins; 2008.10. fife km, colman mh, stevens gn, et al.determinants of outcome in melanoma patientswith cerebral metastases. j clin oncol.2004;22:1293-300.11. bhatnagar a, flickinger j, kondziolka d,lunsford l. stereotactic radiosurgery for fouror more intracranial metastases. int j radiatoncol biol phys. 2006;64(3):898–903. 12. manon r, o’neill a, knisely j, et al. phase ii trialof radiosurgery for one to three newlydiagnosed brain metastases from renal cellcarcinoma, melanoma, and sarcoma: an easterncooperative oncology group study (e 6397). jclin oncol. 2005;23(34):8870-6.13. meier s, baumert bg, maier t, et al. survivaland prognostic factors in patients with brainmetastases from malignant melanoma.onkologie 2004;27:145-9.14. chiarion-sileni v, murr r, pigozzo j, et al. brainmetastases from malignant melanoma. forum(genova). 2003;13(2):170-82.15. rao g, klimo p, thompson c, et al. stereotacticradiosurgery as therapy for melanoma, renalcarcinoma, and sarcoma brainmetastases:impact of added surgical resection andwhole-brain radiotherapy. int j radiat oncolbiol phys. 2006;66(4):s20-5.16. kocher m, soffietti r, abacioglu u, et al.adjuvant wholebrain radiotherapy versusobservation after radiosurgery or surgicalresection of one to three cerebralmetastases:results of the eortc 22952–26001 study. j clinoncol. 2011;29(2):134–41.17. aoyama h, shirato h, tago m, et al. stereotacticradiosurgery plus whole-brain radiationtherapy vs stereotactic radiosurgery alone fortreatment of brain metastases: a randomizedcontrolled trial. jama. 2006; 295(21):2483–91.18. agarwala s, kirkwood j, gore m, et al.temozolomide for the treatment of brainmetastases associated with metastaticmelanoma: a phase ii study. j clin oncol.2004;22(11):2101–7.19. goldinger sm, panje c, nathan p. treatment ofmelanoma brain metastases. curr opin oncol.2016;28(2):159-65. https://doi.org/10.1007/bf02782192 https://doi.org/10.7150/thno.14018 https://doi.org/10.1155/2011/845863 https://doi.org/10.1023/a:1006308808769 https://doi.org/10.1159/000048381 https://doi.org/10.1200/jco.2004.08.140 https://doi.org/10.1016/j.ijrobp.2005.08.035 https://doi.org/10.1200/jco.2005.01.8747 https://doi.org/10.1159/000076903 https://doi.org/10.1016/j.ijrobp.2006.05.078 https://doi.org/10.1200/jco.2010.30.1655 https://doi.org/10.1001/jama.295.21.2483 https://doi.org/10.1200/jco.2004.11.044 https://doi.org/10.1097/cco.0000000000000270 international journal of cancer therapy and oncology www.ijcto.org copyright © gill issn 2330-4049 treatment planning for the lung cancer sukhdeep gill department of radiation oncology, university of toledo, toledo, ohio, usa. received february 13, 2014; revised march 10, 2014; accepted march 12, 2014; published online march 16, 2014 letter to editor volumetric modulated arc therapy (vmat) and intensity modulated radiation therapy (imrt) are commonly used treatment techniques for cancer treatment, and both the vmat and imrt techniques use the photon beam (mega-voltage x-rays) to deliver radiation dose to the tumor. the capability of modulating radiation beam has increased the ability of delivering more conformal dose distributions to tumor volume while minimizing dose to the normal tissues. the vmat planning generally involves one or multiple arcs with gantry rotating around the patient, whereas the imrt planning involves multiple static beams. current literature on radiation therapy for the lung cancer shows the publication of good number of dosimetric studies, which are typically focused on the treatment planning techniques 1-7 and dose calculation algorithms.8-16 the treatment planning studies comparing the dosimetric quality between the imrt and vmat, however, do not provide the definitive conclusion, especially for the normal lung tissue. for example, verbakel et al. 1 performed the dosimetric study on 14 lung cancer cases and compared the imrt and vmat plans. it was reported that the v5 of the normal lung tissue was higher in the vmat plans than in the imrt plans. ong et al. 2 and jiang et al. 3 also reported higher v5 of the lung in the vmat plans. the v5 of the lung from these studies 1-3 show that the imrt could be better at sparing the lung than the vmat. however, the vmat plans could produce lower values for the lung if dosimetric evaluation is done using different parameters. in the study by jiang et al. 3, normal lung was also evaluated for the mean dose, v20, and v30, and the results showed lower values in the vmat plans than in the imrt plans.3 this leads to the questionwhich dosimetric parameter for the normal lung tissue is more important when plan evaluation is done? in addition to the sparing of normal tissues, the target coverage and dose homogeneity within the target volume are also equally important in radiation therapy. jiang et al. 3 found that the vmat could produce better target coverage when compared to the imrt. however, rao et al. 4, who performed study on 8 lung cases, found comparable target coverage in the vmat and imrt plans. dose to the target volume was found to be similar in the vmat and imrt plans.3-5 the variation in the reported results from various studies on lung cancer 1-7 can be attributed to different factors such as plan optimization technique, experience of the treatment planner, treatment volume margins, dose prescription, location of the tumor, and dose calculation algorithms. the treatment plan optimization interface within the treatment planning system can let the user to assign weightings and objectives for the target and normal tissues. the final dosimetric results in the treatment plan may depend on the selection of weightings and objectives for the structures. additionally, the plan optimization can be repeated with same set of optimization parameters or different ones if the dosimetric results have deviation from the compliance criteria. dose calculation algorithm incorporated in the treatment planning system can also affect the dosimetric results of the treatment plans, especially for the lung cancer, which includes the low-density medium. when radiation beam traverses the human body before it reaches the tumor, tissues of different electron density are encountered in the beam path. presence of heterogeneity along the beam path may change the dose contribution to the tumor when compared to the homogeneous geometry. such situation requires the dose calculation algorithm to consider the tissue heterogeneity correction when dose computations are performed on the cancer treatment plans. recent literature shows that the monte carlo based dose calculation algorithm is more appropriate for dose computations in the lung plans.8-10 several investigators compared the analytical anisotropic algorithm (aaa) with the most recent algorithm called acuros xb for the lung plans 9-16, and valicorresponding author: sukhdeep gill; department of radiation oncology, university of toledo, toledo, ohio, usa. cite this article as: gill s. treatment planning for the lung cancer. int j cancer ther oncol 2014; 2(1):020117. doi: 10.14319/ijcto.0201.17 http://ijcto.org/index.php/ijcto/index http://dx.doi.org/10.14319/ijcto.0201.17 2 gill: treatment planning for the lung cancer international journal of cancer therapy and oncology www.ijcto.org copyright © gill issn 2330-4049 dation studies on acuros xb show its superiority over the aaa, especially in inhomogeneous media.8-9, 11, 17-18 the beam modeling within the acuros xb algorithm considered to be based on the monte carlo approach.18 the literature comparing the aaa and acuros xb in the lung plans showed that the acuros xb could produce higher values for the v20 11, 12 and v5.10-12 if the acuros xb is considered to be more accurate than the aaa, does the aaa underestimate the lung dose? it was also reported that the higher number of monitor units (mus) will be required for the acuros xb in order to achieve the target coverage similar to that of the aaa.9 the decreased target coverage using acuros xb for the same number of mus as in the aaa plans may not be clinically acceptable. if the treatment planning systems have an option to normalize the plan (e.g., target volume receiving certain percentage of the prescription dose), the acuros xb plans can be normalized to achieve the desired target coverage, but such method may also increase the mus, and this will increase the normal tissue dose and hot spot. hence, treatment plans computed with different dose calculation algorithms are likely to provide different dosimetric results. treatment plans calculated with different beam energy may also produce difference dosimetric results.19, 20 although there are uncertainties in the dosimetric results between the imrt and vmat plans, the common agreement among different published studies 1-7 is the decreased delivery time and a smaller number of mus using the vmat than using the imrt. clinical trials comparing the imrt and vmat may be more helpful in establishing superiority of one technique over another. multi-institutional study using the same dataset, beam parameters, and dose calculation algorithms/treatment planning system would help in reducing the uncertainties in the dosimetric results of the lung treatment plans. studies based on the radiobiological models in the treatment planning could also be beneficial for more accurate prediction of tumor control and normal tissue complication.21 conflict of interest the authors declare that they have no conflicts of interest. the authors alone are responsible for the content and writing of the paper. references 1. verbakel wf, van reij e, ladenius-lischer i, et al. clinical application of a novel hybrid intensity-modulated radiotherapy technique for stage iii lung cancer and dosimetric comparison with four other techniques. int j radiat oncol biol phys 2012; 83:e297-303. 2. ong cl, verbakel wf, cuijpers jp, et al. stereotactic radiotherapy for peripheral lung tumors: a comparison of volumetric modulated arc therapy with 3 other delivery techniques. radiother oncol 2010; 97:437-42. 3. jiang x, li t, liu y, zhou l, et al. planning analysis for locally advanced lung cancer: dosimetric and efficiency comparisons between intensity-modulated radiotherapy (imrt), single-arc/partial-arc volumetric modulated arc therapy (sa/pa-vmat). radiat oncol 2011; 6:140. 4. rao m, yang w, chen f, et al. comparison of elekta vmat with helical tomotherapy and fixed field imrt: plan quality, delivery efficiency and accuracy. med phys 2010; 37:1350-9. 5. holt a, van vliet-vroegindeweij c, mans a, et al. volumetric-modulated arc therapy for stereotactic body radiotherapy of lung tumors: a comparison with intensity-modulated radiotherapy techniques. int j radiat oncol biol phys 2011; 81:1560-7. 6. zhang gg, ku l, dilling tj, et al. volumetric modulated arc planning for lung stereotactic body radiotherapy using conventional and unflattened photon beams: a dosimetric comparison with 3d technique. radiat oncol 2011; 6:152. 7. merrow ce, wang iz, podgorsak mb. a dosimetric evaluation of vmat for the treatment of non-small cell lung cancer. j appl clin med phys 2012; 14:4110. 8. lu l. dose calculation algorithms in external beam photon radiation therapy. int j cancer ther oncol 2013; 1:01025. 9. rana s. clinical dosimetric impact of acuros xb and analytical anisotropic algorithm (aaa) on real lung cancer treatment plans: review. int j cancer ther oncol 2014; 2:02019. 10. knöös t, wieslander e, cozzi l, et al. comparison of dose calculation algorithms for treatment planning in external photon beam therapy for clinical situations. phys med biol 2006; 51:5785-807. 11. rana s, rogers k, pokharel s, cheng c. evaluation of acuros xb algorithm based on rtog 0813 dosimetric criteria for sbrt lung treatment with rapidarc. j appl clin med phys 2014; 15:4474. 12. kathirvel m, subramanian s, clivio a, et al. critical appraisal of the accuracy of acuros-xb and anisotropic analytical algorithm compared to measurement and calculations with the compass system in the delivery of rapidarc clinical plans. radiat oncol 2013; 8:140. 13. ojala jj, kapanen mk, hyödynmaa sj, et al. performance of dose calculation algorithms from three generations in lung sbrt: comparison with full monte carlo-based dose distributions. j appl clin med phys 2014; 15:4662. http://www.ncbi.nlm.nih.gov/pubmed/22579380 http://dx.doi.org/10.1016/j.radonc.2010.09.027 http://dx.doi.org/10.1186/1748-717x-6-140 http://dx.doi.org/10.1118/1.3326965 http://dx.doi.org/10.1016/j.ijrobp.2010.09.014 http://dx.doi.org/10.1186/1748-717x-6-152 http://www.ncbi.nlm.nih.gov/pubmed/23318374 http://dx.doi.org/10.14319/ijcto.0102.5 http://dx.doi.org/10.14319/ijcto.0201.9 http://dx.doi.org/10.1088/0031-9155/51/22/005 http://www.ncbi.nlm.nih.gov/pubmed/24423844 http://dx.doi.org/10.1186/1748-717x-8-140 http://www.ncbi.nlm.nih.gov/pubmed/24710454 volume 2 • number 1 • 2014 international journal of cancer therapy and oncology 3 www.ijcto.org copyright © gill issn 2330-4049 14. fogliata a, nicolini g, clivio a, et al. critical appraisal of acuros xb and anisotropic analytic algorithm dose calculation in advanced non-small-cell lung cancer treatments. int j radiat oncol biol phys 2012; 83:1587-95. 15. oyewale s. dose prediction accuracy of collapsed cone convolution superposition algorithm in a multi-layer inhomogenous phantom. int j cancer ther oncol 2013; 1:01016. 16. liu hw, nugent z, clayton r, dunscombe p, lau h, khan r. clinical impact of using the deterministic patient dose calculation algorithm acuros xb for lung stereotactic body radiation therapy. acta oncol 2013. [epub ahead of print] 17. bush k, gagne im, zavgorodni s, et al. dosimetric validation of acuros xb with monte carlo methods for photon dose calculations. med phys 2011; 38:2208-21. 18. vassiliev on, wareing ta, et al. validation of a new grid-based boltzmann equation solver for dose calculation in radiotherapy with photon beams. phys med biol 2010; 55:581-98. 19. hawke s, torrance a, tremethick l. evaluation of planned dosimetry when beam energies are substituted for a fraction of the treatment course. int j cancer ther oncol 2013; 1:01014. 20. pokharel s. dosimetric impact of mixed-energy volumetric modulated arc therapy plans for high-risk prostate cancer. int j cancer ther oncol 2013; 1:01011. 21. mavroidis p. clinical implementation of radiobiological measures in treatment planning. why has it taken so long? int j cancer ther oncol 2013; 1:01019. http://dx.doi.org/10.1016/j.ijrobp.2011.10.078 http://dx.doi.org/10.14319/ijcto.0101.6 http://dx.doi.org/10.1118/1.3567146 http://dx.doi.org/10.1088/0031-9155/55/3/002 http://dx.doi.org/10.14319/ijcto.0102.4 http://dx.doi.org/10.14319/ijcto.0101.1 http://dx.doi.org/10.14319/ijcto.0101.9 international journal of cancer therapy and oncology www.ijcto.org copyright © sherwani et al. issn 2330-4049 nasal glioma with psammomatous calcificationan unusual presentation rana k sherwani1, kafil akhtar1*, prasenjit s ray1, sayed s ahmad2 1department of pathology, jawaharlal nehru medical college, aligarh muslim university, aligarh, india. 2department of oral maxillo-facial surgery, sir ziauddin dental college, aligarh muslim university, aligarh, india. received january 14, 2014; revised march 18, 2014; accepted march 20, 2014; published online april 09, 2014 case report abstract congenital midline swellings of nose are encountered rarely, and nasal gliomas constitute about 5% of such lesions. various theories have been suggested to explain the pathogenesis. imaging preferably by mri is mandated to study the extent and to rule out intracranial extension. clinically, these masses are firm and incompressible. histologically, they are made up of astrocytes and neuroglial cells, embedded in fibrous and vascular connective tissue. the mainstay of treatment is conservative sur gical excision because nasal gliomas are slow-growing, rarely recurrent, and have no malignant potential. we present a case of congenital extranasal glioma with psammomatous calcification and without any intracranial extension in an eighteen month old boy. keywords: extranasal glioma; child; psammomatous calcification introduction the developmental anomalies of the nose encompass a diverse group of conditions, which include nasal dermoids, gliomas, encephaloceles, nasal clefts, proboscis lateralis, polyrrhinia, nasopharyngeal teratoma, and epignathus.1 the most common are nasal dermoids, nasal gliomas and nasal (meningo) encephaloceles, which are clinically significant because some of them might have an effective or potential connection with the central nervous system (cns). nasal gliomas are one form of the congenital midline nasal masses that usually present at birth. they are rare, benign, congenital tumours, which arise from abnormal embryonic development. they are nonencapsulated cns masses of neurogenic origin, which have lost their intracranial connections, and present as an obvious external or intranasal mass at birth, without associated surgical symptoms.2, 3 the term "nasal glioma" is a confusing misnomer as it implies a neoplastic condition with malignant potential, which it is not. around 15 to 20 % of nasal gliomas have a fibrous stalk connecting to the central nervous system. it should be differentiated from glioma, which is a malignant tumor of the brain. in addition, it should be differentiated from a primary encephalocele, which is herniation of the cranial contents through a bone defect in the skull, through which it retains an intact connection with the central nervous system.4, 5 an accurate diagnosis permits proper management and prevents potentially life-threatening intracranial complications. severe complications such as meningitis or a brain abscess can be avoided if the lesions are removed at an early stage. we report a case of extranasal glioma with psammomatous calcifications in eighteen months old boy. case report an eighteen month old boy presented with a swelling over his nasal bridge. the swelling had been present since birth but did not cause any nasal obstruction. there was no history of epistaxis or any other nasal discharge. he was born at full-term and had a normal vaginal delivery. his elder sibling had no congenital abnormalities and the family history was unremarkable. on physical examination, the boy had a 3 × 3 cm superficial purple, soft to firm mass with a smooth surface over his nasal bridge. it was neither tender nor pulsatile. there was no intranasal mass. clinically, the mass was diagnosed as nasal dermoid/hemangioma. *corresponding author: dr. kafil akhtar; department of pathology, jawaharlal nehru medical college, aligarh muslim university, aligarh, india. cite this article as: sherwani rk, akhtar k, ray ps, ahmad ss. nasal glioma with psammomatous calcificationan unusual presentation. int j cancer ther oncol 2014; 2(2):02027. doi: 10.14319/ijcto.0202.7 http://ijcto.org/index.php/ijcto http://dx.doi.org/10.14319/ijcto.0202.7 2 sherwani et al.: nasal glioma with psammomatous calcification international journal of cancer therapy and oncology www.ijcto.org copyright © sherwani et al. issn 2330-4049 magnetic resonance imaging (mri) of the brain showed a well-defined soft tissue attenuation lesion, at the root of the nose without any underlying bony defect or intracranial extension, measuring 2.9 × 2.9 × 2.5 cm. (figure 1)the lesion showed mild heterogenous enhancement with evidence of concentric calcifications within the lesion. fig. 1: mri of the brain shows a well-defined soft tissue attenuation lesion, at the root of the nose without any underlying bony defect or intracranial extension, measuring 2.9 × 2.9 × 2.5cm. the tumour was excised externally under general anaesthesia, using a left lateral elliptical skin incision. the margin was taken down to the cartilaginous pyramid. grossly, it appeared as a lobulated, well-circumscribed, and unencapsulated whitish pink firm mass. microscopic sections demonstrated the presence of glial tissue with a fibrillary background and interspersed fibrovascular stroma with psammomatous calcifications. (figure 2 and 3). no meningeal or dural tissue was identified. the glial nature of the tumour was confirmed by a positive reaction for s100 protein (figure 4), and a definitive diagnosis of nasal glioma was made. fig. 2: photomicrograph shows glial tissue with a fibrillary background and interspersed fibrovascular stroma. haematoxylin and eosin × 10 fig. 3: photomicrograph shows glial tissue with a fibrillary background and interspersed fibrovascular stroma with psammomatous calcifications. haematoxylin and eosin × 40 the postoperative recovery was uneventful and the cosmetic result was satisfactory. follow-ups performed over the last 12 months using brain mri showed no residual parts or recurrence of the glioma. fig. 4: photomicrograph shows glial tissue with a positive reaction for s100 protein. s-100 × 10 discussion the term nasal glioma has been used to describe a congenital benign tumor of the nasal region containing neural tissue. schmidt was the first scientist to describe the comprehensive nature of the nasal glioma in 1900. however, the term he used is a misnomer.3, 5 nasal gliomas are not true neoplasms; they originate from ectopic glial tissue left extracranially following abnormal closure of the nasal and frontal bone during embryonic development.1, 4, 6 therefore, some authors recommend using the term ‘glial heterotopia’ instead.3 nasal gliomas generally present at birth, rarely in adults, as a mass without associated nasal symptoms. they have a 3:1 male predominance, with no familial or hereditary predisposition volume 2 • number 2 • 2014 international journal of cancer therapy and oncology 3 www.ijcto.org copyright © sherwani et al. issn 2330-4049 and no malignant potential.3, 7 the tumour growth rate is consistent with the patient’s body growth. there are intranasal (30%), extranasal (60%), or combined (10%) types of nasal gliomas.6 our case was of an extranasal glioma. most nasal gliomas are diagnosed at birth or during early childhood, with relative peaks of occurrence between 5 and 10 years of age. although the majority of patients present with signs and symptoms during the first year of life, a later presentation may be due to a specialist’s failure to recognize a subclinical lesion in childhood or because of a trauma.2, 5 unlike dermoids, they do not necessarily occur in the midline, or attach to sinuses or skin. gliomas form an uncompressible mass that does not increase in size on the valsalva testing and does not transilluminate. extranasal gliomas are usually located at the glabella level, but they may be present laterally. intranasal gliomas are associated most frequently with the middle turbinate or higher structures, and may mimic nasal polyps. combined intra/extranasal gliomas have a typical dumbbell shape with a connecting band. fifteen percents of gliomas are connected with the dura, either through the foramen cecum or through the fonticulus. patients may present with a unilateral nasal obstruction, unilateral nasal mass, epistaxis, or cerebrospinal rhinorrhea.4, 5 as gliomas are nonencapsulated accumulations of glial cells situated outside the cns, the possible theories of development include the following: 1) sequestration of glial tissue of the olfactory bulb entrapped during cribriform plate fusion; 2) ectopic neural tissue cells; 3) pinched encephalocele; and 4) inappropriate closure of the anterior neuropore (fonticulus frontalis), with the failure of mesoderm to enter the region, resulting in an inadequate bone formation.7, 8 histologically, nasal gliomas are composed of astrocytes and neuroglial cells, embedded in fibrous and vascular connective tissue.5 they have no true capsule and mitosis is rarely noted. multinucleated or gemistocytic astrocytes may be present but it is rare to find neurons. the presence of abundant neurons raises the possibility of an encephalocoele. the glial nature of the cells can be further confirmed by immunohistochemical demonstration of s100 protein and gfap. these two proteins can identify neurological cells with high specificity, and help to distinguish nasal gliomas from other tumours such as meningiomas and granular cell tumours.5, 8 in our case, both s100 and gfap staining were positive. hence, a definitive diagnosis of nasal glioma was made. the clinical differential diagnosis includes several various congenital and acquired disorders, which could be manifested by nasal masses. nasal glioma should be differentiated from several common or important lesions, among which: 1) nasal dermoids, which are epithelial-lined cavities or sinus tracts with variable numbers of skin appendages, including hair follicles, sebaceous glands, and eccrine glands. they constitute the most common congenital nasal anomaly. 2) encephaloceles point to the herniation of neural tissue through defects in the skull. they may contain meninges (meningocele) or brain matter and meninges (encephalomeningocele), or they may communicate with a ventricle (encephalomeningocystocele). encephaloceles have an etiology similar to that of gliomas. twenty percents of all encephaloceles occur in the cranium. of those, 15 % are nasal. 3) hemangioma, which are the most frequent benign vascular tumors in infancy.9-11 the diagnosis is corroborated by ct scan, which shows a bony defect. mr imaging is obligatory in patients with suspected glioma to determine possible intracranial extension of the nasal cavity lesion and the brain.12, 13 the treatment of choice of nasal gliomas is complete surgical excision.1 gliomas are benign but incomplete excision results in a 4 % to 10 % recurrence rate. the approach depends upon the location and extent of the lesion and levels of expertise available. when facilities are available, intranasal endoscopic surgery is considered most appropriate approach for the removal of intranasal glioma having no intracranial extension as this approach allows precise excision with minimal trauma to the surrounding tissues.9 if however intracranial extension is evident, than frontal craniotomy, multidisciplinary team approach may be required in specialized neurosurgical or craniofacial centers to ensure complete and safe excision of the lesions.10 conclusion nasal gliomas are rare congenital anomalies. it is mandatory to rule out intracranial extension by cross-sectional imaging, preferably by mri before performing any invasive procedure. conservative surgical excision is the mainstay of the management of an extranasal glioma, as it is slow-growing, rarely recurrent, and has no malignant potential. conflict of interest the authors declare that they have no conflicts of interest. the authors alone are responsible for the content and writing of the paper. references 1. chang kc, leu ys. nasal glioma: a case report. ear nose & throat j 2001; 80: 410-1. 2. ducic y. nasal gliomas. j otol 3. verney y, zanolla g, teixeira r, oliveira lc. midline nasal mass in infancy: a nasal glioma case report. eur j pediatr surg 2001; 11: 324-327. aryngol 1999; 28: 285-7. http://www.ncbi.nlm.nih.gov/pubmed/11433845 http://www.ncbi.nlm.nih.gov/pubmed/10579160 http://www.ncbi.nlm.nih.gov/pubmed/10579160 http://dx.doi.org/10.1055/s-2001-18547 4 sherwani et al.: nasal glioma with psammomatous calcification international journal of cancer therapy and oncology www.ijcto.org copyright © sherwani et al. issn 2330-4049 4. hyams vj, batsakis jg, michaels l. tumors of the upper respiratory tract and ear. atlas of tumor pathology, 2nd series, fascicle 25, armed forces institute of pathology, washington d.c; 1988: 251-7. 5. cerda-nicolas m, sanchez fernandez de sevilla c, lopez-gines c, peydro-olaya a, llombartbosch a. nasal glioma or nasal heterotopia? morphological, immunohistochemical and ultrastructural study of two cases. clin neuropathol 2002; 21:66-71. 6. michaels l and hellquist hb. neuroectodermal tumours in ear, nose and throat histopathology, 2nd ed. berlin: springer; 2001: 203-17. 7. verney y, zanolla g, teixeira r, oliveira lc. midline nasal mass in infancy: a nasal glioma case report. eur j pediatr surg 2001; 11: 324-7. 8. nada v, dejan v, dragan d, ljiljana j. nasal glioma. archive of oncology 2006; 14: 57-9. 9. hoeger ph, schaefer h, ussmueller j, helmke k. nasal glioma presenting as capillary haemangioma. eur j pediatr 2001; 160: 84-7. 10. dasgupta nr and bentz ml. nasal gliomas: identification and differentiation from hemangiomas. j craniofac surg 2003; 14: 736-8. 11. jartti ph, jartti ae, karttunen ai, paakko el, herva rl, pirila to. mr of a nasal glioma in a young infant. acta radiol 2002; 43:141-3. 12. yokoi h, wada r, ichikawa g. endoscopic treatment of so-called intranasal glioma. rhinology 2002; 40: 217-9. http://www.ncbi.nlm.nih.gov/pubmed/12005254 http://dx.doi.org/10.1007/978-1-4471-0235-9 http://dx.doi.org/10.1055/s-2001-18547 http://dx.doi.org/10.1007/s004310000602 http://dx.doi.org/10.1097/00001665-200309000-00025 http://dx.doi.org/10.1080/028418502127347899 http://www.ncbi.nlm.nih.gov/pubmed/12526252 international journal of cancer therapy and oncology www.ijcto.org corresponding author: keith r davis; biotechnology program, indiana university, bloomington, indiana, usa. cite this article as: davis kr, inaba j. lunasin—a multifunctional anticancer peptide from soybean. int j cancer ther oncol. 2016; 4(2):4218. doi: 10.14319/ijcto.42.18 © davis et al. issn 2330-4049 lunasin—a multifunctional anticancer peptide from soybean keith r. davis1, jun-ichi inaba2 1biotechnology program, indiana university, bloomington, indiana, usa 2owensboro cancer research, university of louisville, louisville, kentucky, usareceived april 03, 2016; revised june 15, 2016; accepted june 20, 2016; published online june 30, 2016 scientific note abstractlunasin is a bioactive peptide that was originally isolated from soybean and hassince been shown to have a number of biological activities, including both cancerchemopreventive and therapeutic activities. our recent focus has been ondetermining the range of cancer types that lunasin can affect and the mechanism ofaction against specific cancers. we recently found that lunasin has significanttherapeutic activity against non-small cell lung cancer (nsclc) both in vitro and invivo. mechanistic studies using lunasin-sensitive and lunasin-resistant nsclc celllines revealed the lunasin blocks cell proliferation by inhibiting cell cycleprogression at the g1/s phase interface and that this inhibition was associatedwith reduced akt signaling. in addition, we found that these effects were linked tothe inhibition of integrin signaling through αv-containing integrins. our resultsprovide strong support for the hypothesis that direct effects on integrin signalingrepresent a major mode of action responsible for lunasin’s anticancer activity. keywords: lunasin, bioactive peptide, cancer therapeutic, integrins, cell cycle,non-small cell lung cancer 1. introductionnumerous studies over the years have found a stronglinkage of high soy consumption with a number of healthbenefits, including lower rates of cancer. in recent years,it has become clear that at least part of the anticanceractivity of soy is due the presence of the peptide-lunasin. lunasin is a 43-44-amino acid peptide that is acomponent of the soybean 2s albumin protein that wasinitially shown to cause mitotic arrest and cell death inmammalian cancer cells.1 recent studies have nowshown that lunasin has the capacity to inhibit the growthof many cancer cell types including breast cancer, coloncancer and lung cancer.2-4 thus, it is clear that lunasinmay have potential as a therapeutic agent for thetreatment of several deadly cancers.lunasin has three motifs that may be responsible for itsbiological activity against cancer; 1) a predicted helixdomain homologous to a conserved region ofchromatin-binding proteins, 2) a arg-gly-asp (rgd) celladhesion motif, and 3) a unique polyaspartic-acid tail(figure 1). it was initially speculated that the rgd celladhesion motif is involved in lunasin internalization intothe cell, and that helix domain and poly-d tail is requiredfor binding with core histone h3 and h4.5 based onthese hypotheses, the initial proposed mechanism forlunasin action was that lunasin competes with histone acetyltransferases by binding to deacetylated histones,resulting in an inhibition of histone acetylation and aconcomitant down regulation of cell cycle-relatedprotein expression and the activation of apoptosis.based on these studies, my laboratory has focused oncharacterizing the effects of lunasin on lung cancer andelucidating its mechanism of action. figure 1: amino-acid sequence and functional motifs oflunasin. 2. results and discussionour focus on lung cancer is based on the fact that it is theleading cause of cancer-related deaths among both menand women in the united states, and increasingly,around the world. lung cancer is divided into two types,small cell lung cancer and non-small cell lung cancer(nsclc); more than 80% of all incidences of lung cancerare nsclc6. our initial studies focused on assessing the http://www.ijcto.org/ http://dx.doi.org/10.14319/ijcto.42.18 2 davis et al.: lunasin inhibits integrin signaling international journal of cancer therapy and oncology www.ijcto.org © davis et al. issn 2330-4049 effects of lunasin on established nsclc cell lines in vitro. these studies revealed that all the nsclc linestested were sensitive to lunasin; however, the surprisingfinding was that only one cell line, h661, was sensitivewhen assayed in standard adherent culture conditions.the other cell lines were only sensitive when assayed innon-adherent, anchorage independent conditions usinga colony-formation assay.4 our subsequent studiesdemonstrated that lunasin was also able to significantlyinhibit tumor growth in a mouse xenograft model ofnsclc. lunasin treatment (30 mg/kg body weight)reduced tumor size of subcutaneous tumors initiated byimplanting nsclc h1299 cells in nude mice by 63%(figure 2).4 figure 2: reduction of nsclc h1299 tumor grown in vivo.adapted from mcconnell et al.4these findings are very encouraging and showed for thefirst time that lunasin was active against nsclc. furtherstudies on the molecular mechanism oflunasin-mediated inhibition of cell proliferation weredone by comparing the responses of nsclc cells underadherent conditions where line h611 islunasin-sensitive and h1299 cells are resistant. thesestudies revealed that lunasin’s ability to inhibit h611proliferation was due to the suppression ofphoslphorylation of the retinoblastoma protein and theconcomitant inhibition of cell cycle progression at theg1/s phase transition.4 a summary of these results isdepicted in figure 3 which identifies key regulatorypoints where lunasin appears to have an effect. figure 3: model for lunasin inhibition of cell cycleprogression. red and green arrows indicate the activationor inhibition, respectively, of key cell cycle regulatoryproteins.as previously discussed, earlier reports showed lunasininhibits histone acetyltransferases activity under in vitro condition, and it is well documented that epigeneticchanges involving histone modifications are importantin initiating and maintaining a cancer cell phenotype.7-9several studies have documented a direct interaction oflunasin with the core histones h3 and h4 in vitro, so weinitiated experiments to see if we could detectinteractions of h3 and h4 in cells. for this, proximityligation assays (plas) were used to demonstrate lunasininteracts with histone in vivo using cell lines h661 andh1299 grown in adherent culture conditions. thelunasin-h3 interaction levels were significantly higher inlunasin-sensitive h661 cells compared to thelunasin-insensitive h1299 cells, whereas lunasin-h4interaction levels were similar in both cell lines.10 thesehistone interactions were associated with inhibition ofhistone acetylation at h4k8 and h4k12 in the both celllines (figure 4). interestingly, h661 exhibited increasedhistone acetylation level at h4k16 compared to h1299,suggesting a role for this histone acetylation mark inlunasin sensitivity.10 further studies are required tofunctionally test whether lunasin-histone interactionsare required for lunasin’s antiproliferative effects andthe specific epigenetic changes associated with lunasinsensitivity. figure 4: lunasin-induced changes in histone acetylation innsclc cells. from inaba et al.10.besides affecting histone acetylation, it is possible thatlunasin could also affect integrin signaling through itsrgd domain. integrins are well known regulators of cellgrowth, migration, survival, and differentiation.11-13integrins are heterodimeric transmembrane receptorcomposed of two distinct α and β subunits. the integrinsignaling cascade starts with activation by binding ofvarious extracellular matrix proteins such as fibronectin,vitronectin and thrombospondin to the integrinextracellular domain.14, 15 when integrins are inactive,the integrin β subunit cytoplasmic tail forms a saltbridge with the integrin α subunit tail.16, 17 the binding volume 4 • number 2 • 2016 international journal of cancer therapy and oncology 3 www.ijcto.org © davis et al. issn 2330-4049 of extracellular ligands with the extracellular domaindisrupts α and β subunit cytoplasmic tail associations,triggering binding of activation proteins such as kindlinto integrin β subunit tails and the initiation of furtherdownstream signaling.18-23we tested whether lunasin could affect integrin in twoways. first, we used plas to assess the ability of lunasinto interact with integrins, followed by investigationsassessing lunasin effects on downstream signalingevents. we found that lunasin interacted with integrinsubunits α5 and αv in lunasin-sensitive h661 andlunasin-insensitive h1299 cells; however, theinteraction level with integrin αv was significantlyhigher in h661. based on the differential bindingintensities of lunasin to different integrin subunits, wehypothesize that in h661 cells, lunasin suppresses cellproliferation through binding to integrin vβ3. weconfirmed that lunasin does indeed bind with vβ3using co-immunoprecipitation assays (figure 5).furthermore, lunasin treatment in h661 impairedbinding of the direct effectors ilk, fak and kindlin tointegrin β1 and β3 cytoplasmic tails, which is theimportant initial step for activation of integrinsignaling.24, 25 a similar disruption of direct effectorinteractions with integrins was not detected in thelunasin-insensitive h1299 cells. to functionally confirmthat the effects of lunasin are mediated by an vsubunit-containing integrin, we used sirna-mediatedgene silencing to knock out expression of v in h661cells. although h661 cells with silenced v expressionexhibited reduced proliferation in the absence of lunasin(thus verifying that v is indeed a therapeutic target inthis cell line), treatment with lunasin did not induce anyfurther decrease in proliferation. this represents the first clear demonstration that lunasin’s ability to inhibitproliferation in nsclc cells requires an vcontainingintegrin.to further assess lunasin effects on integrin signalingand extend our functional studies, we examined theactivation of key integrin signaling components that areknown to ultimately regulate cell proliferation usingwestern blot analyses. these studies revealed thatlunasin treatment reduces integrin signal-regulatedphosphorylation on fak, akt and erk1/2 in h661 butnot in h1299. taken together, all of these resultsstrongly suggest that in nsclc cells, lunasin functions asan integrin-signaling antagonist to inhibit cellproliferation. our current working model describinglunasin’s mechanism of action is shown in figure 6. figure 5: co-immunoprecipitation (ip) and western blotanalyses of lunasin-vβ3 interactions. nsclc h661 cellswere treated with 100 µm lunasin for 24 h. cell lysateswere prepared and immune-precipitates isolated usinganti-lunasin or anti-αvβ3 antibodies. ips were subjected toimmunoblot analyses using the indicated probe antibodies. figure 6: model for lunasin’s inhibition of cell cycle progression through suppression of integrin signalin g. red and greenarrows indicate the activation or inhibition, respectively, of key regulatory proteins. red x’s indicate disruption of keyprotein-protein interactions. 4 davis et al.: lunasin inhibits integrin signaling international journal of cancer therapy and oncology www.ijcto.org © davis et al. issn 2330-4049 3. conclusionlunasin is an intriguing multifunctional bioactivepeptide that has significant potential to be developedinto an anticancer therapeutic and/or chemopreventionagent. our studies showed that lunasin has substantialanticancer activity against nsclc cells both in vitro andin an in vivo mouse xenograft model. extensivefunctional studies demonstrated that lunasin interactswith αv-containing integrins and likely functions as anintegrin signaling antagonist. we have recently extendedour studies into malignant melanoma and shown similaranticancer effects both in vitro and in vivo for this deadlycancer. current studies are focused on the furtherdevelopment of lunasin as a therapeutic. conflict of interestji declares that he has no competing interests. krd islisted as an inventor on two issued patents relating tothe expression and purification of lunasin peptides andmay benefit financially if the technologies described inthese patents are licensed or sold. acknowledgementwe thank owensboro grain company (owensboro, ky)and the kentucky soybean board for their continuedsupport of our research. ji was supported by a jspspostdoctoral fellowship for research abroad. thesefunders had no role in study design, data collection andanalysis, decision to publish, or preparation of themanuscript. references1. galvez af, de lumen bo. a soybean cdnaencoding a chromatin-binding peptide inhibitsmitosis of mammalian cells. nat biotechnol.1999;17(5):495-500.2. dia vp, mejia eg. lunasin promotes apoptosis inhuman colon cancer cells by mitochondrialpathway activation and induction of nuclearclusterin expression. cancer lett.2010;295(1):44-53.3. hsieh cc, hernandez-ledesma b, de lumen bo.lunasin, a novel seed peptide, sensitizes humanbreast cancer mda-mb-231 cells toaspirin-arrested cell cycle and induced apoptosis.chem bio interact. 2010;186(2):127-34.4. mcconnell ej, devapatla b, yaddanapudi k, et al.the soybean-derived peptide lunasin inhibitsnon-small cell lung cancer cell proliferation bysuppressing phosphorylation of theretinoblastoma protein. oncotarget. 2014;6(7):4649-4662.5. galvez af, chen n, macasieb j, et al.chemopreventive property of a soybean peptide(lunasin) that binds to deacetylated histones and inhibits acetylation. cancer res.2001;61(20):7473-8.6. esposito l, conti d, ailavajhala r, et al. lungcancer: are we up to the challenge? currgenomics. 2010;11(7):513-8.7. jeong hj, jeong jb, kim ds, et al. inhibition of corehistone acetylation by the cancer preventivepeptide lunasin. j agric food chem.2007;55(3):632-7.8. hernandez-ledesma b, hsieh cc, de lumen bo.relationship between lunasin's sequence and itsinhibitory activity of histones h3 and h4acetylation. mol nutr food res.2011;55(7):989-98.9. galvez af, huang l, magbanua mm, et al.differential expression of thrombospondin(thbs1) in tumorigenic and nontumorigenicprostate epithelial cells in response to achromatin-binding soy peptide. nutr cancer.2011;63(4):623-36.10. inaba j, mcconnell ej, davis kr. lunasin sensitivityin non-small cell lung cancer cells is linked tosuppression of integrin signaling and changes inhistone acetylation. int j mol sci.2014;15(12):23705-24.11. howe a, aplin ae, alahari sk, et al. integrinsignaling and cell growth control. curr opin cellbiol. 1998;10(2):220-31.12. dedhar s. cell-substrate interactions and signalingthrough ilk. curr opin cell biol. 2000;12(2):250-6.13. shattil sj, kim c, ginsberg mh. the final steps ofintegrin activation: the end game. nat rev mol cellbiol. 2010;11(4):288-300.14. giancotti fg, ruoslahti e. integrin signaling.science. 1999;285(5430):1028-32.15. hsu ar, veeravagu a, cai w, et al. integrin alpha vbeta 3 antagonists for anti-angiogenic cancertreatment. rec patents anti-cancer drug discov.2007;2(2):143-58.16. hughes pe, diaz-gonzalez f, leong l, et al.breaking the integrin hinge. a defined structuralconstraint regulates integrin signaling. j biol chem.1996;271(12):6571-4.17. vinogradova o, velyvis a, velyviene a, et al. astructural mechanism of integrin alpha(iib)beta(3)"inside-out" activation as regulated by itscytoplasmic face. cell. 2002;110(5):587-97.18. tadokoro s, shattil sj, eto k, et al. talin binding tointegrin beta tails: a final common step in integrinactivation. science. 2003;302(5642):103-6.19. kloeker s, major mb, calderwood da, et al. thekindler syndrome protein is regulated bytransforming growth factor-beta and involved inintegrin-mediated adhesion. j biol chem.2004;279(8):6824-33.20. shi x, ma yq, tu y, et al. the mig-2/integrininteraction strengthens cell-matrix adhesion and volume 4 • number 2 • 2016 international journal of cancer therapy and oncology 5 www.ijcto.org © davis et al. issn 2330-4049 modulates cell motility. j biol chem.2007;282(28):20455-66.21. bouaouina m, lad y, calderwood da. then-terminal domains of talin cooperate with thephosphotyrosine binding-like domain to activatebeta1 and beta3 integrins. j biol chem.2008;283(10):6118-25.22. bottcher rt, lange a, fassler r. how ilk andkindlins cooperate to orchestrate integrinsignaling. curr opin cell biol. 2009;21(5):670-5.23. puklin-faucher e, sheetz mp. the mechanicalintegrin cycle. j cell sci. 2009;122(pt 2):179-86.24. morse em, brahme nn, calderwood da. integrincytoplasmic tail interactions. biochemistry.2014;53(5):810-20.25. hohenester e. signalling complexes at thecell-matrix interface. curr opin struct biol.2014;29:10-6. international journal of cancer therapy and oncology www.ijcto.org corresponding author: aida mhiri; department of nuclear medicine, salah azaiez institute, tunis, tunisia. cite this article as: mhiri a, slim i, slimène m. dosimetry estimation of spect/ct for iodine 123-labeled metaiodobenzylguanidine in children. int j cancer ther oncol 2015; 3(3):323. doi: 10.14319/ijcto. 33.3 © mhiri et al. issn 2330-4049 dosimetry estimation of spect/ct for iodine 123-labeled metaiodobenzylguanidine in children aida mhiri, ihsen slim, mohamed faouzi slimène department of nuclear medicine, salah azaiez institute, tunis, tunisia [presented at the 4th african regional irpa congress (afrirpa04), which was held from september 13-17, 2014 in rabat, morocco. this paper was reviewed and accepted by the scientific committee of the 4th african regional irpa congress] conference proceeding abstract purpose: to evaluate the additional radiation exposure in terms of effective dose incurred by patients in the ct (computed tomography) portion of 123i-mibg (123ii-metaiodobenzylguanidine) study with spect/ct (single photon emission computed tomography associated to computed tomography) in some pediatric patients of our department. methods: data from 123ii-mibg scans comprising 50 children were presented in this study. the contribution of total effective dose imparted by the nuclear tracer and patient's age was calculated. effective dose from the ct portion of the examination is also estimated. spect acquisitions were performed with a dual-headed spect unit with an integrated 2-slice ct scanner (symbia t e-cam, siemens medical systems, erlangen, germany). the ct acquisition were performed using a tube current modulation system (care dose 4d). parameters used were: tube current of 30 60 mas, slice thickness of 3-5 mm, and tube voltage of 110 kv. results: our results show that spect dosimetry depends on administered activity and patient’s age and weight. for ct scan, effective dose is affected by tube current (ma), tube potential (kvp), rotation speed, pitch, slice thickness, patient mass, and the exact volume of the patient that is being imaged. conclusion: for children, 123ii-mibg study with spect/ct should be performed using the lowest available voltage and current. a sensible choice of these two parameters used can significantly reduce radiation dose, without any compromise in the quality of the diagnostic information. keywords: 123ii-metaiodobenzylguanidine; spect-ctpediatric; dosimetry introduction metaiodobenzylguanidine (mibg) is used for scintigraphic imaging of the adrenomedullary tumors pheochromocytoma and neuroblastoma in children. the use of i23i-l for labeling takes advantage of the better physical properties of i23i for imaging, allows higher activities to be administered with favorable radiation dosimetry and greater photon flux resulting in higher count, higher quality planar images and permits the performance of the single photon computed tomography (spect).1-3 single photon emission computed tomography associated to x-ray computed tomography (spect/ct) is a nuclear medicine tomographic imaging technique which improves diagnostic accuracy for particular clinical indications due to the possible attenuation and/or scatter correction of the spect functional images and the availability of helpful anatomic information.4 also, the interpretation of scintigraphic images can be confounded by physiological uptake, which can be better identified with spect/ct. however, it results in a significant increase of patient dose. in fact, according to literature data spect/ct compared to spect alone causes more radiation to the patient which is not sufficient to cause deterministic effects.2, 4, 5, 6 for spect effective dose depends on administered activity and patient’s age. the average radiopharmaceutical effective dose varies from tens to thousands of msv for some nuclear medicine exams.4 however, the introduction of ct in nuclear diagnostic process results in a significant increase of the patient dose. in general, effective dose (e) for ct examinations can be higher than most other diagnostic imaging modalities6. some authors have questioned the need to reduce doses particularly in children.7-8 understanding radiation dosimetry and its potential for deleterious health effects, having knowledge of the magnitude of the effective dose and the dose to specific organs from spect and ct, and considering the role of ct in the context of spect/ct will allow the reader to reduce the radiation dose to the patient without compromising the quality of the patient’s care.9 in this article, we will present the dosimetry associated with pediatric spect/ct for iodine 123-labeled metaiodobenzylguanidine, in terms of effective dose, in some pediatric patients of our department. factors affecting the radiation dose associated with spect, using 123ii-mibg in children will be described. the dosimetry associated with http://www.ijcto.org/ http://www.ejourpub.com/ http://dx.doi.org/10.14319/ijcto.33.3 2 mhiri et al.: spect-ct dosimetry for iodine 123-labeled metaiodobenzylguanidine international journal of cancer therapy and oncology www.ijcto.org © mhiri et al. issn 2330-4049 the ct component will be also noted. methods and materials data from 123ii-mibg scans comprising 50 children aged between 1 and 10 years, were presented in this study. the contribution of total effective dose imparted by the nuclear tracer and patient's age was calculated. effective dose from the ct portion of the examination is also estimated. spect acquisitions were performed with a dual-headed spect unit with an integrated 2-slice ct scanner (symbia t e-cam, siemens medical systems, erlangen, germany). the ct acquisition were performed using a tube current modulation system (care dose 4d). parameters used were: tube current of 30 60 mas, slice thickness of 3-5 mm, and tube voltage of 110 kv. for each child the ct was acquired immediately after spect; the patient being kept in the same position to minimize offsets due to movement and allow proper registration on fused imaging. the contribution of total effective dose imparted by the nuclear tracers for each child was calculated by multiplying the average administered activity for all patients by the “effective dose per unit administered activity” conversion factors listed in the international commission on radiological protection (icrp) publication 53 7 and 80 10-11. the effective dose from the ct portion of the examination is estimated from the product of the dose length product (dlp) and a body-region-specific conversion factor, k (msv mgy-1 cm-1), which take into account the varying biological sensitivities of different organs as given in table 1.12 dlp is a patient-specific value determined by the scan length and the acquisition parameters; it represents the total amount of radiation delivered in the acquisition. ct scan was acquired immediately following completion of the spect study with the child in the same position to minimize motion errors. results while for spect, dosimetry is dependent on administered activity and the patient’s age and weight; for ct scan, there are many factors which affect dosimetry. dose estimates (table 2) are dependent on tube current (ma), tube potential (kvp), rotation speed, pitch, slice thickness, patient mass, and the exact volume of the patient that is being imaged. according to the literature data, for children, mibg imaging can be performed using the lowest available voltage and current. discussion according to gelfand 13 and fahey 9, combined imaging results in a significant increase of the patient dose. effective dose is directly dependent on administered activity and the patient’s age for spect; whereas as described by mhiri 14, for ct scan, it depends on tube current, tube potential, rotation speed, pitch, slice thickness, patient mass, and the exact volume of the patient that is being imaged. a sensible choice of these parameters used, can significantly reduce radiation dose, without any compromise in the quality of the diagnostic information, according to piwowarska 15 and larking 5. the dose in the patient must be as low as compatible with the medical purpose. for larkin 5 and valentin 7, practice leading to a medical exposure must be clearly justified and protection against radiation must be optimized, particularly for children. also, quality control procedures have to be defined because of the coupling between the two devices.16 table 1: factors for dpl/effective dose conversion over various body regions and patient ages.12 region of body effective dose per dlp (msv (mgy cm)-1) by age < 1-year-old 1-year-old 5-year-old 10-year-old head and neck 0.013 0.0085 0.0057 0.0042 head 0.011 0.0067 0.0040 0.0032 neck 0.017 0.012 0.011 0.0079 chest 0.039 0.026 0.018 0,013 abdomen and pelvis 0.049 0.030 0.020 0.015 trunk 0.044 0.028 0.019 0.014 table 2: effective doses (e) delivered by 123 i-mibg spect-ct scintigraphy over patient ages and body regions. spect portion ct portion spect-ct examination average ac* (mbq/kg) average e* (msv) average e* (msv) e over regions (msv) total e* (msv) % increase of e* by the inclusion of the cttrunk abd 1-year-old 6 3.4 1.72 1.44 1.98 5.12 50% 5-year-old 5 4.4 1.24 1.20 1.34 5.64 28% 10-year-old 5 4.1 1.36 1.24 1.51 5.46 33% *ac = activity; *e = exposure volume 3 • number 3 • 2015 international journal of cancer therapy and oncology 3 www.ijcto.org © mhiri et al. issn 2330-4049 conclusion compared to planer images, 123i-mibg study with spect/ct increases significantly the number of lesions detected and allows better anatomic localization of neuroblastoma deposits and delineation of normal bowel activity. however, patient dose increases significantly also. then, reducing the patient dose should be a constant preoccupation of prescribing physician, nuclear physician's and qualified personnel performing the act, particularly for child. every effort should be made to adhere to the “as low as reasonably achievable (alara)” principle and ensure that the patient is not subjected to unnecessarily high levels of radiation, still more at young age. conflict of interest the authors declare that they have no conflicts of interest. the authors alone are responsible for the content and writing of the paper. references 1. shulkin bl, shapiro b. current concepts on the diagnostic use of mibg in children. j nucl med 1998; 39:679-88. 2. leung a, shapiro b, hattner r, et al. specificity of radioiodinated mibg for neural crest tumors in childhood. j nucl med 1997; 38:1352-7. 3. rozovsky k, koplewitz bz, krausz y, et al. added value of spect/ct for correlation of mibg scintigraphy and diagnostic ct in neuroblastoma and pheochromocytoma. ajr am j roentgenol 2008; 190:1085-90. 4. mhiri a, slim i, ghezaiel m, et al. l’apport de l’imagerie hybride temp/tdm dans la prise en charge du cancer différencié de la thyroïde. médecine nucléaire 2012; 36:554-60. 5. larkin am, serulle y, wagner s, et al. quantifying the increase in radiation exposure associated with spect/ct compared to spect alone for routine nuclear medicine examinations. int j mol imag 2011; 2011:897202. 6. wall bf, hart d. revised radiation doses for typical x-ray examinations. report on a recent review of doses to patients from medical x-ray examinations in the uk by nrpb. national radiological protection board. br j radiol 1997; 70:437-9. 7. valentin j. international commission on radiation protection. managing patient dose in multi-detector computed tomography (mdct). icrp publication 102. ann icrp 2007; 37:1-79, iii. 8. the measurement, reporting, and management of radiation dose in ct. report of aapm task group 23, aapm report no. 96, diagnostic imaging council ct committee 2008. available from http://www.aapm.org/pubs/reports/rpt_96.pdf 9. fahey fh. dosimetry of pediatric pet/ct. j nucl med 2009; 50:1483-91. 10. valentin j. radiation dose to patients from radiopharmaceuticals: (addendum 2 to icrp publication 53) icrp publication 80 approved by the commission in september 1997. annals of the icrp 1998; 28: 1-126. 11. international commission on radiological protection. radiation dose to patients from radiopharmaceuticals. oxford, pergamon press 1987. publication 53; 18: 4. 12. shrimpton pc, hillier mc, lewis ma, dunn m. national survey of doses from ct in the uk: 2003. br j radiol 2006; 79:968-80. 13. gelfand mj, lemen lc. pet/ct and spect/ct dosimetry in children: the challenge to the pediatric imager. semin nucl med 2007; 37:391-8. 14. mhiri a, slim i, ghezaiel m, et al. estimation of radiation dosimetry for some common spect-ct exams. international journal of biotechnology for wellness industries 2012; 1: 266-9. 15. piwowarska-bilska h, hahn lj, birkenfeld b, et al. optimization of low-dose ct protocol in pediatric nuclear medicine imaging. j nucl med technol 2010; 38:181-5. 16. acquah gf, schiestl b, cofie ay, nkansah jo. radiation dose reduction without degrading image quality during computed tomography examinations: dosimetry and quality control study. int j cancer ther oncol 2014; 2:02039. http://www.ncbi.nlm.nih.gov/pubmed/9544682 http://www.ncbi.nlm.nih.gov/pubmed/9293786 http://dx.doi.org/10.2214/ajr.07.2107 http://dx.doi.org/10.1016/j.mednuc.2012.08.008 http://dx.doi.org/10.1155/2011/897202 http://dx.doi.org/10.1259/bjr.70.833.9227222 http://dx.doi.org/10.2967/jnumed.108.054130 http://www.aapm.org/pubs/reports/rpt_96.pdf http://dx.doi.org/10.1016/s0146-6453(99)00006-8 http://www.icrp.org/publication.asp?id=icrp%20publication%2053 http://dx.doi.org/10.1259/bjr/93277434 http://dx.doi.org/10.1053/j.semnuclmed.2007.05.002 http://dx.doi.org/10.2967/jnmt.109.073486 http://dx.doi.org/10.14319/ijcto.0203.9 international journal of cancer therapy and oncology www.ijcto.org corresponding author: ashok komaranchath; department of medical oncology, kidwai memorial institute of oncology, bangalore, india. cite this article as: lingegowda a, kuntegowdenahalli l, komaranchath a, devi l, kumari p, kamath m. an analysis of the demographic profile, clinical manifestations, investigations and outcome of paediatric myelodysplastic syndrome: a single centre, cross-sectional study. int j cancer ther oncol 2015; 3(3):337. doi: 10.14319/ijcto.33.7 © lingegowda et al. issn 2330-4049 an analysis of the demographic profile, clinical manifestations, investigations and outcome of paediatric myelodysplastic syndrome: a single centre, cross-sectional study appaji lingegowda1, lakshmaiah kuntegowdenahalli2, ashok komaranchath2, lakshmi devi3, prasanna kumari3, mangesh kamath2 1department of pediatric oncology, kidwai memorial institute of oncology, bangalore, india 2department of medical oncology, kidwai memorial institute of oncology, bangalore, india 3department of pathology, kidwai memorial institute of oncology, bangalore, india received february 19, 2015; revised march 10, 2015; accepted april 05, 2015; published online june 04, 2015 original article abstract purpose: pediatric myelodysplastic syndrome (mds) is a relatively rare entity, with distinct clinical features and more ag gressive course than its adult counterpart. the aim of this study was to analyze the incidence of pediatric myelodysplastic syndrome at a tertiary cancer care center in southern india along with clinical manifestations, investigations and outcome. methods: on retrospective analysis of 1094 cases of pediatric hematological malignancies over a five-year period from september 2009 to august 2014, a total of seven cases of pediatric myelodysplastic syndrome were identified. presenting complaints, physical examination, investigations including haemogram, biochemistry, bone marrow examination and cytogenetics were reviewed. the diagnosis of mds was made if there was dysplasia in at least 10% of cells in two or more cell lineages. all patients were ris k stratified using the revised ipss. results: out of 1094 cases of pediatric hematological malignancies presenting at our institute within the study period, there were only seven cases of pediatric mds with an incidence of 0.65%. there were no genetic predispositions nor any cases of therapy related mds. the most common presentation was with fever and all patients had signif icant splenomegaly. all patients had anemia (median-6.2 gm / dl) with elevated wbc counts (median-30,900 / ul) and thrombocytopenia (median-50,000 / ul). the marrow cytogenetics was normal in five patients. most patients fell into the high and very high-risk category of the revised ipss, with only two patients of low risk. all seven patients were given only supportive care but one progressed to aml for which he was treated with remission induction. only two patients were alive at the time of analysis and median survival was 9 months. conclusion: pediatric mds is a rare disease with a short clinical history, aggressive course and generally poor outcomes as compared to the adult variant. a hematopoietic stem cell transplant may be the only viable option for survival. keywords: pediatric myelodysplastic syndrome; mds introduction the myelodysplastic syndrome (mds) represents a heterogeneous group of stem cell malignancies characterized by dysplastic and ineffective hematopoiesis and a variable risk of transformation to acute leukemia. myelodysplastic syndrome in the pediatric age group is uncommon and constitutes a distinct entity different in many ways from adult mds. they have certain unique clinical features, a more aggressive clinical course with a shorter overall survival. epidemiological data for pediatric mds is limited not only because it is relatively rare, but also because of the difficulty in diagnosis as well as classification. however, there have been several case series of pediatric mds reported.1-9 the largest series was from japan by sasake et al. who submitted a retrospective analysis of 189 patients of mds less than 16 years of age from sixty-two centers in japan over a period of 7 years. there has been only one such study from india, by chatterjee et al. where 21 patients with mds from northern india aged less than 17 years were evaluated.10 compared to this study, the median age of presentation was lower in our institution (4 years vs. 9 years). all patients presented with pallor and a majority had fever and bleeding diathesis. the overall survival was dismal and the best prognosis appeared to be for those with refractory cytopenias with a low blast count. we have classified our patients on the basis of both the type of mds as well as the revised ipss scoring system. http://ejourpub.com/ http://dx.doi.org/10.14319/ijcto.33.7 http://www.ijcto.org 2 lingegowda et al.: demographic profile and outcome of pediatric mds international journal of cancer therapy and oncology www.ijcto.org © lingegowda et al. issn 2330-4049 consensus on the treatment of pediatric mds is also uncertain, with allogenic stem cell transplant the only chance of cure. chemotherapy is reserved for patients in more advanced stage of the disease. the newer hypomethylating agents used in adult mds have not yet been approved in pediatric mds. here, we present our institution’s experience with pediatric mds, where we had seven cases over a five-year period from september 2009 to august 2014. we have analyzed their demographic profile, presenting features, clinical findings, investigative reports, treatment and outcome. methods and materials on retrospective analysis of 1094 cases of pediatric hematological malignancies over a five year period from september 2009 to august 2014, a total of seven cases of pediatric myelodysplastic syndrome were identified of which there were 4 boys and 3 girls with a median age of 4 years. presenting complaints, physical examination, investigations including haemogram, biochemistry, bone marrow examination and cytogenetics were analyzed. the patients were classified according to the pediatric adaptation of the 2008 who classification of myelodysplastic syndromes. four patients were classified as raeb of which one patient progressed to raeb-t and finally to acute myeloid leukemia. he had a total wbc count >100,000/ul, 13% blasts in bone marrow at presentation, trisomy 8 on karyotyping and r-ipss score of 6.5 (very high). the other three patients were classified as rcc. there were no predisposing syndromes nor any cases of therapy related mds. all patients were risk stratified using the revised ipss. all patients had fever and splenomegaly on presentation, and only one patient presented with bleeding diathesis. anemia and thrombocytopenia were present in all patients and all except two patients had normal cytogenetics. treatment was mainly supportive. the one patient who progressed to raeb-t was treated with a standard 7+3 remission induction protocol, but failed to achieve remission and progressed to acute myeloid leukemia with 90% blasts in peripheral blood. outcome was measured by calculating median overall survival. results a total of seven patients were identified with pediatric myelodysplastic syndrome. on comparison, this constituted only around 0.65% of all pediatric hematological malignancies at our institute. patient profiles there were four boys and three girls with ages ranging from 2 years to 14 years with a median age of 4 years. there were 4 patients classified as raeb and 3 as refractory cytopenia of childhood (rcc) as per the revised who classification of childhood myelodysplastic syndromes (2008). there were no constitutional predispositions like down’s syndrome, fanconi’s anemia, pearson’s syndrome, etc. there were no cases of therapy related mds either. clinical presentation all seven patients had fever as a presenting complaint, three had abdominal pain and distension, one presented with bleeding from the gums and one had recurrent vomiting. the median duration of symptoms were 21 days with a range of 10 to 60 days. all patients except one had a performance status </= 2. six of the patients had clinical pallor and two patients had palpable lymphadenopathy. all seven patients had palpable splenomegaly and a mean spleen size of 3.8 cm under the left costal margin. three of these patients also had palpable hepatomegaly. (chart 1) chart 1: presenting complaints (no. of patients with the mentioned presenting complaint). investigations six of the patients had a hemoglobin of less than 10 g/dl and mean hemoglobin was 7.2 g/dl. total wbc count was also elevated in most cases with a median count of 30900/ul. platelet counts were also low, ranging from 12000/ul to 128,000/ul with a median value of 50000/ul. renal and liver function tests were normal in all seven cases. there were bone marrow blasts ranging from 6% to 15% at presentation in four cases and <1% blasts in the other three. another finding that suggested a high burden of disease was a high ldh value, which was seen in all seven cases ranging from 392-2780 iu/l with a mean value of 1238 iu/l. (table 1) cytogenetics bone marrow cytogenetics were done on all seven patients and showed a normal karyotype in five patients. one patient had trisomy 8 and another had monosomy 7 (chart 2). there were no complex cytogenetic abnormalities. chart 2: cytogenetics (no. of patients with the mentioned cytogenetic abnormality). volume 3 • number 3 • 2015 international journal of cancer therapy and oncology 3 www.ijcto.org © lingegowda et al. issn 2330-4049 table 1: patient characteristics. sl. no. age /sex hb. tlc plt bm blasts(%) ldh cytogenetics classification 1 5/f 8.3 6000 50000 6 1050 monosomy 7 raeb 2 13/m 5.9 30900 27000 <2 1090 normal rcc 3 14/m 6.2 2500 128000 <2 2780 normal rcc 4 4/m 9.8 >100000 60000 13 1103 trisomy 8 raeb 5 2/f 3.6 34900 26000 15 1300 normal raeb 6 3/f 6.1 >100000 124000 <2 392 normal rcc 7 3/m 10.8 22700 12000 12 950 normal raeb chart 3: revised ipss score (no. of patients in each risk group). risk stratification risk stratification was done using the revised ipss, which takes into account cytogenetics, bone marrow blast percentage, hemoglobin, platelet count and absolute neutrophil count at the time of presentation. the median r-ipss score was 5.0 (high risk), with 2 very high, 2 high, 1 intermediate and 2 low risk groups (chart 3). outcome none of the patients were willing for either intensive chemotherapy or stem cell transplant initially and were started on best supportive care with repeated transfusion of blood products, antibiotics and other measures. out of the seven patients, one progressed on follow-up to acute leukemia with more than 20% blasts and was given remission induction chemotherapy with a standard 7 + 3 protocol with cytarabine and daunorubicin. the patient however, failed to achieve remission with the same and was continued on best supportive care as he was not affordable for high dose chemotherapy and stem cell transplant. on follow up of the patients, the survival ranged from 1-49 months with a median survival on 9 months. five of the seven patients died due to various complications. one patient died from pneumonia, four from bleeding diathesis, out of which one was the patient who had progressed to aml and had received remission induction. two of our patients were alive at the end of the study period, of which one had survived for 49 months. of note is that this patient presented with normal leucocyte counts, platelet count of more than 100,000/ul, occasional bone marrow blasts, normal cytogenetics and had the lowest r-ipss score of 2.5 among all the patients. he is also transfusion free for the past 2 years. discussion although myelodysplastic syndrome is predominantly a disease of the elderly, there has been several case series describing this disease in children. in general, mds is an uncommon disease with an incidence ranging from 4.1 per 100,000 11 to 1.24 per 100,000 in recent series 12. the incidence is considerably lower in children with hasle et al. describing it as 3.4 in 1,000,000 in children less than 15 years of age.2 a population based survey from denmark had similar values of incidence which set the number of pediatric mds at around 2-3% of all pediatric hematological malignancies.2, 13 there have been no epidemiological studies for childhood mds in southern india. acute leukemias account for approximately 35-45% of the almost 50,000 childhood malignancies in india 14 and in our center, out of the 1094 cases of pediatric hematological malignancies over the past 5 years, we have seen only seven cases of childhood mds with an incidence of 0.65%. this incidence appears to be much lower than that seen in most western countries and we believe it may be due to both misdiagnoses and possibility of late presentation of several cases as frank aml. almost 60% of our patients presented in an advanced stage of disease with excess blasts and a high r-ipss score (median of 5.0). they also appeared to have a higher burden of disease with high ldh levels and all patients had anemia and thrombocytopenia. marrow cytogenetic analysis showed normal cy4 lingegowda et al.: demographic profile and outcome of pediatric mds international journal of cancer therapy and oncology www.ijcto.org © lingegowda et al. issn 2330-4049 togenetics in five patients and only two patients showing cytogenetic abnormalities. due to financial constraints, none of our patients could afford stem cell transplants and only one was treated aggressively because of progression of disease. as per the ewog-mds 98 study by strahm et al. the 3-year disease free survival of hematopoietic stem cell transplant is around 50%.15 the one patient who received chemotherapy did not achieve remission and eventually succumbed to the disease. in a trial comparing the outcome of chemotherapy in mds versus acute myeloid leukemia, less than 30% of pediatric mds patients survived for more than 3 years.16 the overall survival was dismal, with a median os of only 9 months. in view of the several differences between pediatric and adult mds (table 2) 17, the who classification, which was developed based on adult cases, is considered inadequate for classifying pediatric mds. table 2: differences between adult and pediatric mds.17 feature adult mds pediatric mds refractory anemia (ra) anemia always present not always present (44% can have hb levels >10g/dl) ra-significant dyserythropoiesis always present may be subtle and overlooked ra-course protracted (median survival 66 months) transformation to aml or more aggressive form of mds occurs with short lag time refractory anemia with ringed sideroblasts constitutes 10-12% of cases exceedingly rare mds assoc. with isolated 5q deletion occurs predominantly in middle age to older women not described constitutional abnormalities rare often observed incidence more common rare clinical features )a(symptoms )b(signs majority are asymptomatic majority symptomatic hepatosplenomegaly and granulocytic sarcoma more prevalent prognosis relatively good to poor poor even in ra role of ipss for predicting outcome significant role only cytogenetic pattern is of prognostic value cytogenetics most conspicuous difference monosomy 7 -5,-5q,-y -7q, +8(trisomy 8) constitutional genetic abnormalities rare noted in <5% of adult ra commonly present rare 35% carry constitutional genetic abnormalities most common cytogenetic abnormality in refractory cytopenias of children common commonest abnormalities are monosomy 7 and trisomy 8 table 3: pediatric adaptation of the 2008 who classification.19 myelodysplastic syndromes refractory cytopenias (blood blasts <2%, bone marrow blasts <5%). refractory anemia with excessive blasts (blood blasts <2%, bone marrow blasts <5%-19%). refractory anemia with excess blasts in transformation (bone marrow blasts 20-29%) or acute myelogenous leukemia with mds-related changes (peripheral blood or marrow blasts >20%). myelodysplastic/myeloproliferative disease juvenile myelomonocytic leukemia down syndrome disease transient abnormal myelopoiesis myeloid leukemia of down syndrome to overcome this, hasle et al. had proposed a pediatric approach to the who classification, which emphasizes the subtypes found in pediatric age group and deleting some of the adult subtypes, which are rare or unseen in the pediatric population. the who pediatric modification was first proposed in 2003 18 and later modified in 2008. presently, the pediatric who adaptation defined in 2008 (table 3)19 is being used worldwide and applies to more than 99% of all childhood mpd cases. in the revised who (2008) classification, the mdss were further subdivided into refractory cytopenia, refractory anemia with excess blasts (raeb), and refractory anemia with excess blasts in transformation (raeb-t) and has a separate section on childhood mds, where jmml and ml-ds are distinct disorders. this update also defines the criteria for defining refractory cytopenia of childhood (rcc). children with <2% blasts in blood, <5% blasts in the bone marrow, and persistent cytopenias associated with dysplasia in at least two cell lines are included in this group. treatment of adult volume 3 • number 3 • 2015 international journal of cancer therapy and oncology 5 www.ijcto.org © lingegowda et al. issn 2330-4049 mds with hypomethylating agents have shown great promise, but these agents are yet to be tried in the pediatric setting. considering the poor prognosis in children trials with these newer agents may be warranted. conclusion even though myelodysplastic syndrome is rare in childhood, the diagnosis must be kept in mind when children present with refractory cytopenias and a short symptom duration. pediatric mds is very different from that of the adult variant in presentation, clinical features, cytogenetics and survival. the age of presentation was lower than that found by chatterjee et al. in northern india. they present with a shorter history and are more likely to have multilineage dysplasia. in our series, there were only 2 patients with cytogenetic abnormalities with all others having normal karyotypes. the clinical course is more aggressive and they tend to have shorter survivals as compared to adult mds. hence, early diagnosis and management is essential. median survival in our series was similar to that of western data which showed a median survival of 9 months. outcome with supportive care alone is dismal. a hematopoietic stem cell transplant may be the only viable option and should be performed early in the course of disease. the use of hypomethylating agents in pediatric mds needs to be evaluated further. conflict of interest the authors declare that they have no conflicts of interest. the authors alone are responsible for the content and writing of the paper. references 1. sasaki h, manabe a, kojima s, et al. myelodysplastic syndrome in childhood: a retrospective study of 189 patients in japan. leukemia 2001;15:1713-20. 2. hasle h, jacobsen bb, pedersen nt. myelodysplastic syndromes in childhood: a population based study of nine cases. br j haematol 1992;81:495-8. 3. tuncer ma, pagliuca a, hicsonmez g, et al. primary myelodysplastic syndrome in children: the clinical experience in 33 cases. br j haematol 1992;82:347-53. 4. creutzig u, cantù-rajnoldi a, ritter j, et al. myelodysplastic syndromes in childhood. report of 21 patients from italy and west germany. am j pediatr hematol oncol 1987;9:324-30. 5. hasle h, kerndrup g, jacobsen bb. childhood myelodysplastic syndrome in denmark: incidence and predisposing conditions. leukemia 1995;9:1569-72. 6. bader-meunier b, mielot f, tchernia g, et al. myelodysplastic syndrome in childhood: report of 49 patients from a french multicentre study. br j haematol 1996; 92:344-50. 7. luna-fineman s, shannon km, atwater sk, et al. myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. blood 1999; 93:459-66. 8. passmore sj, hann im, stiller ca, et al. pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. blood 1995;85:1742-50. 9. hasle h, wadsworth ld, massing bg, et al. a population-based study of childhood myelodysplastic syndrome in british columbia, canada. br j haematol 1999; 106: 1027-32. 10. aul c, gattermann n, schneider w. age-related incidence and other epidemiological aspects of myelodysplastic syndromes. br j haematol 1992; 82:358-67. 11. chatterjee t, mahapatra m, dixit a, et al. primary myelodysplastic syndrome in children--clinical, hematological and histomorphological profile from a tertiary care center in india. hematology 2005;10:495-9. 12. sant m, allemani c, tereanu c, et al. incidence of hematological malignancies in europe by morphologic subtype: results of the haemacare project. blood 2010; 116: 3724-34. 13. hasle h, kerndrup g, jacobsen bb. childhood myelodysplastic syndrome in denmark: incidence and predisposing conditions. leukemia 1995;9:1569-72. 14. three year report of the population based cancer registries 2009-2011: report of 25 pbcrs; national cancer registry programme, indian council medical research, bangalore 2013. 15. strahm b, nollke p, zecca m, et al. hematopoietic stem cell transplantation for advanced myelodysplastic syndrome in children: results of the ewog-mds 98 study. leukemia 2011;25:455-62. 16. hasle h, kerndrup g, yssing m, et al. intensive chemotherapy in childhood myelodysplastic syndrome. a comparison with results in acute myeloid leukemia. leukemia 1996; 10:126973. 17. tilak v, sookmane dd, gupta v, shukla j. myelodysplastic syndrome. indian j pediatr 2008; 75:729-32. 18. hasle h, niemeyer cm, chessells jm, et al. a pediatric approach to the who classification of myelodysplastic and myeloproliferative diseases. leukemia 2003;17:277-82. 19. swerdlow sh, campo e, harris nl, et al. who classification of tumours of hematopoietic and lymphoid tissues, 4th ed. lyon, france: iarc press; 2008; 2. http://dx.doi.org/10.1038/sj.leu.2402271 http://dx.doi.org/10.1111/j.1365-2141.1992.tb02980.x http://dx.doi.org/10.1111/j.1365-2141.1992.tb06428.x http://dx.doi.org/10.1097/00043426-198724000-00009 http://www.ncbi.nlm.nih.gov/pubmed/7658725 http://dx.doi.org/10.1046/j.1365-2141.0000.d01-1480.x http://dx.doi.org/10.1046/j.1365-2141.0000.d01-1480.x http://www.ncbi.nlm.nih.gov/pubmed/9885207 http://www.ncbi.nlm.nih.gov/pubmed/7703482 http://dx.doi.org/10.1046/j.1365-2141.1999.01645.x http://dx.doi.org/10.1111/j.1365-2141.1992.tb06430.x http://dx.doi.org/10.1080/10245330500155556 http://dx.doi.org/10.1182/blood-2010-05-282632 http://www.ncbi.nlm.nih.gov/pubmed/7658725 http://www.icmr.nic.in/ncrp/pbcr_report%202009_2011/all_content/all_pdf/preliminary_pages.pdf http://dx.doi.org/10.1038/leu.2010.297 http://www.ncbi.nlm.nih.gov/pubmed/8709630 http://dx.doi.org/10.1007/s12098-008-0138-y http://dx.doi.org/10.1038/sj.leu.2402765 http://apps.who.int/bookorders/anglais/detart1.jsp?codlan=1&codcol=70&codcch=4002 database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! database connection failed! international journal of cancer therapy and oncology www.ijcto.org corresponding author: biniam tesfamicael; department of radiation oncology, mclaren regional medical center, flint, michigan, usa. cite this article as: tesfamicael b, gueye p, avery s, lyons d, mahesh m. a portable secondary dose monitoring system using scintillating fibers for proton therapy of prostate cancer: a geant4 monte carlo simulation study. int j cancer ther oncol. 2016; 4(1):4115. doi: 10.14319/ijcto.41.15 © tesfamicael et al. issn 2330-4049 a portable secondary dose monitoring system using scintillating fibers for proton therapy of prostate cancer: a geant4 monte carlo simulation study biniam tesfamicael1, paul gueye2, stephen avery3, donald lyons3, mahadevappa mahesh4 1department of radiation oncology, mclaren regional medical center, flint, michigan, usa 2department of physics, hampton university, hampton, virginia, usa 3department of radiation oncology, university of pennsylvania, philadelphia, pennsylvania, usa 4department of radiology and radiological sciences, john hopkins university, baltimore, maryland, usareceived july 05, 2015; revised january 29, 2016; accepted february 07, 2016; published online february 12, 2016 original article abstract purpose: the main purpose of this study was to monitor the secondary dosedistribution originating from a water phantom during proton therapy of prostatecancer using scintillating fibers. methods: the geant4 monte carlo toolkit version9.6.p02 was used to simulate a proton therapy of prostate cancer. two cases werestudied. in the first case, 8 × 8 = 64 equally spaced fibers inside three 4 × 4 × 2.54cm3 delrin® blocks were used to monitor the emission of secondary particles inthe transverse (left and right) and distal regions relative to the beam direction. inthe second case, a scintillating block with a thickness of 2.54 cm and equal verticaland longitudinal dimensions as the water phantom was used. geometrical cutswere implemented to extract the energy deposited in each fiber and inside thescintillating block. results: the transverse dose distributions from the detectedsecondary particles in both cases are symmetric and agree to within <3.6%. theenergy deposited gradually increases as one moves from the peripheral row offibers towards the center of the block (aligned with the center of the prostate) by afactor of approximately 5. the energy deposited was also observed to decrease asone goes from the frontal to distal region of the block. the ratio of the energydeposited in the prostate to the energy deposited in the middle two rows of fibersshowed a linear relationship with a slope of (-3.55±2.26) × 10-5 mev per treatmentgy delivered. the distal detectors recorded a negligible amount of energydeposited due to higher attenuation of the secondary particles by the water in thatdirection. conclusion: with a good calibration and with the ability to define a goodcorrelation between the radiation flux recorded by the external fibers and the dosedelivered to the prostate, such fibers can be used for real time dose verification tothe target. the system was also observed to respond to the series of bragg peaksused to generate the spread out bragg peak inside the water phantom. such braggpeaks were detected by the fibers. the energy deposited inside the lateral blockswere also observed to decrease as one goes away from the beam nozzle due toincreased attenuation. keywords: proton therapy; prostate cancer; scintillating fibers; geant4;hadrontherapy; secondary dose 1. introductionradiation therapy has been one of the most commonlyused treatment options for cancer patients. the externalbeam radiation therapy is performed using high energy photons as well as charged particles, mainly electronsand protons. due to the sharp characteristic bragg peakit possesses and the technological ability to spread the http://www.ijcto.org/ http://www.ejourpub.com/ http://dx.doi.org/10.14319/ijcto.41.15 2 tesfamicael et al.: secondary dose monitoring system in proton therapy international journal of cancer therapy and oncology www.ijcto.org © tesfamicael et al. issn 2330-4049 bragg peak to cover the entire tumor size in the beamdirection, proton therapy has shown a therapeuticadvantage over the conventional photon therapy insparing much of the surrounding healthy tissue in thetreatment of deep seated malignancies like the prostatecancer.1-8 in proton therapy, the beam can be deliveredin either an active mode or passive mode.5-7 in theformer, an aperture and a compensator that aregenerated from the treatment planning system arefabricated and utilized to conform the beam to the targetshape both laterally and in the beam direction,respectively.the major concern regarding proton therapy, however,has been the production of secondary particles,especially neutrons, through inelastic interactions of theenergetic protons with the beam delivery systemcomponents and the patient body.9,10 the former wasfound to be the major source of neutrons.9, 10 the dosedelivered to patients by such secondary particles hasbeen of great concern and a main topic of study by anumber of researchers.4,11-15 results showed that thedose from neutrons is very low and the secondarycancer incidence from such a dose is very scarce.16 theproduction of neutrons was found to be high when usinga passive beam delivery mode. this is due to presence ofthe scatterers and apertures, which are the maincontributors in neutron production in the beam line.binns et al.12 measured the neutron dose equivalent atthe patient position to be in the range of 33 msv to 80msv per treatment gy when a proton beam of 200 mevmean energy was delivered using a passive beamdelivery mode. around the treatment nozzle, anequivalent dose of 0.91 msv to 15 msv per treatment gywas measured at the harvard cyclotron laboratory byyan et al.14 from 160 mev proton beam with a passivebeam delivery mode.the equivalent dose from secondary neutrons decreaseswith a decrease in the treatment field, an increase in thedistance from the nozzle as well as a decrease in theenergy of the primary proton beam. agosteo et al.11reported a monte carlo simulation estimation of amaximum neutron dose of 10-4gy per treatment gy inthe healthy tissue behind the eye from a passivelyscattered ocular treatment beam line using a 65 mevproton beam at the center antoine-lacassagne infrance. with an active beam delivery mode, the absenceof scatterers and apertures greatly reduces the neutronproduction.17 uwe et al.15 measured the dose deliveredto the healthy tissue by the secondary neutrons for largeand medium targets to be approximately 4 msv and 2msv per treatment gy, respectively when a 177 mevproton beam was used to irradiate the tumor in a spotscanning beam delivery mode.in this work, a geant4 monte carlo simulation toolkit18,19was used to study the distribution of the secondaryparticles around a 36 cm × 22 cm × 24 cm water phantom. the energy deposited around the waterphantom by these secondary particles was analyzed. thedose monitoring system constructed in this study ismainly based on the energy deposited external to thewater phantom. this work follows a recent paper thatfocused in the dose distribution near and in the prostategland.20 in the previous paper, a dose monitoring systemwas constructed to study the dose delivered to the rectalwall in the proton therapy of prostate cancer. thesimulation included thin scintillating fibers attached toan endorectal balloon to record the dose delivered to theballoon surface. this represents the dose to the innerrectal wall, which is in physical contact with the balloon.the results obtained indicated that a good correlationcan be built between the dose delivered to the prostateand the dose to the scintillating fibers, thus an in-vivodose monitoring to the rectal wall as well as the targetprostate can be achieved. 2. methods and materialsthe geant4 monte carlo toolkit version 4.9.6 p02 wasused to simulate a proton therapy of prostate cancerwith an endorectal balloon as an internal immobilizer.the simulation was based on the hadrontherapyexample application available with the geant4package21-25, modified for the present study. the detailsof the simulation developed are described in theprevious paper.20 for the secondary dose monitoringsystem, three detectors were constructed around thewater phantom. from the beam's eye view, twodetectors were placed in the lateral directions and onein the distal. two sets of detectors were designed forthis study. in the first case, a 4 cm × 4 cm delrin® blockwas used to house a total of 8× 8 = 64 fibers ofdimension 1 mm × 1 mm, evenly spaced by a center-to-center distance of 4.556 mm from each other both in thevertical and lateral directions. the length of the fiberswas defined by the thickness of the delrin® block, whichis 2.54 cm. in the second case, a 36 cm × 22 cm × 2.54 cmblock made entirely of scintillating material was used forradiation detection. each block was aligned to the centerof the prostate. in both cases, the detectors were placedat a distance of 4 cm away from the surface of the waterphantom. the placement of the scintillating fibers insidethe delrin® block and the scintillating blocks are shownin figures 1 and 2.the modulator wheel was rotated from 00 to 3590 insteps of 10 to spread out the bragg peak in the beamdirection. the beam was laterally conformed to thetarget shape using patient specific collimator located atthe end of the beam line. with the delrin® block, thesimulation was run for four different number of eventsper degree of the modulator wheel rotation: 500, 1000,2000, 3000. the results obtained were analyzed to studythe linear response of the scintillating detectors to thedose delivered. for the case of the scintillating block,however, the simulation was run solely for 3000 events volume 4 • number 1 • 2016 international journal of cancer therapy and oncology 3 www.ijcto.org © tesfamicael et al. issn 2330-4049 per degree of modulator wheel rotation to evaluate theeffect of delrin® material as a host to the dosemonitoring fibers as in the former case. 3. resultsthe fibers were uniformly spaced within the blocks,with the fiber id running from 1 to 64 as shown infigure 1. the beam direction is from left to right,irradiating the whole prostate. in the root file26generated from the simulation run, the energy depositedin all the fibers inside the three blocks were returnedunder one tree by implementing a cut in the volumename. to analyze the energy deposited in each fiber, theknowledge of the geometrical location of the individualfibers inside the blocks is required. the plots of theinteraction points in the fibers in the x-y (along thebeam direction) and z-y (along the length of the fibers)planes in the lateral blocks are shown in figure 2. the geometry simulating the prostate is centered at y = z = 0and x = 21.5 cm. the right block (z > 0) is the reflectionof the left block (z < 0) with the x-axis as a mirror at z =0. hence, it is sufficient to obtain the informationregarding the geometric location of the fibers from oneblock only. the information for the other lateral blockfibers will be a mirror reflection of the first block fibersalong the x-axis, i.e. setting z > 0 will give thecoordinates of the fibers in the right block and z < 0 willbe that of the fibers in the left block from the beam's eyeview.from the two plots above, the coordinates that definethe volume of the individual fibers was generated. theinformation was later used to calculate the totalintegrated energy deposited in each fiber located insidethe left and right blocks. figure 1: left panel: the top view of the simulation design in and around the water phantom. right panel: the placement ofthe 64 scintillating fibers inside the lateral delrin® blocks. the blocks are aligned to the center of the prostate and wereplaced 4 cm away from the surface of the water phantom both in the two lateral and distal regions. figure 2: the interaction points inside the left block fibers along the fiber length (y-z plot) and in (y-x) the beam direction(beam direction is along the x axis). 4 tesfamicael et al.: secondary dose monitoring system in proton therapy international journal of cancer therapy and oncology www.ijcto.org © tesfamicael et al. issn 2330-4049 figure 3: the interaction points of the radiation within the distal block fibers. the fiber id goes from 1 to 64 from the top -leftto the bottom-right corner. figure 4: the total integrated energy deposited inside the right and left fiber within the delrin® block for the 2000 and 3000events per degree of modulator rotation. the same results were observed for the 500 and 1000 events per modulator wheelrotation – (not shown for clarity). figure 5: the energy deposited in the left and right fiber blocks with and without the virtual cut. both simulation runs werefor 3000 events per degree of modulator rotation. volume 4 • number 1 • 2016 international journal of cancer therapy and oncology 5 www.ijcto.org © tesfamicael et al. issn 2330-4049 figure 6: the energy deposited in the prostate and the total energy in the 16 fibers located in rows 4 and 5 above (+1.8 mm)and below (-1.8 mm) the center of the prostate, respectively. the plot also shows the ratio of the two energies deposited(e_prostate/e_ fibers), which is scaled up by 8,000 for clarity.for the fibers in the distal region, the beam was movedforward with its momentum in the positive x direction.such setup results in more interaction points inside thedistal block fibers, hence giving a clear image of thegeometry of the fibers. from the plot of the interactionpoints, the geometrical information regarding the 64fibers was generated and later used to calculate the totalintegrated energy deposited inside each fiber. the plotof the interaction points in the fibers inside the distalblock are shown in figure 3.once the geometrical coordinates for all the fibers wereextracted, the simulation was run for the differentnumber of events per modulator wheel rotation forproton beam energy of 200 mev as listed in section ii.the plot of the integrated energy deposited in the fibersfor the lateral blocks is shown in figure 4.figure 4 shows a clear symmetry in the energydeposited between the left and right block fibers. theplot also shows symmetry in the energy deposited in thefibers across the rows. the fibers in the first row, whichare physically located at the top of the block (see figure1), record relatively the same amount of energydeposited as those in the eighth row, which are locatedat the bottom of the block. the same relationship existsbetween the second and seventh, third and sixth as wellas fourth and fifth row fibers. such pairs of row fibersare located at the same distance from the center of theprostate. the energy deposited in the fibers increase from row 1(and 8) to row 3 (and 6), then slightly decreases in row 4(and 5). fibers in rows 1 and 8 are at comparativelylonger distances from the center of the prostate. hence,the secondaries will travel a longer distance to arrive atthose fibers, experiencing a relatively higherattenuation. for the fibers in rows 3 and 6, the distancedecreases, resulting in lower attenuation and higherdeposited energy as compared to the energy recordedby the fibers in rows 1 and 8. the energy depositedcontinues to increase as one move from the edge, rows 1and 8, towards the middle, rows 4 and 5. a slightdecrease in the energy deposited in rows 4 and 5 couldbe attributed to the spherical geometry of the prostate,which makes it thicker at the center. this affects theenergy deposited inside the fibers in rows 4 and 5 thatare located slightly above and below the center of theprostate, respectively.in the second case, the delrin® block was replaced by afull solid scintillating slab of dimensions 36 cm × 22 cm× 2.5 cm. this simulation was run for 3000 events permodulator rotation and virtual cuts were applied toobtain the energy deposited in the geometrical locationof the fibers. the geometrical information of the fibersgenerated from figure 2 was used for the virtual cut andthe integrated energy deposited was calculated and isdepicted in figure 5.the plots overlap very well indicating that the delrin®material used to house the individual fibers has no effect 6 tesfamicael et al.: secondary dose monitoring system in proton therapy international journal of cancer therapy and oncology www.ijcto.org © tesfamicael et al. issn 2330-4049 on the reading of the fibers. in the four different runs,the energy deposited in the prostate as well as the totalenergy deposited in the sixteen fibers in rows 4 and 5were recorded and analyzed. the plot of the energydeposited as a function of the number of events permodulator wheel rotation (i.e., dose) for both theprostate and these fibers is shown in figure 6. linear fitsapplied for each plot showed a slop of 17.2±0.35 for theprostate and 6.5±0.13 for the fibers in the two middlerows. the plot for the ratio of the energy deposited inside theprostate to that recorded by the fibers is relativelyconstant, with a slope of (-3.55±2.26) × 10-5 mev pertreatment gy to the prostate. the results obtainedensures a direct scaling between the two energiesdeposited. thus, defining a precise correlation betweenthe energy deposited in the prostate and the energydeposited in the 16 fibers located outside of the waterphantom will enable one to get a good prediction of thedose to the prostate from the measurement of theradiation flux in the fibers. figure 7: the ratio of the energy deposited for the 3000 events per degree of modulator wheel rotation run. the plot showsthe ratio of the energy deposited in the left fibers to those in the right fibers for both the block and virtual cut cases. figure 8: contour plot of the interaction points in the distal scintillating block. beam direction in the x axis. left panel is inbeam's eye view and right panel transverse to beam direction. volume 4 • number 1 • 2016 international journal of cancer therapy and oncology 7 www.ijcto.org © tesfamicael et al. issn 2330-4049 figure 9: the energy deposited in thin slabs of the right scintillating block at different locations along the beam direction. figure 10: the energy deposited as a function of depth in the lateral region. 4. discussionfrom the results obtained, one could notice a definitesymmetry in the distribution of the secondary particlesin the lateral (right and left) regions in both cases asdepicted in figures 4 and 5. this indicates a uniformdistribution of the radiation exiting the water phantom.the plot of the ratio of the energy deposited in the leftand right regions for both cases is shown in figure 7. figure 7 shows the ratio of the energy deposited in theleft to that of the right fibers for both cases (inside thedelrin® block and for the full scintillating slab). thedata analysis showed that the flux in the two lateralregions match to within 3.6% in both cases. the linear fitperformed over a selected region also showed a verysmall slope, with a y-intercept close to 1, with the twodata sets fluctuating around 10% (1σ). the selected 8 tesfamicael et al.: secondary dose monitoring system in proton therapy international journal of cancer therapy and oncology www.ijcto.org © tesfamicael et al. issn 2330-4049 region for the linear fit was the fibers located betweenrows 2 and 7, where there is sufficient statistics.moreover, the ratio of the data obtained from the fibersinside the delrin® block to that of the virtual cuts insidethe scintillating slab was analyzed for both regions. thedata match to within 3.5%, which indicates that thematerial housing the dose monitoring fibers has lesseffect on the energy deposited inside those fibers.the secondary dose monitoring fibers and thescintillating block in the distal region, however,recorded very minimum energy deposited. this is due tothe higher attenuation the secondary particlesexperience in arriving at those fibers for the selectedbeam energy. the primary purpose of this detector wasto obtain information on the beams centroid in order toprovide a correction on the beam alignment.to generate the contour plot in figure 8, a proton beamof energy 250mev was used with the beam sourcepositioned at around the center of the water phantom toovercome the higher attenuation. observed from thebeam's eye view, the left panel shows the detection ofmore secondaries around the center. the right panelshows the side view of the scintillating block detector,i.e. transverse to the beam direction. more secondarieswere detected at the frontal edge around the center ofthe detector.further analysis of the data showed that the energydeposited in the fibers located in each row fluctuates,following a relatively similar pattern in all the rows. asshown in figures 4 and 5, the "up-down" patternappears in both cases, i.e. when using a delrin® block tohouse the monitoring fibers as well as when the wholescintillating block was used with a virtual cut. the fibersthat are housed inside the delrin® block in each rowwere spaced at 4.6 mm from each other. to understandthis fluctuation, the scintillating block located on theright side of the water phantom, viewed from the beam'seye view, was virtually dissected in the vertical direction(slices run along beam direction) in thicknesses of 0.5mm. in the y and z directions (height and thickness,respectively), the whole size of the block wasconsidered. such slices (0.5 mm × 22 cm × 2.45 cm)were used to calculate the integrated energy depositedand the results obtained are shown in figure 9.the panel in the top left shows the scattered plot of thesecondaries within the scintillating block. panel (a)represents the energy distribution in the proximalregion. the spread in the energy variation is equivalentto one standard deviation (sd). hence, this variation isattributed to statistical fluctuation. in (b), however, thefluctuation follows a certain pattern that repeats over agiven region, i.e. around the location of the spread outbragg peak (sobp). the repetitive spikes correspond tothe large number of pristine bragg peaks involved to generate the sobp (18 in number). the sobp wasgenerated by a modulator wheel of 18 slices, each with athickness of 0.3 cm stacked together to form a staircase.the secondary dose monitoring fibers as well as thescintillating block located outside of the water phantomwere able to "sense" those pristine bragg peaks,resulting in the formation of the spikes. in (c), which islocated in the distal region of the right block, no suchspikes were observed due to attenuation and smearingin water. such spike patterns were also observed insidethe prostate. the spikes generated, however, were lesspronounced due to a higher contribution of low energysecondaries that are suppressed from reaching theexternal detectors due to attenuation.from figures 9(a, b and c), one notices that the energydeposited gradually decreases as one moves towards thedistal section of the scintillating block. to understandthe distribution of the energy deposited, further analysisof the data was conducted. in this case, the scintillatingblock was virtually dissected into thin slices of thickness3.5 cm each along the beam direction. the energydeposited in each slice was calculated and plotted asshown in figure 10.from the plot, it can be noticed that the energydeposited is higher in the proximal region and decreasestowards the distal region. the peak at the depth ofaround 12 cm shows a turning point, which is inagreement to the plots in figure 9 (a) and (b). beyondthat point, the energy deposited starts decreasing and isclose to zero at depths of around 30 cm and beyond. thisis due to the attenuation of the mainly low energysecondaries that are generated at depths beyond thelocation of the sobp. the result obtained is in closeagreement with those obtained by wroe et al.27, whoused a different setup for their experiment. the reasonattributed for higher energy deposited in the proximalregion is due to the higher production of high energysecondaries, like neutrons and electrons inside the beamline components which are closer to the proximal edgeof the scintillating block. for the distal region, however,the main contribution comes from the secondaryparticles generated inside the water phantom. thesecondaries from the water phantom are produced withcomparatively lower energies. 5. conclusiona geant4 monte carlo simulation was designed tomonitor the total external radiation flux and a possiblecorrelation of the measured flux with the dose deliveredto the prostate. the previous work20 was mainlyfocusing on using thin scintillating fibers attached to awater filled endorectal balloon to monitor the dose tothe rectal wall as well as the prostate. in this work,however, the goal was to develop a dose monitoringsystem based on the radiation flux recorded fromoutside of the water phantom. volume 4 • number 1 • 2016 international journal of cancer therapy and oncology 9 www.ijcto.org © tesfamicael et al. issn 2330-4049 the results obtained were in good agreement to resultsfrom literature review. a linear response of the fibers tothe dose delivered to the prostate was observed, aproperty of the fibers studied by a number ofresearchers. secondary dose monitoring withscintillating fibers could be used to give a relatively goodprediction (with a precision higher than 97%) of thedose to the prostate. the multiple bragg peaks usedduring clinical treatment to generate an sobp could beobserved and monitored to estimate the non-uniformdistribution of the dose within the sobp region. furtherstudies on the biological effect of such dose noneuniformity distribution is planned.the grant allocated for this study was mainly forprostate cancer case. the simulation, however, can bemodified, with little work, to study other cases. in thefuture, there is a plan by the authors to apply the montecarlo simulation developed to investigate the treatmentof other anatomical sites. the authors are also lookingfor a fund for equipment purchase and beam time toconduct experimental measurements based on thesimulation design. the results from the experimentalmeasurements will be compared with the results fromthe simulation. conflict of interestthe authors declare that they have no conflicts ofinterest. the authors alone are responsible for thecontent and writing of the paper. acknowledgementthis work was partly supported by the department ofenergy national security administration under awardnumber de-na0000979. references1. wilson rr. radiological use of fast protons.radiology.1946;47:487-91.2. miller dw. a review of proton beam radiationtherapy. med phys. 1995;22:1943-54.3. hill-kayser ce, both s, tochner z. protontherapy: ever shifting sands and theopportunities and obligations within. frontoncol. 2011;1:24.4. fontenot jd, lee ak, newhauser wd. risk ofsecondary malignant neoplasms from protontherapy and intensity-modulated x-ray therapyfor early-stage prostate cancer. int j radiatoncolbiol phys. 2009;74:616-22.5. levin wp, kooy h, loeffler js, delaneytf.proton beam therapy.br j cancer.2005;93:849-54.6. newhauser wd, giebeler a, zhu r, et al.uncertainty in dose per monitor unit estimatesfor passively scattered proton therapy: the role of compensator and patient scatter in prostatecases. jour proton ther. 2015;1:116.7. rana s, pokharel s, zheng y, et al. treatmentplanning study comparing proton therapy,rapidarc and imrt for a synchronous bilaterallung cancer case. int j cancer ther oncol. 2014;2:020216.8. slater jd. clinical applications of protonradiation treatment at loma linda university:review of a fifteen-year experience. technolcancer res treat. 2006;5:81-9.9. perez-andujar a, newhauser wd, deluca pm.neutron production from beam modifyingdevices in a modern double scattering protontherapy beam delivery system. phys med biol.2009; 54:993-1008.10. zheng y, newhauser w, klein e, low d. montecarlo simulation of the neutron spectral fluenceand dose equivalent for use in shielding aproton therapy vault.phys med biol. 2009;54:6943-57.11. agosteo s, birattari c, caravaggio m, et al.secondary neutron and photon dose in protontherapy. radiotheroncol.1998;48:293-305.12. binns pj, hough jh. secondary dose exposuresduring 200 mev proton therapy. radiat protdosimetry. 1997;70:441-4.13. polf jc, newhauser wd. calculations of neutrondose equivalent exposures fromrange-modulated proton therapy beams. physmed biol. 2005;50:3859-73.14. yan x, titt u, koehler am, newhauser wd.measurement of neutron dose equivalent toproton therapy patients outside of the protonradiation field. nuclinstrum methods phys res.2002;476:429-34.15. schneider u, agosteo s, pedroni e, besserer j.secondary neutron dose during proton therapyusing spot scanning. int j radiat oncol biolphys. 2002;53:244-51.16. murray l, henry a, hoskin p, et al. secondprimary cancers after radiation for prostatecancer: a review of data from planning studies.radiat oncol. 2013;8:172.17. brenner dj, hall ej. secondary neutrons inclinical proton radiotherapy: a charged issue.radiother oncol. 2008;86:165-170.18. stefano a, allison j, amakok, et al. geant4 – asimulation toolkit. nucl instrum methods physres. 2003; 506:250-303.19. allison j, amako k, araujo h, et al. geant4developments and applications. ieee transnucl sci. 2006; 53:270-8.20. tesfamicael by, avery s, gueye p, et al.scintillating fiber based in-vivo dosemonitoring system to the rectum in protontherapy of prostate cancer: a geant4 montecarlo simulation. int j cancer ther oncol. 2014;2:02024. http://dx.doi.org/10.1148/47.5.487 http://dx.doi.org/10.1118/1.597435 http://dx.doi.org/10.3389/fonc.2011.00024 http://dx.doi.org/10.1016/j.ijrobp.2009.01.001 http://dx.doi.org/10.1038/sj.bjc.6602754 http://dx.doi.org/10.14319/jpt.11.6 http://dx.doi.org/10.14319/jpt.11.6 http://dx.doi.org/10.14319/ijcto.0202.16 http://dx.doi.org/10.1177/153303460600500202 http://dx.doi.org/10.1088/0031-9155/54/4/012 http://dx.doi.org/10.1088/0031-9155/54/22/013 http://dx.doi.org/10.1016/s0167-8140(98)00049-8 http://dx.doi.org/10.1093/oxfordjournals.rpd.a031993 http://dx.doi.org/10.1088/0031-9155/50/16/014 http://dx.doi.org/10.1016/s0168-9002(01)01483-8 http://dx.doi.org/10.1016/s0360-3016(01)02826-7 http://dx.doi.org/10.1186/1748-717x-8-172 http://dx.doi.org/10.1016/j.radonc.2007.12.003 http://dx.doi.org/10.1016/s0168-9002(03)01368-8 http://dx.doi.org/10.1109/tns.2006.869826 http://dx.doi.org/10.14319/ijcto.0202.4 10 tesfamicael et al.: secondary dose monitoring system in proton therapy international journal of cancer therapy and oncology www.ijcto.org © tesfamicael et al. issn 2330-4049 21. cirrone gap, cuttone g, di rosa f, et al.validation of geant4 physics models for thesimulation of the proton bragg peak. proc. ieeenucl sci simp. 2006;6:788-92.22. cirrone gap, cuttone g, di rosa f, et al. thegeant4 toolkit capability in the hadron therapyfield: simulation of a transport beam line. nuclphys b proc suppl. 2006;150:54-7.23. cirrone gap, cuttone g, guatelli s, et al.implementation of a new monte carlo-geant4simulation tool for the development of a protontherapy beam line and verification of therelated dose distributions. ieee trans nucl sci.2005;52:262-5. 24. cirrone gap, cuttone g,mazzagliase, et al.hadrontherapy: a geant4 based tool forproton/ion therapy studies. ieee trans nuclsci.2011;2:207-12.25. cirrone gap, cuttone g, di rosa f, et al. montecarlo based implementation of an energymodulation system for proton therapy. ieeenucl sci simp. 2004;4:2133-7.26. available fromhttps://root.cern.ch/drupal/[accessed on1/21/2015]27. wroe a, rosenfeld a, schulte r. out-of-fielddose equivalents delivered by proton therapyof prostate cancer. med phys.2007;34:3449-56. http://dx.doi.org/10.1109/nssmic.2006.355969 http://dx.doi.org/10.1016/j.nuclphysbps.2005.04.061 http://dx.doi.org/10.1109/tns.2004.843140 http://dx.doi.org/10.15669/pnst.2.207 http://dx.doi.org/10.1109/nssmic.2004.1462684 http://dx.doi.org/10.1118/1.2759839 international journal of cancer therapy and oncology www.ijcto.org corresponding author: shyamal patel, md; department of radiation oncology, montefiore medical center, bronx, new york, usa. cite this article as: patel s, mourad wf, patel r, kabarriti r, young r, yaparpalvi r, hong l, lasala p, guha c, kalnicki s, garg mk. the role of preand post-srs systemic therapy in patients with nsclc brain metastases. int j cancer ther oncol 2016; 4(1):413. doi: 10.14319/ijcto.41.3 © patel et al. issn 2330-4049 the role of preand post-srs systemic therapy in patients with nsclc brain metastases shyamal patel1, waleed f mourad1, rajal patel1, rafi kabarriti1, rebekah young1, ravi yaparpalvi1, linda hong1, patrick lasala2, chandan guha1, shalom kalnicki1, madhur k garg1 1department of radiation oncology, montefiore medical center, bronx, new york, usa 2department of neurosurgery, montefiore medical center, bronx, new york, usareceived september 07, 2015; revised november 28, 2015; accepted november 30, 2015; published online december 07, 2015 original article abstract purpose: we report our experience with stereotactic radiosurgery (srs) fornsclc brain metastases. we then assess the prognostic value of preand post-srssystemic therapy (prsst and posst) and evaluate the timing of posst. methods: inthis retrospective study, we analyzed 96 patients with lung cancer and ecog ps ≤ 3who underwent srs during 2007-2013. recorded factors included srs treatmentparameters, systemic status of disease (sds) at time of srs, and the use of prsstand posst. sds was designated as pulmonary disease or extrapulmonary disease.for analysis, the srs-posst interval (spi) was divided into ≤30 days and >30 days.univariate and multivariate analyses were performed. results: 85 patients withnsclc were included in this analysis. 48% received prsst and 48% receivedposst. 57% of patients had pulmonary disease while 40% had extrapulmonarydisease. 46% of patients had synchronous metastases. at a median follow -up of 6months, the median survival was 6.4 months and the actuarial overall survival at 3,6, 12, and 36 months was 80%, 52%, 31%, and 6%. extrapulmonary disease (p =0.008) negatively predicted for survival while the receipt of any systemic therapy(p = 0.050) or posst alone (p = 0.039) positively predicted for survival. in patientsreceiving posst, an spi >30 days positively predicted for survival (hr 0.28, 95% ci0.13-0.62, p = 0.002) regardless of sds. conclusion: our results indicate theprognostic importance of systemic therapy and specifically posst. additionally,delaying the initiation of posst to >30 days seems beneficial. this finding waspotentially influenced by neurotoxicity after srs. further investigation iswarranted to define the optimal spi. keywords: srs and chemotherapy; lung cancer brain metastases; srschemotherapy interval; srs for nsclc brain metastases 1. introductionit is estimated that 170-200,000 new cases of brainmetastases are diagnosed each year in the unitedstates1, and lung cancer remains as the predominantsource accounting for up to 50% of cases. of patientswith lung cancer, at least 19% will develop brainmetastases.2the traditional treatment for brain metastases entailedthe use whole brain radiation therapy (wbrt). patchell et al. demonstrated a survival benefit with the additionof metastectomy prior to wbrt, and subsequently found an improvement in locoregional control with theaddition of wbrt to resection.3,4 with the advent ofnewer radiation technology, the utilization of more focaltherapy – stereotactic radiosurgery (srs) has gainedmore traction in addressing brain metastases. whilerandomized controlled trials have shown that srs canbe used in addition to5 or instead of6,7 wbrt, theaddition of wbrt to srs continues to depend oninstitutional bias and patient selection criteria in anattempt to balance intracranial control withpreservation of cognitive function. http://www.ijcto.org/ http://www.ejourpub.com/ http://dx.doi.org/10.14319/ijcto.41.3 2 patel et al.: srs and systemic therapy in nsclc international journal of cancer therapy and oncology www.ijcto.org © patel et al. issn 2330-4049 the use of systemic therapy (chemotherapy or targetedtherapies) in patients with brain metastases from lungcancer has also been examined.8,13 while theeffectiveness of systemic therapy in patients with brainmetastases has been questioned, some studies havedemonstrated an intracranial response after systemicagents in patients with or without wbrt.14,16 in patientswith metastatic disease, the goal of treatment is not onlyto treat localized areas of disease but also to targetdistant disease and prevent further dissemination ofdisease, which has typically been accomplished withsystemic agents. as oncologists have not typicallyespoused the concurrent treatment of patients withbrain radiation and systemic therapy due to thepotential for neurotoxicity, the delivery of srs ratherthan wbrt in selected patients has been favored as itsubsequently allows the quicker initiation orresumption of systemic therapy.there is, however, no report in the literature examiningthe timing of post-srs systemic therapy (posst). whilethe importance of systemic therapy in managingmetastatic patients is clear, the evaluation of thesignificance of systemic therapy before (pre-srssystemic therapy, prsst) and after srs (posst) and theidentification of an optimal time interval between srsand posst may result in improved outcomes. thus, thepurpose of our study is not only to report ourinstitutional experience, but also to assess the role ofsystemic therapy before and after srs, and to evaluatethe prognostic value of its timing after srs. 2. methods and materialswe reviewed our institutional database for patientsundergoing srs for brain metastases between 2007 and2013 and found 241 consecutively treated patients. ofthese, 96 patients had primary lung cancer with 1-4brain metastases; 6 patients with small cell lung cancerand 5 patients who expired ≤30 days after srs wereexcluded leaving 85 patients with nsclc for analysis inthis study. all patients had ecog ps ≤3 and were treatedwith a linear accelerator (linac) utilizing the brainlabsystem (brainlab inc, munich, germany).all procedures followed were in accordance with theethical standards of the responsible committee onhuman experimentation (institutional and national) andwith the helsinki declaration of 1975, as revised in2008. the risks, benefits, and logistics of srs werediscussed with all patients after which informed consentfor srs was obtained by the radiation oncology team.the prescription dose was based on the target volume,any history of prior irradiation, and the proximity ofcritical organs at risk. the treatment plans werenormalized so that the minimum tumor dose was theprescription dose. in most cases plans were optimized such that >99.5% of the tumor volume received >99.5%of the prescription dose. patients were generally seen 1month after srs and then 1-3 months thereafter.follow-up information was obtained from the electronicmedical record (emr) or by contacting the patient’sfamily in cases where patients were lost to follow-up.for analysis, clinical factors were recorded includingecog performance status (ps), whether the patientunderwent metastectomy or wbrt prior to srs, thehistologic diagnosis, the systemic status of disease (sds)at time of srs, and the use and duration of preandpost-srs systemic therapy (prsst and posst). prsstincluded any systemic therapy given to the patient priorto srs regardless of whether the patient had only localor distant disease. the sds was designated as eitherpulmonary disease (one or both lungs with adjacentnodal involvement) or distant extrapulmonary disease.srs treatment-related factors were also recorded andincluded number of lesions, target volume size, andprescription dose. dates of primary diagnosis, first cnsdisease, and posst initiation were recorded as well.all statistical tests were performed utilizing spss v21.0(spss inc., chicago, il) with a level of significance at p =0.05. actuarial survival analysis was performed.univariate analysis of the aforementioned variables wasperformed using log-rank and regression tests. variablesthat were found to be significant were then entered intoa multivariate survival analysis utilizing the coxproportional hazards model. subsequently, subsetanalysis of patients with synchronous metastases(diagnosed ≤2 months from primary diagnosis) wasperformed. 3. resultspatient demographics and treatment characteristics areshown in table 1; a total of 85 patients were included inthis study. prsst and posst were given at the discretionof the medical oncologist. before srs, 41 patientsreceived prsst of which 21 patients had recordsaccessible to us with documentation of the agentsutilized. of these, 15 received chemotherapy alone, 1received targeted therapy alone, and 5 received both.after srs, 41 patients received posst. thirty-threepatients received chemotherapy alone, 1 patientreceived targeted therapy alone, and 7 patients receivedboth. eighteen patients received both prsst and posst,while 64 received either. chemotherapy consisted of anumber of different agents given in differentcombinations and included carboplatin, paclitaxel,pemetrexed, cisplatin, etoposide, and gemcitabine.targeted agents included erlotinib and bevacizumab. ofthe 20 patients with known and available egfr status,only 1 was positive for the mutation. volume 4 • number 1 • 2016 international journal of cancer therapy and oncology 3 www.ijcto.org © patel et al. issn 2330-4049 table 1: patient demographics and treatment characteristicsno. patients 85age, median 65 years (41-85)gendermalefemale 47 pts (55%)38 pts (45%)racewhiteblackhispanicasianmissing 31 pts (37%)27 pts (32%)23 pts (27%)3 pts (4%)1 pt (1%)ecog performance status0123missing 35 pts (41%)16 pts (19%)5 pts (6%)5 pts (6%)24 (28%)histologyadenocarcinomasquamous cell carcinomapoorly differentiatedother 56 pts (66%)11 pts (13%)14 pts (17%)4 pts (5%)prior to srsmetastectomywbrtboth 22 pts (26%)9 pts (11%)4 pts (5%)srs parametersno. lesions12345target volume, mediantarget volume, interquartile rangeprescription dose, median 13547 pts (55%)30 pts (35%)5 pts (6%)2 pts (2%)1 pt (1%)1.6 cc (0.1-21.8)0.5-4.8 cc21 gy (12-25)systemic status of disease (sds) at srspulmonaryextrapulmonarynot specified 48 pts (57%)34 pts (40%)3 pts (4%)primary to cns disease diagnosis interval, median 2 months (0-88)pre-srs systemic therapy (prsst)receivedduration, median 41 pts (48%)5 months (1-60)post-srs systemic therapy (posst)receivedduration, median 41 pts (48%)2 months (1-19)prsst and posstreceived 18 pts (21%)srs to posst interval (spi) in pts receiving posstspi, medianspi, interquartile rangespi ≤ 30 daysspi > 30 days 32 days (1-252)19-59 days19 pts (45%)23 pts (55%) 4 patel et al.: srs and systemic therapy in nsclc international journal of cancer therapy and oncology www.ijcto.org © patel et al. issn 2330-4049 figure 1: actuarial survival for all patients figure 2: kaplan meier survival curve comparing systemicstatus of disease (extrapulmonary vs. pulmonary) figure 3: kaplan meier survival curve comparing the srs topost-srs systemic therapy interval (spi) at a median follow-up of 6 months (1-59), the mediansurvival (ms) was 6.4 months. figure 1 shows theactuarial survival for the cohort. the actuarial overallsurvival (os) at 3, 6, 12, and 36 months was 80%, 52%,31%, and 6%, respectively. the median time intervalbetween srs and posst initiation (spi) was 32 days. forfurther analysis, the spi was divided into ≤30 days and>30 days. table 2 shows significant predictors for survival basedon univariate analysis. age (p = 0.092), race (p = 0.862),histology (p = 0.180), and metastectomy (p = 0.878) orwbrt (p = 0.520) prior to srs were not significant. srstreatment factors including number of lesions (p =0.738), target volume (p = 0.160), and prescription dose(p = 0.150) were not significant. the primary-to-cnsdisease interval (p = 0.893) and the receipt of prsst (p =0.490) were not significant. receipt of both prsst andposst was not significant.significant clinical predictors by multivariate analysisare shown in table 3. ecog ps was not entered into thisanalysis due to the lack of data in approximately 1/3 ofpatients. the use of any systemic therapy (prsst orposst) as well as the use of posst wereremoved fromthis analysis because of the linear dependence of spi onposst. extrapulmonary disease was found to negativelypredict for survival while an spi >30 days was found topositively predict for survival. figures 2 and 3 showkaplan meier survival curves comparing sds and thespi, respectively.given that the ecog ps, sds, and receipt of prsst couldpotentially influence the significance of the spi, log-ranktests were performed comparing spi after stratifying byeach of these factors. this revealed that spi >30 dayswas prognostic in patients with ecog ps = 0 (p = 0.003)and regardless of sds (p = 0.00049). spi >30 daysremained significant in both patients who receivedprsst (p = 0.024) and in those who had not receivedprsst (p = 0.003).thirty-nine (46%) patients were found to havesynchronous brain metastases (diagnosed atpresentation or ≤2 months of primary diagnosis).analysis of these patients revealed that sds did notsignificantly predict for survival by log-rank test (p =0.841). even after further stratifying sds intounilateral lung, bilateral lung, and extrapulmonarydisease, sds remained nonsignificant (p = 0.923). thereceipt of posst continued to be prognostic (p = 0.020),and an spi >30 days also continued to predict forimproved survival (p = 0.001). volume 4 • number 1 • 2016 international journal of cancer therapy and oncology 5 www.ijcto.org © patel et al. issn 2330-4049 table 2: significant predictors for survival based on univariate analysis by log-rank test clinical predictor number of patients, n = 96 median survival (months), 95% confidence interval p-valueecog performance status0123missing 35 (41%)16 (19%)5 (6%)5 (6%)24 (28%) 9, 2.4-15.63, 2.4-3.63, 0.9-5.15, 0-13.6 0.029 systemic status of disease (sds) at srsextrapulmonary distantpulmonary 34 (40%)58 (57%) 4, 1.6-6.48, 3.8-12.2 0.008 any systemic therapynoyes 21 (25%)64 (75%) 3, 1.9-4.16, 4.0-8.0 0.050post-srs systemic therapy (posst)noyes 41 (48%)41 (48%) 3, 1.9-4.19, 4.8-13.2 0.039srs to posst interval (spi) in ptsreceiving posst, n = 42≤30 days>30 days 19 (45%)23 (55%) 5, 2.9-7.113, 8.5-17.5 0.00019 table 3: multivariate analysis of clinical predictors for survival by cox regression in patients who received post -srssystemic therapy clinical predictor hr, 95% confidence interval p-valuesystemic status of disease (sds) 2.13, 1.05-4.32 0.036srs to psst interval (spi) 0.28, 0.13-0.62 0.002 4. discussionstudies examining outcomes after srs for brainmetastases from lung cancer primaries have revealedms times ranging from 3-15 months17,25 depending onvarying prognostic factors. we found a ms of 6.4 monthsin our cohort, which is on the lower end of the survivalspectrum found in the literature. however, our inclusioncriteria were broader than those in a number of thesestudies, and included patients with varying performancestatuses and various resection statuses for the lesion ofinterest.in patients with multiple metachronous brainmetastases from nsclc treated with srs, retrospectivereviews have found median survivals of 7-11months.17,18,21,23,24,26 diluna et al. found a significantsurvival difference in patients treated with srs for 1-3brain metastases versus those with ≥4; however, ourstudy, along with those performed by likhacheva et al.,jezierska et al., and smith et al. found no difference insurvival based on number of intracranial lesions.24,27additionally, intracranial lesion size did not impactsurvival in our study but was found to be significant inother studies.17, 26 performance status has also been utilized to predictsurvival in patients with brain metastases treated withsrs. while li et al. did not find karnofsky performancestatus (kps) to predict survival, a number of otherstudies have.19,23,24,26,28 in the patients for which we hadecog ps available, we found better ps to be prognostic.we also found limited extracranial disease at srs to besignificantly associated with improved survival, and thiswas similarly noted in other retrospectivereviews.17,21,24,26,27 this makes sense as patients withdistant diffuse disease would be expected to succumb totheir illness faster than those with better systemiccontrol.in addition to reporting our institutional experience, thefocus of this paper is to explore the significance of pre -and post-srs systemic therapy (prsst and posst).furthermore, we wish to discuss our interesting findingsconcerning the timing of posst initiation. as the goal ofmetastatic disease treatment in patients with good psremains administration of systemic agents, there hasbeen a shift in recent years to deliver srs rather thanwbrt in selected patients thereby allowing the quickeradministration of systemic therapy after addressingintracranial disease. 6 patel et al.: srs and systemic therapy in nsclc international journal of cancer therapy and oncology www.ijcto.org © patel et al. issn 2330-4049 chemotherapy traditionally played a limited role in thetreatment of brain metastases as the integrity of theblood-brain-barrier was thought to limit delivery ofdrugs to the site of brain metastases.8,29 however, thetumor-specific enhancing properties of agents used inct and mr suggest that the bbb may not be completelyintact in patients with established brain metastases. inpatients who have not been heavily pretreated withchemotherapy, the responses of brain metastasesgenerally have been similar to extracranially locatedtumors of like histology.9,29 phase ii trials havedemonstrated that temozolomide, topotecan, andpaclitaxel with wbrt elicit some intracranial response.first-line combination chemotherapy consisting ofpaclitaxel/cisplatin and gemcitabine/vinorelbine/carboplatin in patients with brain metastases fromnsclc have yielded intracranial responses similar toextracranial responses suggesting the utility of systemictherapy.30,31 other radiosensitizing agents such asgefitinib, motexafin gadolinium, efaproxiral, andbromodeoxyuridine have also been studied with apotential improvement in local control.8,13 theanti-angiogenic agent bevacizumab is the first targetedagent that demonstrated superior efficacy overchemotherapy alone as first-line treatment of advancednon-squamous nsclc patients.9,11while there have been a number of prospective trialsexamining the impact of systemic therapy incombination with wbrt12, there is limited data availableon the use of systemic therapy after srs despite itswidespread use in the last decade. diluna et al.reviewed 334 patients with intracranial disease fromnsclc, breast cancer, and melanoma who underwentsrs as initial therapy.27 in the subgroup of patients with≥4 brain metastases, receipt of chemotherapy wasassociated with decreased survival but did not reachstatistical significance (p = 0.077).in a phase iii trial, sperduto et al. compared wbrt andsrs alone to wbrt and srs with temozolomide orerlotinib for nsclc and 1-3 brain metastases.10 the mstimes between the arms were not significantly different.time to cns progression and ps at 6 months was betterin the wbrt and srs arm, and grade 3-5 toxicity wassignificantly worse in the temozolomide and erlotinibarms (p < 0.001). they concluded that the addition oftemozolomide or erlotinib to wbrt and srs did notimprove survival and possibly had a deleterious effect.in our study, receipt of any systemic therapy (prsst orposst) and the receipt of posst alone were prognostic.conversely, receipt of prsst alone or both prsst andposst were not significant leading us to conclude that itwas the posst that contributed more to improvedsurvival vs. the prsst. as patients who died within 30days after srs may have not received systemic therapydue to deteriorating ps, we did not include them inorder to prevent them from confounding our analysis ofthe value of posst and its timing. multivariate analysis showed the absence of extrapulmonary disease and ansrs-to-posst interval (spi) >30 days to significantlyimprove survival. the latter is a new and interestingfinding as conventional thinking has suggested initiationor resumption of systemic therapy as soon as possibleafter srs in order to prevent systemic diseaseprogression. srs has also been favored in certain casesover intracranial resection because of the ability toresume systemic therapy more rapidly after radiationversus surgery.32 we initially thought that ecog ps mayimpact this finding as patients with better ps may dobetter regardless of spi; however spi >30 days remainedsignificant even when controlling for ps. receipt ofprsst may have also impacted the significance of an spi>30 days given that a)patients who had already receivedprsst immediately prior to srs may have been delayedin their initiation of posst as they already had systemictherapy onboard or b)patients who had received prsstmay have been escalated to 2nd or 3rd line treatmentsthus indicating an already worse prognosis. however, anspi >30 days predicted for improved survival in bothpatients who had received prsst and those who had not.lastly, the extent of distant disease may have alsoimpacted the significance of an spi >30 days, as moreadvanced systemic disease would likely require quickerinitiation of systemic therapy after srs. however, ourfindings remained even after stratifying patients by sds.this seems to suggest that the rapid initiation ofchemotherapy after srs could be detrimental, possiblydue to an increase in neurological complications.while a number of phase i/ii trials were conducted toevaluate the safety and efficacy of srs prior to itsadoption as a treatment standard for 1-3 brainmetastases in certain patients, limited data existscomparing the safety and efficacy of srs with or withoutsystemic therapy, and no data was found in theliterature regarding the optimal timing of systemictherapy after srs. sperduto et al. demonstrated anincrease in grade 3-5 toxicity in the drug arms but wasunderpowered to prove that these toxicities led to adecrease in survival.10we also sought to determine whether epidermal growthfactor receptor (egfr) status impacted outcome giventhat egfr inhibitors have been found to have anintracranial response.33 to do this, we utilized the egfrstatus of the primary lesion which has been shown to bea good surrogate for the egfr status of the brainmetastasis.34 however, only 20 patients in our cohorthad this information determined and available and onlyone of these patients had the mutation preventing anymeaningful analysis.patients with synchronous intracranial metastases fromnsclc are also thought to represent a uniquepopulation, and there is evidence supporting aggressivelocal and systemic therapy for these patients.35,38 in ourstudy, the subset of patients with synchronousmetastases benefited from the addition of systemictherapy after srs. again, interestingly, these patients volume 4 • number 1 • 2016 international journal of cancer therapy and oncology 7 www.ijcto.org © patel et al. issn 2330-4049 also seemed to benefit from delaying systemic therapyto >30 days after srs. prospective studies would need tobe conducted in order to evaluate the optimal timing ofposst initiation in all patients with nsclc brainmetastases.a strength of this study is the large cohort of patientswith primary nsclc with brain metastases treated at asingle institution by designated radiation oncology andneurosurgical teams over a period of six years. whilethere are a number of studies which have reported theirexperience with srs, our work represents the firstradiosurgery study to evaluate the prognostic value ofthe timing of posst initiation. limitations of this studyinclude those inherent to the retrospective nature of thisreview as well as the somewhat heterogeneous cohort ofpatients included in this study in regards to systemictherapy – various regimens were used at various timepoints and for different reasons depending on themedical oncologist. additionally, we only had psdocumented for approximately 2/3 of our patients inthis study via our emr. a full dataset would haveallowed better and more complete analysis of ourfindings. also, due to follow-up data on a number ofpatients being obtained from the hospital emr,neurologic toxicities from radiation therapy were notconsistently and accurately documented preventingsignificant analysis of adverse late effects ofradiosurgery and posst. this also prevented ameaningful comparison in neurologic toxicities inregards to spi. 5. conclusionthis study shows that the use of systemic therapy beforeand after srs is beneficial in patients with nsclc brainmetastases. our results also suggest that delaying theinitiation of systemic therapy after srs to >30 days maypotentially improve survival, even in patients withsynchronous metastases. this finding may havepotentially been influenced by neurotoxicity after srs.as there is a paucity of evidence regarding the timing ofsystemic therapy after srs, further investigation iswarranted to define the optimal srs-posst interval. conflict of interestthe authors declare that they have no conflicts ofinterest. the authors alone are responsible for thecontent and writing of the paper. references 2. davis fg, dolecek ta, mccarthy bj, et al.toward determining the lifetime occurrence ofmetastatic brain tumors estimated from 2007 united states cancer incidence data. neurooncol 2012;14:1171-7.3. patchell ra, tibbs pa, regine wf, et al.postoperative radiotherapy in the treatment ofsingle metastases to the brain: a randomizedtrial. jama 1998; 280:1485-9.4. patchell ra, tibbs pa, walsh jw, et al. arandomized trial of surgery in the treatment ofsingle metastases to the brain. n engl j med1990;322:494-500.5. andrews dw, scott cb, sperduto pw, et al.whole brain radiation therapy with or withoutstereotactic radiosurgery boost for patientswith one to three brain metastases: phase iiiresults of the rtog 9508 randomised trial.lancet 2004;363:1665-72.6. chang el, wefel js, hess kr, et al.neurocognition in patients with brainmetastases treated with radiosurgery orradiosurgery plus whole-brain irradiation: arandomised controlled trial. lancet oncol2009;10:1037-44.7. tsao m, xu w, sahgal a. a meta-analysisevaluating stereotactic radiosurgery,whole-brain radiotherapy, or both for patientspresenting with a limited number of brainmetastases. cancer 2012;118:2486-93.8. langer cj, mehta mp. current management ofbrain metastases, with a focus on systemicoptions. j clin oncol 2005;23:6207-19.9. walbert t, gilbert mr. the role ofchemotherapy in the treatment of patients withbrain metastases from solid tumors. int j clinoncol 2009;14:299-306.10. sperduto pw, wang m, robins hi, et al. a phase3 trial of whole brain radiation therapy andstereotactic radiosurgery alone versus wbrtand srs with temozolomide or erlotinib fornon-small cell lung cancer and 1 to 3 brainmetastases: radiation therapy oncology group0320. int j radiat oncol biol phys2013;85:1312-18.11. lombardi g, di stefano al, farina p, et al.systemic treatments for brain metastases frombreast cancer, non-small cell lung cancer,melanoma and renal cell carcinoma: anoverview of the literature. cancer treat rev2014;40(8):951-9.12. zimmermann s, dziadziuszko r, peters s.indications and limitations of chemotherapyand targeted agents in non-small cell lungcancer brain metastases. cancer treat rev2014;40:716-22.13. dawe de, greenspoon jn, ellis pm. brainmetastases in non-small-cell lung cancer. clinlung cancer 2014;15:249-57.14. fidler ij. the biology of brain metastasis:challenges for therapy. cancer j2015;21:284-93. 1. palmieri d. central nervous system metastasis,the biological basis and clinical considerations.new york: springer; 2012. http://dx.doi.org/10.1007/978-94-007-5291-7 http://dx.doi.org/10.1093/neuonc/nos152 http://dx.doi.org/10.1093/neuonc/nos152 http://dx.doi.org/10.1001/jama.280.17.1485 http://dx.doi.org/10.1056/nejm199002223220802 http://dx.doi.org/10.1016/s0140-6736(04)16250-8 http://dx.doi.org/10.1016/s1470-2045(09)70263-3 http://dx.doi.org/10.1002/cncr.26515 http://dx.doi.org/10.1200/jco.2005.03.145 http://dx.doi.org/10.1007/s10147-009-0916-1 http://dx.doi.org/10.1016/j.ijrobp.2012.11.042 http://dx.doi.org/10.1016/j.ctrv.2014.05.007 http://dx.doi.org/10.1016/j.ctrv.2014.03.005 http://dx.doi.org/10.1016/j.cllc.2014.04.008 http://dx.doi.org/10.1097/ppo.0000000000000126 8 patel et al.: srs and systemic therapy in nsclc international journal of cancer therapy and oncology www.ijcto.org © patel et al. issn 2330-4049 15. hu j, kesari s. strategies for overcoming theblood-brain barrier for the treatment of brainmetastases. cns oncol 2013;2:87-98.16. puhalla s, elmquist w, freyer d, et al.unsanctifying the sanctuary: challenges andopportunities with brain metastases. neurooncol 2015;17:639-51.17. kim ys, kondziolka d, flickinger jc, et al.stereotactic radiosurgery for patients withnonsmall cell lung carcinoma metastatic to thebrain. cancer 1997;80:2075-83.18. williams j, enger c, wharam m, et al.stereotactic radiosurgery for brain metastases:comparison of lung carcinoma vs. non-lungtumors. j neurooncol 1998;37:79-85.19. li b, yu j, suntharalingam m, et al. comparisonof three treatment options for single brainmetastasis from lung cancer. int j cancer2000;90:37-45.20. serizawa t, ono j, iichi t, et al. gamma kniferadiosurgery for metastatic brain tumors fromlung cancer: a comparison between small celland non-small cell carcinoma. j neurosurg2002;97:484-88.21. zabel a, milker-zabel s, thilmann c, et al.treatment of brain metastases in patients withnon-small cell lung cancer (nsclc) bystereotactic linac-based radiosurgery:prognostic factors. lung cancer 2002;37:87-94.22. noel g, medioni j, valery ca, et al. threeirradiation treatment options includingradiosurgery for brain metastases fromprimary lung cancer. lung cancer2003;41:333-43.23. kress ma, oermann e, ewend mg, et al.stereotactic radiosurgery for single brainmetastases from non-small cell lung cancer:progression of extracranial disease correlateswith distant intracranial failure. radiat oncol2013;8:64.24. jezierska d, adamska k, liebert w. evaluationof results of linac-based radiosurgery for brainmetastases from primary lung cancer. reppract oncol radiother 2014;19:19-29.25. smith tr, lall rr, lall rr, et al. survival aftersurgery and stereotactic radiosurgery forpatients with multiple intracranial metastases:results of a single-center retrospective study. jneurosurg 2014:1-7.26. likhacheva a, pinnix cc, parikh nr, et al.predictors of survival in contemporary practiceafter initial radiosurgery for brain metastases.int j radiat oncol biol phys 2013;85:656-61.27. diluna ml, king jt, jr., knisely jp, et al.prognostic factors for survival after stereotacticradiosurgery vary with the number of cerebralmetastases. cancer 2007;109:135-45.28. yomo s, hayashi m. upfront stereotacticradiosurgery in patients with brain metastases from small cell lung cancer: retrospectiveanalysis of 41 patients. radiat oncol2014;9:152.29. davey p. brain metastases: treatment optionsto improve outcomes. cns drugs2002;16:325-38.30. bernardo g, cuzzoni q, strada mr, et al.first-line chemotherapy with vinorelbine,gemcitabine, and carboplatin in the treatmentof brain metastases from non-small-cell lungcancer: a phase ii study. cancer invest2002;20:293-302.31. cortes j, rodriguez j, aramendia jm, et al.front-line paclitaxel/cisplatin-basedchemotherapy in brain metastases fromnon-small-cell lung cancer. oncology2003;64:28-35.32. lippitz b, lindquist c, paddick i, et al.stereotactic radiosurgery in the treatment ofbrain metastases: the current evidence. cancertreat rev 2014;40:48-59.33. luo d, ye x, hu z, et al. egfr mutation status andits impact on survival of chinese non-small celllung cancer patients with brain metastases.tumour biol 2014;35:2437-44.34. jamal-hanjani m, spicer j. epidermal growthfactor receptor tyrosine kinase inhibitors in thetreatment of epidermal growth factorreceptor-mutant non-small cell lung cancermetastatic to the brain. clin cancer res2012;18:938-44.35. arrieta o, villarreal-garza c, zamora j, et al.long-term survival in patients with non-smallcell lung cancer and synchronous brainmetastasis treated with whole-brainradiotherapy and thoracic chemoradiation.radiat oncol 2011;6:166.36. funai k, suzuki k, sekihara k, et al. five-yeartumor-free survival after aggressive trimodalitytherapy for t3n0m1b non-small cell lung cancerwith synchronous solitary brain metastasis.gen thorac cardiovasc surg 2012;60:370-2.37. gray pj, mak rh, yeap by, et al. aggressivetherapy for patients with non-small cell lungcarcinoma and synchronous brain-onlyoligometastatic disease is associated withlong-term survival. lung cancer2014;85:239-44.38. griffioen gh, toguri d, dahele m, et al. radicaltreatment of synchronous oligometastaticnon-small cell lung carcinoma (nsclc): patientoutcomes and prognostic factors. lung cancer2013;82:95-102. http://dx.doi.org/10.2217/cns.12.37 http://dx.doi.org/10.1093/neuonc/nov023 http://dx.doi.org/10.1002/(sici)1097-0142(19971201)80:11%3c2075::aid-cncr6%3e3.0.co;2-w http://dx.doi.org/10.1023/a:1005958215384 http://dx.doi.org/10.1002/(sici)1097-0215(20000220)90:1%3c37::aid-ijc5%3e3.0.co;2-7 http://www.ncbi.nlm.nih.gov/pubmed/12507082 http://dx.doi.org/10.1016/s0169-5002(02)00030-2 http://dx.doi.org/10.1016/s0169-5002(03)00236-8 http://dx.doi.org/10.1186/1748-717x-8-64 http://dx.doi.org/10.1016/j.rpor.2013.06.006 http://dx.doi.org/10.3171/2014.4.jns13789 http://dx.doi.org/10.1016/j.ijrobp.2012.05.047 http://dx.doi.org/10.1002/cncr.22367 http://dx.doi.org/10.1186/1748-717x-9-152 http://dx.doi.org/10.1186/1748-717x-9-152 http://dx.doi.org/10.2165/00023210-200216050-00005 http://dx.doi.org/10.1081/cnv-120001173 http://dx.doi.org/10.1159/000066520 http://dx.doi.org/10.1016/j.ctrv.2013.05.002 http://dx.doi.org/10.1007/s13277-013-1323-9 http://dx.doi.org/10.1158/1078-0432.ccr-11-2529 http://dx.doi.org/10.1186/1748-717x-6-166 http://dx.doi.org/10.1007/s11748-012-0007-5 http://dx.doi.org/10.1016/j.lungcan.2014.06.001 http://dx.doi.org/10.1016/j.lungcan.2013.07.023 database connection failed! international journal of cancer therapy and oncology www.ijcto.org corresponding author: getachew dagne; department of epidemiology and biostatistics, university of south florida, tampa, usa. cite this article as: dagne g, odedina f, aime n, young m. area-level factors associated with spatial variation of prostate cancer incidence for black men.. 2017; 5(1):5123. doi: 10.14319/ijcto.51.23 © dagne et al. issn 2330-4049 area-level factors associated with spatial variation of prostate cancer incidence for black men getachew dagne1, folakemi odedina2, nickyjeanna aime3, mary ellen young4 1department of epidemiology and biostatistics, university of south florida, tampa, usa 2department of pharmacotherapy & translational research, university of florida research and academic center, orlando, usa 3department of radiation oncology, florida a&m university, tallahassee, usa 4department of occupational therapy, university of florida, gainesville, usareceived august 23, 2017; revised december 17, 2017; accepted december 20, 2017; published online december 24, 2017 original article abstract purpose: black men are disproportionately affected by prostate cancer (cap)compared to any other racial/ethnic groups within the united states. identifyingcap hotspots along with associated local area-level risk factors is crucial to tacklingthe significant burden of cap and the disparity seen in black men. the objective ofthis study was to determine the scope of geographical variation in cap incidencesand to assess the degree to which this variation is associated with county -level riskand protective factors. methods: the study population was black men diagnosedwith prostate cancer between 2006-2010 in florida. county-level cap incidencerates were computed as the ratios of the numbers of new cap cases diagnosedbetween 2006 and 2010 to the corresponding 2000 us census population of blackmen 20 and over years old data (us census 2000). other county-levelenvironmental and health care factors were also obtained. a random effectspoisson model and geographical information system (gis) were used to map andassess the spatial patterns of cap incidences in 67 florida counties. thesestatistical techniques involved a bayesian approach for estimating the underlyingcounty-specific cap risk since the data are very sparse. results: the findingsshowed that an increasing cap incidence of black men in florida was significantlyassociated with an increasing unemployment rate ( 2 = .1379 with 95% ci:(.0025, .2703), does not include zero suggesting significance) and with increasingnumber of physicians per capita after controlling for other county characteristics.there was a negative association between poverty and cap incidence. regardingspatial distribution of cap incidence, we observed that there are clustering andhotspots of high cap incidence rates in palm beach county in south florida, andalachua and marion counties in north florida. conclusion: our findings showedthat indicators of socioeconomic status and accessibility of health care servicessuch as poverty, unemployment and health care providers are important variable sthat explain spatial variation of prostate cancer incidence rates of black men.better understanding of such risk factors and identifying specific counties with adisproportionate burden of cap disease may help formulate targeted interventionsand resource allocation by state and local public officials. keywords: bayesian inference, health disparity, prostate cancer, poisson model. 1. introductionprostate cancer (cap) is one of the most commoncancers experienced by men in the united states (us),and the second leading cause of cancer-related deaths.1black men are disproportionately affected by capcompared to any other racial/ethnic groups in the us.compared to us white men, black men are about twotimes more likely to develop cap and die from the disease.1 although the causes for these disparities arenot yet completely known, genetic heritage, variation inlife styles, health care availability, environmental riskfactors have been suggested as plausible explanations.2-8to examine the influence of environmental risk factorson cap incidence in a geographic context, the studyobjectives were: (1) to estimate the association between 2 dagne et al.: spatial variation of prostate cancer incidence international journal of cancer therapy and oncology www.ijcto.org © dagne et al. issn 2330-4049 county-specific relative risk for prostate cancer andcounty-level characteristics such as socio-economicstatus, health care access, poverty, unemployment andwater supply, and (2) to develop spatial mapping of capincidence for black men in florida.although some studies have examined the relationshipbetween environmental factors and cancer incidencespatial variations9-14, there is limited publications on thespatial pattern variations of cap incidence in floridablack men. knowledge of the spatial distribution of capincidence has significant public health implication. forexample, the cap burden can be mitigated throughidentifying major health determinants, and allocatingproper public health resources and policies at the locallevel. for this study, we examined the associationbetween spatial variations in cap incidence and thefollowing county-level environmental and health carefactors: availability of physicians, body weight,environmental exposures, demographic indicators andsocio-economic indicators.15 specifically, determiningthe role of spatial, environmental, and socio-economicheterogeneity in prostate cancer disparities provides abasis for developing public health interventions that willprevent and control prostate cancer in affectedcommunities.in this paper, we used bayesian spatial models todescribe the spatial pattern of cap incidence for blackmen in florida's 67 counties. in addition, we assessedthe contribution of socioeconomic, environmental, andhealth care availability in explaining area-levelvariations. 2. methods and materials 2.1. study setting and sources of datathe study setting was florida and the targetedpopulation was all black men diagnosed with capbetween 2006 and 2010. county-level cap cases wereobtained from the florida cancer data system (fcds)database which is florida's legislatively mandated,population-based, statewide cancer registry.16county-level cap incidence rates are computed as theratios of the numbers of new cap cases diagnosedbetween 2006 and 2010 to the corresponding 2000 uscensus population of black men 20 and over years olddata (us census 2000). the 2000 us census is chosen sothat presumed exposures occurred before cap diagnosisin 2006-2010, the study period. the countycharacteristics that may be associated with capincidence were identified from the florida departmentof health division of public health statistics &performance management (see table 1). some of thesecharacteristics are socio-economic indicators (e.g.percentage of unemployed adults, high schoolgraduation), demographic indicators (e.g. percentage ofindividuals with rural residence), health care resources(e.g. licensed florida physicians; adults who could notsee a doctor at least once in the past year due to cost),environment indicator (e.g. community water supply).we used the most representative data available for thesecounty-level characteristics for the period of 2006-2010. table 1: description statistics of county-level characteristicscharacteristics mean sd min maxprostate cancer cases 163.6 347.512 1.0 1963.0unemployed for yr. 2008 (%) 6.209 1.332 4.000 10.20median income for yr. 2009 43960 7554.062 29640 63630number of physicians for yr. 2008 (per 100,000)high school graduate for yr. 2009 (%)below poverty level for yr. 2009 (%)two or more servings of fruit for yr. 2007 (%)current smoker for yr. 2007 (%)medical checkup for yr. 2007 (%)overweight for yr. 2010 (%)community water supply rate for yr. 2010black population for yr. 2010 (%)not seek medical due to cost for yr. 2007 (%)rural resident for yr. 2010 (%) 139.780.5815.4832.4922.2366.8766.892.189014.5915.2442.02 98.3618.0554.8615.6104.7757.0255.7230.90869.3466.03733.762 12.658.607.4018.5014.2047.3054.300.51683.106.200.10 615.296.5026.4046.1033.6079.8082.005.30555.2043.30100.00 volume 5• number 1 • 2017 international journal of cancer therapy and oncology 3 www.ijcto.org © dagne et al. issn 2330-4049 2.2. statistical methodswe considered a geographical region divided into gcontiguous small areas (e.g., counties) represented as=1,…, . let denote observed counts of diseasecases (e.g., prostate cancer) and a q-dimensional vectorcontains county-level covariates with associatedparameters . we assumed that follows a poissondistribution with mean satisfyinglog( )= log( )+ log( ) (1)where is the expected number of cases in the ithcounty, and calculated as = (∑∑ ); is numberof individuals at risk of prostate cancer; and is anunknown county-specific relative risk of prostate cancerand further decomposed aslog( )= + + (2)in model (2), the county-specific random effects, =+ , was further decomposed into an unstructuredheterogeneity and a spatially structured localrandom effects to account for the tendency ofneighboring counties to have similar relative risksbecause of sharing common risk factors.17specifically, for the florida prostate cancer cases forblack men, the log of the relative risk was modeled as    1 2 3 4 5 6 7 8 9 10 log log         i i i i i i i i i i income unemploy poverty overweight smoker watersupply prcntblack medicalcheckup fruitconsumption edu                        11 12                 (3)                    i i i i i cation physician rural u v       the covariates in (3) were defined in section 2.1 andtable 1. the above random-effect poisson regression modelswere used to produce smoothed spatial maps of capincidence rates by incorporating the associationsbetween incidence and county-level covariates. therelative risk in each county was estimated using abayesian approach based on markov chain monte carlo(mcmc) methods which were implemented in winbugssoftware.18 winbugs has a built-in conditionalautoregressive (car) distribution for handling spatialautocorrelation. non-informative prior distributionswere used for the unknown parameters of (3), andsensitivity analyses with different prior specifications were conducted to assess the effect of choices of vaguepriors. 3. resultsbased on the fcds, a total of 10,799 black men werediagnosed with prostate cancer between 2006 and 2010in florida. the map in figure 1 shows the number ofprostate cancer cases per county, with the lowest indixie county and highest in miami-dade and browardcounties. there is a strong variation in geographicaldistributions of these cap cases. the variation may bedue to some counties having low cases, sparse sizes ofpopulation of adult black men, or both. to incorporatethe variation in population sizes across counties, wecalculated the expected number of cap cases for eachcounties as = (∑ /∑ ). then, thestandardized morbidity ratio (smr) was computed asthe ratio of the number of observed cases ( ) toexpected number of cases ( ) for each county. thesesmrs were mapped in figure 2. the changes fromobserved cases to smr are most striking in charlotteand levy counties, showing that the cap cases (4 and 21,respectively) in these counties are very small. thespatial pattern variation across the counties suggeststhat there is local instability in both observed counts andsmr since they do not take into consideration forsampling errors. a solution for filtering the signal fromthe random noise is to use statistical methods byintroducing random effects and county-level covariatesto explain such strong heterogeneity across counties.random-effect poisson regression models described in(ref# 1,3) were fitted to the observed data to getgeographical maps of county-specific relative risks ofcap and assess the associations between county-specificrelative risks and county-level covariates given in table1. the posterior means, standard deviations and 95%credible interval (ci) of the coefficients of the covariatesare presented in table 2. the results show that anincreasing cap incidence of black men in florida issignificantly associated with increasing unemploymentrate ( 2 =.1379 with 95% ci: (.0025, .2703), which doesnot include zero) and with increasing number ofphysicians per capita in a county ( 11 =.00212 with 95%ci: (.00006, .0042) after controlling for other countycharacteristics. this implies that the more the number ofphysicians in a county, the higher cap diagnosed casesdue to accessibility to health services. in the case ofpoverty, however, there is an inverse relationshipbetween cap incidence and percent of adult individualswho were below poverty level in 2009 in a county. thatis, a decreasing cap incidence of black men in florida issignificantly associated with increasing percentage ofpersons below poverty level ( 3 =-.0583 with 95% ci:(-.1039, -.0132), which confirms findings of otherstudies.19 4 dagne et al.: spatial variation of prostate cancer incidence international journal of cancer therapy and oncology www.ijcto.org © dagne et al. issn 2330-4049 figure 1: spatial distribution of prostate cancer cases for black men in florida (2006 -2010) figure 2: spatial distribution of ratios of observed and expected cases for black men in florida (2006 -2010). volume 5• number 1 • 2017 international journal of cancer therapy and oncology 5 www.ijcto.org © dagne et al. issn 2330-4049 table 2: a summary of the estimated posterior mean (pm) and standard deviation (sd) of population parameters andlower limit ( ) and upper limit ( ) of $95% equal-tail credible interval (ci).predictor parameter pm sd )interceptmedian income -.1538.1469 .04399.4574 -.2434-.7498 -.0681.045unemployment .1379 .0677 .0025 .2703poverty -.0583 .0232 -.1039 -.0132overweightcurrent smokercommunity water supplyblack populationmedical checkuptwo or more fruithigh school graduationphysicianrural resident .0079.0304.0096.0104.0026.0080-.0131.0021.0023 .0144.0167.0895.0091.0115.0143.0099.0010.0048 -.0205-.0027-.1661-.0073-.0204-.0198-.0326.00006-.0074 .0362.0635.1846.0283.0251.0364.0063.0042.0116 figure 3: spatial distribution of posterior medians of standardized morbidity ratios of prostate cancer for blackmen in florida (2006-2010). a byproduct of the random-effect poisson regressionmodel is the estimated cap relative risk in each countyafter adjusting for the effect of county-levelcharacteristics. the posterior median of the smoothedcap relative risk was mapped in figure 3 which showsthe spatial pattern inherent in the observed cases (seefigure 1). looking at the map in figure 3, we observethat there are clustering and hotspots of high capincidence rates in palm beach county in south florida, and alachua and marion counties in north florida. atleast 60% of the counties in florida exhibitdisproportional burden of prostate cancer by havingmore than expected relative risk ( >1 ). thus, furtherinvestigation into identifying and understandingunderlying causal mechanisms in the communities isparamountly significant for reducing the burden of thisdisease. specifically, targeted interventions can also be 6 dagne et al.: spatial variation of prostate cancer incidence international journal of cancer therapy and oncology www.ijcto.org © dagne et al. issn 2330-4049 designed for those counties with high prostate cancerrelative risks. 4. discussionin this spatial study, we assessed the link between thegeographical variation of cap incidence for black men inflorida and potential county-level risk factors. theresults show that countyspecific cap relative ratios arehigher in counties where there are higher proportion ofunemployed, higher number of florida licensedphysician, and lower proportion of persons belowpoverty level. although not statistically significant atcounty level, median income, percentage of overweight,percentage of current smoking status, community watersupply per capita, percentage of blacks, percentage ofmedical checkup, percentage of persons consuming twoor more fruits daily, high school graduation, andpercentage of rural residents have positive associationwith prostate cancer incidence. these findings are alsoshown in some other studies.20,21after adjusting for county-level characteristics, thesmoothed cap incidence for black men was used toidentify counties with higher or lower than expectedratios (see figure 3) if every county is equally likely tohave cap cases. accordingly, some counties in northeast,central and south florida tend to have higher capincidence than expected. these findings suggest thatmore detailed study of cap incidence in counties withhigher concentration of cases is warranted. in addition,looking into variation within the black ethnicity such asus-born, caribbean-born and africa-born may throwlight on endogenous and exogenous healthdeterminants, which are unique to each subgroup.it is noted that, as in any ecological study, caution needsto be taken when interpreting ecological analysisresults.22 this is because associations assessed betweenrisk factors and cap incidence at a county level may notnecessarily imply that the risk factors are associatedwith an individual's chance of having cap. unmeasuredconfounders (e.g., prostate-specific antigen (psa) ordigital rectal exam (dre) screening) are potentialsources of discrepancies between results of county leveland individual level analysis.23,24 thus, the goal of thisarticle is to investigate risk factors that may contributeto the geographic pattern of cap incidence of black menwithin florida using a bayesian approach.the bayesian method was chosen since it is flexible toincorporate a spatially structured variation via aconditional autoregressive function, accounting forspatial dependence of adjacent neighbors, andheterogeneity.25,26 the bayesian method uses mcmc toestimate the parameters of the poisson random effectsmodel based on non-informative prior distributions forcoefficients of covariates, spatial and heterogeneityparameters. furthermore, the estimation process can be easily carried out using the publicly available winbugspackage.18 this makes our approach quite powerful andaccessible to practitioners in the field.there are some limitations to our study. the currentstudy has a spatial dimension only since aggregate dataover the 2006-2010 study periods were used butignores the temporal feature of the observed cases. thereason is that the observed cases are very sparse atcounty level for each year in the study period and thusnot enough data for analyzing temporal trend. forexample, 14 out of the 67 counties have less or equal to10 cases aggregated over the 5 year period. thecounty-level covariates chosen for the analysis arelimited by the availability of data on importantprotective and risk factors for cap. other measures ofenvironmental exposure, diet intake, socio-economicand demographic characteristics of the 67 countiesshould be considered in future analysis. 5. conclusionthis study shows that county-level indicators ofsocioeconomic background and health care servicessuch as number of physicians explain spatialheterogeneity of prostate cancer incidence rates. betterunderstanding of such risk factors and identifyingspecific counties with a disproportionate burden of capdisease may help formulate targeted interventions andresource allocation by state and local public officials. infuture, given availability of data, further analysisfocusing on geographic variation of treatment modalityand mortality will be useful. conflict of interestthe following teams and people are acknowledged fortheir support on this study: florida department ofhealth cancer epidemiology office, university of floridacollege of pharmacy it team, florida cancer datasystem, mr. cameron schiller, dr. jenn nguyen and mshannah asfaw. fundingthis study is funded by the department of defense pcrpaward w81xwh1310473. references1. american cancer society (acs). cancer facts &figures 2016. american cancer society, atlanta;2016.2. powell ij. prostate cancer and african-americanmen. oncol. 1977;11:599-618.3. powell ij. prostate cancer in theafrican-american: is this a different disease?semin urol. 1988;16:221-6. volume 5• number 1 • 2017 international journal of cancer therapy and oncology 7 www.ijcto.org © dagne et al. issn 2330-4049 4. merrill rm, brawley ow. prostate cancerincidence and mortality rates among white andblack men. epidemiology. 1997;8:126-31.5. brawley ow, knopf k, thompson i. theepidemiology of prostate cancer part ii: the riskfactors. semin urol oncol. 1988;16:193-201.6. montie je, pienta kj. a unifying model toexplain the increased incidence and highermortality of prostate cancer in black men.urology. 1999;53:1073-6.7. du xl, fang s, coker al et al. racial disparityand socioeconomic status in association withsurvival in older men with local/regional stageprostate carcinoma: findings from a largecommunity-based cohort. cancer.2006;106:1276-85.8. goovaerts p, xiao h, gwede ck et al. impact ofage, race and socio-economic status ontemporal trends in late-stage prostate cancerdiagnosis in florida. spat stat. 2015;14:321-37.9. toledano m, jarup l, best n, et al. spatial andtemporal trends of testicular cancer in greatbritain. br j cancer. 2001;84:1482-7.10. jarup l, toledano mb, best n, et al.geographical epidemiology of prostate cancerin great britain. int j cancer. 2002;97:695-9.11. boffetta p, nyberg f. contribution ofenvironmental factors to cancer risk. br medbull. 2003;68:71-94.12. waller la , gotway ca. applied spatial statisticsfor public health data. new york: john wiley,2004.13. goovaerts p, xiao h. geographical, temporaland racial disparities in late-stage prostatecancer incidence across florida: a multiscalejoinpoint regression analysis. int j healthgeogr. 2011;10:63.14. xiao h, tan f, goovaerts p. racial andgeographic disparities in late-stage prostatecancer diagnosis in florida. j health care poorunderserved. 2011;22(4):187-99.15. signorello lb, adami h. prostate cancer. intextbook of cancer epidemiology edited by: adami h, hunter h, trichopoulos d. oxford,oxford university press; 400-428. 2002.16. hernandez mn, fleming le, mackinnon ja, et al. cancer in florida persons of african descent1988-2007. miami: florida cancer data system;2010.17. lawson a, bohning d, biggeri a. diseasemapping and risk assessment for publichealth. 2010.18. lunn dj, thomas a, best n et al. winbugs -abayesian modelling framework: concepts,structure, an extensibility. stat and computing.2000;10:325-7.19. boscoe f p, johnson c j, sherman rl et al. therelationship between area poverty rate andsite-specific cancer incidence in the unitedstates. cancer. 2014;120(14):2191-8.20. liu l, cozen w, bernstein l, et al. changingrelationship between socioeconomic status andprostate cancer incidence. j natl cancer inst.2001;93(9):705-9.21. rundle a, neckerman km, sheehan d et al. aprospective study of socioeconomic status,prostate cancer screening and incidence amongmen at high risk for prostate cancer. cancercauses control. 2013; 24(2):297-303.22. freedman da. ecological inference and theecological fallacy. international encyclopediafor the social and behavioral sciences.2001;6:4027-30.23. greenland s, morgenstern h. ecological bias,confounding and effect modification. int jepidemiology. 1989; 18:269-74.24. prentice r, sheppard l. aggregate data studiesof disease risk factors. biometrika. 1995;82:113-25.25. lawson a. statistical methods in spatialepidemiology. 2001.26. best n, richardson s, thomson a. a comparisonof bayesian spatial models for disease mapping.stat methods med res. 2005;14:35-59. international journal of cancer therapy and oncology www.ijcto.org copyright © pokharel et al. issn 2330-4049 shyam pokharel department of medical physics, premier oncology, fort myers, florida, usa received august 02, 2013; revised august 29, 2013; accepted august 31, 2013; published online august 31, 2013 original research abstract purpose: this study investigated the dosimetric impact of mixing low and high energy treatment plans for high prostate cancer treated with volumetric modulated arc therapy (vmat) technique in the form of rapidarc. methods: a cohort of 12 prostate cases involving proximal seminal vesicles and lymph nodes was selected for this retrospective study. for each prostate case, the single-energy plans (seps) and mixed-energy plans (meps) were generated. first, the seps were created using 6 mega-voltage (mv) energy for both the primary and boost plans. second, the meps were created using 16 mv energy for the primary plan and 6 mv energy for the boost plan. the primary and boost meps used identical beam parameters and same dose optimization values as in the primary and boost seps for the corresponding case. the dosimetric parameters from the composite plans (se ps and meps) were evaluated. results: the dose to the target volume was slightly higher (on average <1%) in the seps than in the meps. the conformity index (ci) and homogeneity index (hi) values between the seps and meps were comparable. the dose to rectum and bladder was always higher in the seps (average difference up to 3.7% for the rectum and up to 8.4% for the bladder) than in the meps. the mean dose to femoral heads was higher by about 0.8% (on average) in the meps than in the seps. the number of monitor units and integral dose were higher in the seps compared to the meps by average differences of 9.1% and 5.5%, respectively. conclusion: the preliminary results from this study suggest that use of mixed-energy vmat plan for high-risk prostate cancer could reduce the integral dose and minimize the dose to rectum and bladder, but for the higher femoral head dose. keywords: prostate cancer; mixed energy plan; vmat; rapidarc introduction in external beam radiation therapy, treatment techniques such as 3-dimensional conformal therapy (3dcrt), intensity modulated radiation therapy (imrt), and volumetric modulated arc therapy (vmat) are generally used to treat prostate cancer with an objective of delivering conformal dose distributions to the target while minimizing the doses to the normal tissues. since prostate cancer involves the deep-seated target, the high-energy photon beams are generally used for 3dcrt due to their greater penetrating power.1 however, the photon beams with energy 10 mega-voltage (mv) or higher also create the secondary neutrons due to interaction between the photons and treatment head of the machine.1 despite high-energy photon having an advantage in penetrating power and skin sparing, use of lower energy (6–10 mv) photon beams have been found to be an effective energy choices for the majority of imrt prostate cases.1,2 furthermore, several studies demonstrated no clear dosimetric advantages using high-energy photon beams for imrt prostate cases when compared to the low-energy photon beams.2-8 recently, park et al.8 investigated the effect of changing beam energy according to the penetration depths on the quality of imrt plans for prostate cancer and made the comparisons between mixed-energy plans (meps) and single-energy plans (seps) of either low or high energy. in that study8, park et al. showed that mixing energy in an imrt plan for deep-seated tumors could improve the overall plan quality. however, the dosimetric impact of meps for proscorresponding author: shyam pokharel, phd; premier oncology, 4571 colonial blvd, unit 100, fort myers, fl 33966, usa; email: pokharel@livemail.uthscsa.edu cite this article as: pokharel s. dosimetric impact of mixed-energy volumetric modulated arc therapy plans for high-risk prostate cancer. int j cancer ther oncol 2013;1(1):01011. doi: 10.14319/ijcto.0101.1 dosimetric impact of mixed-energy volumetric modulated arc therapy plans for high-risk prostate cancer http://dx.doi.org/10.14319/ijcto.0101.1 pokharel: dosimetric impact of mixed energy in vmat plans international journal of cancer therapy and oncology www.ijcto.org copyright © pokharel et al. issn 2330-4049 2 tate cancer using vmat technique remains to be addressed. thus, we investigated the effect of mixing the low energy (6 mv) and high energy (16 mv) treatment plans for prostate cancer treated with vmat technique in the form of rapidarc (varian medical systems, palo alto, ca, usa). the dosimetric comparisons between seps and meps were done for 12 prostate cases. methods and materials a cohort of 12 prostate cases involving proximal seminal vesicles and lymph nodes was selected for this retrospective study. all 12 cases were treated with rapidarc technique at premier oncology, fort myers. florida, usa. the computed tomography (ct) simulation of patients was performed in a supine position on the phillips brilliance ct scanner (philips healthcare, andover, ma, usa), and the ct images were acquired with a 3 mm spacing. the contouring of prostate, proximal seminal vesicles, lymph nodes, and organs at risk (oars) (rectum, bladder, and femoral heads) was done on the axial slices of the ct in the eclipse treatment planning system (tps), version 11.1 (varian medical systems, palo alto, ca, usa). the primary clinical target volume (ctvp) was defined as the prostate, seminal vesicles, and lymph nodes, whereas the boost clinical target volume (ctvb) was defined as the prostate only. the primary and boost planning target volume (ptvp and ptvb, respectively) was generated with a margin of 7 mm around the ctvp and ctvb, respectively, in all directions except in the posterior direction, where a margin of 0.5 cm was used. the rapidarc treatment plans of all 12 cases were generated in the eclipse tps using 6 and 16 mv x-ray beams varian clinac ix (varian medical systems, palo alto, ca, usa). each treatment plan consisted of primary and boost plan, and the total prescription dose was 81 gy with a daily dose of 1.8 gy over 45 fractions. furthermore, the prescription dose to the primary plan was 45 gy to the ptvp, and the prescription dose to the boost plan was 36 gy to the ptvb. for each prostate case, the seps and meps were generated. fig. 1: a transversal view of vmat (rapidarc) plan set up for boost ptv (case #7) using one arc in eclipse treatment planning system. abbreviations: vmat = volumetric modulated arc therapy, ptv = planning target volume. first, the seps were created using a 6 mv photon beam for both the primary plan and separate boost plan. the treatment plan was set up using one, two or three arcs depending on the size of the target volume. [figure 1] the length of gantry rotations, collimator angle, and field sizes of the coplanar arcs for the primary as well as boost plans were chosen based on the location of the ptv and oars using the beam-eye-view (bev) graphics. [figure 2] fig. 2: beam's-eye-view of case #7 showing (a) primary planning target volume (ptv), and (b) boost ptv in the eclipse treatment planning system. the isocenter of the plan was placed at the center of the target volume (i.e., ptvp or ptvb). the primary and boost plans were optimized using progressive resolution optimizer (pro) (version 11.1). the dose-volume constraints and their weightings were adjusted during the optimization process of seps such that at least 95% of the target volume was covered by the prescription dose while keeping the dose to the oars as minimum as possible. the plan optimization process was carried out with an objective of meeting the planning criteria listed in table 1. table 1: dose specifications for rectum, bladder, and femoral heads in the composite plan organ limit* d15% d25% d35% d50% rectum < 75 gy < 70 gy < 65 gy < 60 gy bladder < 80 gy < 75 gy < 70 gy <65 gy femoral mean dose < 45 gy *normal organ limit refers to the volume of that organ that should not exceed the dose limit. abbreviation: dx% = dose received by x% of total oar volume, where x % = 15, 25, 35 and 50; oar = organ at risk. second, the meps were created using a 16 mv photon beam for the primary plan and a 6 mv photon beam for the boost plan. specifically, the primary mep used the identical beam parameters and same optimization dose-constraints and their weightings as in the final primary sep plan for the corresponding case. similarly, the boost mep and boost sep had the same beam parameters and plan optimization values for the corresponding case. no modifications of dose-volume constraints and weightings were made during the optimization processes of meps. the optimized seps and meps plans were calculated with the anisotropic analytical algorithm (aaa), version 11.1, using dose calculation grid size of 2.5 mm. all calculated volume 1 • number 1 • 2013 international journal of cancer therapy and oncology www.ijcto.org copyright © pokharel et al. issn 2330-4049 3 plans were then normalized such that at least 95% of the ptv volume was covered by the prescription dose. the primary and boost plans were combined to generate a composite (comp) plan. this allowed us to perform the dosimetric comparison between the seps and meps using the dose-volume histograms (dvhs) of the comp plans that were generated in the eclipse tps. the dvh parameters evaluated for the target volume (ptvb) were: mean dose, maximum dose, conformity index (ci) defined as the ratio of volume of the isodose cloud receiving 100% of the prescription dose (v100%) to volume of the ptvb, and homogeneity index (hi) defined as the ratio of dose at 5% of the ptvb (d5%) to dose at 95% of the ptvb (d95%). for rectum and bladder, the volumes that received 70 gy, 40 gy, and 20 gy, (v70gy, v40gy, and v20gy, respectively) as well as mean dose were compared. the mean dose to the femoral heads was evaluated. in addition, the number of monitor units (mus) and normal tissue integral dose were compared too. for the purpose of comparison, the average percentage difference (davg.) between the seps and meps at the corresponding dosimetric parameter of the same case was calculated using equation 1. where x is a corresponding dosimetric parameter in the comp seps and meps for the nth case. in equation 1, the davg. is expressed in percentage and averaged over all twelve cases in this study. at a given dosimetric parameter, a positive davg. means higher dosimetric value in the seps compared with the meps, and a negative davg. means higher dosimetric value in the meps compared with the seps. the statistical analysis was done using paired two-sided student’s t-test in a microsoft excel spreadsheet, and a pvalue of less than 0.05 was considered to be statistically significant. results table 2 and figures 3, 4, 5, and 6 summarize the dosimetric results in the comp plans, and the values are averaged over the twelve analyzed cases. the dosimetric results obtained in this study were clinically acceptable. the maximum and mean doses to the target volume were slightly higher in the seps than in the meps by an average difference of less than 1%, and the results showed the statistical significance with p-values of 0.001 and 0.044 for the maximum and mean dose, respectively. the ci and hi values between seps and meps were comparable with average differences of 1% for the ci (p = 0.009) and 0.4% for the hi (p = <0.000) showing statistical significance. the dose to the rectum was always higher in the seps and fig. 3: the davg. (%) between seps and meps for the ptv doses, ci, and hi. the values are averaged over the twelve analyzed cases. note: the error bars represent the standard deviations. the davg. (%) is defined in equation 1 (materials and methods). abbreviations: davg. = average difference, seps = single energy plans, meps = mixed energy plans, ptv = planning target volume, ci = conformity index, hi = homogeneity index. fig. 4: the davg. (%) between seps and meps for the v70gy, v40gy, v20gy, and mean does to the rectum. the values are averaged over the twelve analyzed cases. note: the error bars represent the standard deviations. the davg. (%) is defined in equation 1 (materials and methods). abbreviations: davg. = average difference, seps = single energy plans, meps = mixed energy plans, vngy = percentage volume irradiated by n gy or more of a certain structure lower in the meps with an average difference ranging from 0.6% (at v40gy) to 3.7% (at v20gy). the statistical significance was obtained for the mean dose (p = 0.009) and v20gy (p = 0.003), whereas the statistical significance was not seen for the v70gy (p = 0.427) and v40gy (p = 0.277). similar to the dosimetric results for the rectum, the dose to the bladder was higher in the seps and lower in the meps. however, the range of average difference values between the seps and meps were larger for bladder compared to the one for rectum. specifically, the average difference values in bladder ranged from 0.1% (at v20gy) to 8.4% (at v40gy). furthermore, the statistical significance was obtained for the mean dose (p <0.000), v70gy (p = 0.007), and v40gy (p = 0.002), whereas the results for v20gy (p = 0.384) were not statistically significant.       12 n n avg. n=1 n sep mep1 d (x) = ×100 eq.1 12 ep – s         pokharel: dosimetric impact of mixed energy in vmat plans international journal of cancer therapy and oncology www.ijcto.org copyright © pokharel et al. issn 2330-4049 4 fig. 5: the davg. (%) between seps and meps for the v70gy, v40gy, v20gy, and mean does to the bladder. the values are averaged over the twelve analyzed cases. note: the error bars represent the standard deviations. the davg. (%) is defined in equation 1 (materials and methods). abbreviations: davg. = average difference, seps = single energy plans, meps = mixed energy plans, vngy = percentage volume irradiated by n gy or more of a certain structure in contrast to the results seen for the rectum and bladder in this study, the mean dose to the femoral heads was higher in the meps by an average difference of 0.8% with no statistical significance (p = 0.684). in comparison to the meps, the number of mus and integral dose were higher in the seps by average differences of 9.1% (p < 0.000) and 5.5% (p < 0.000), respectively, showing the statistical significances. fig. 6: the davg. (%) between seps and meps for the femoral head mean dose, normal tissue integral dose, and mus. the values are averaged over the twelve analyzed cases. note: the error bars represent the standard deviations. the davg. (%) is defined in equation 1 (materials and methods). abbreviations: davg. = average difference, seps = single energy plans, meps = mixed energy plans, mus = monitor units. discussion in this study, we investigated the dosimetric impact of mixing low energy (6 mv) and high energy (16 mv) treatment plans for prostate cancer treated with rapidarc technique. the results from this study showed no clear dosimetric differences between the seps and meps for the target volume. however, the results suggested that the use of mixed energy treatment plans for prostate cancer could potentially reduce the dose to the oars, especially for bladder and rectum. table 2: comparison of dosimetric parameters for the single and mixed energy composite (primary + boost) plans. sep mep p-value (avg. ± sd) (avg. ± sd) ptvb (127.2 ± 35.2 cc) mean dose (gy) 83.2 ± 0.4 82.9 ± 0.3 0.044 max. dose (gy) 86.3 ± 0.6 85.6 ± 0.6 0.001 ci 1.09 ± 0.05 1.08 ± 0.05 0.009 hi 1.03 ± 0.00 1.03 ± 0.00 <0.000 rectum (77.6 ± 47.1 cc) mean dose (gy) 34.6 ± 3.9 34.3 ± 3.9 0.009 v70gy (%) 6.5 ± 2.8 6.5 ± 2.8 0.427 v40gy (%) 26.1 ± 7.0 25.9 ± 6.9 0.277 v20gy (%) 89.3 ± 3.9 86.1 ± 13.2 0.003 bladder (325.9 ± 218.2 cc) mean dose (gy) 43.2 ± 5.2 42.2 ± 5.0 <0.000 v70gy (%) 9.3 ± 4.3 9.0 ± 4.1 0.007 v40gy (%) 45.4 ± 17.2 41.4 ± 15.3 0.002 v20gy (%) 99.8 ± 0.5 99.7 ± 0.8 0.384 femoral heads (135.7 ± 16.5 cc) mean dose (gy) 28.0 ± 3.8 28.2 ± 3.4 0.684 monitor units (mus) 590 ± 35 538 ± 34 <0.000 integral dose (105 gy-cc) 3.2 ± 0.5 3.0 ± 0.5 <0.000 abbreviations: sep = single energy plan, mep = mixed energy plan, avg. = average, sd = standard deviation, ptv b = boost planning target volume, max. dose = maximum dose, vngy = percentage volume irradiated by n gy or more of a certain structure, ci = conformity index, hi = homogeneity index. (the values are averaged over the 12 analyzed cases. the p-values were obtained from paired two-sided student’s t-test. the p-values less than 0.05 were considered to be statistically significant). volume 1 • number 1 • 2013 international journal of cancer therapy and oncology www.ijcto.org copyright © pokharel et al. issn 2330-4049 5 the use of lower energy photon beams generally minimizes the head leakage, internal scatter, and secondary neutrons.2-7 however, the low-energy photon beams also requires greater number of mus to deposit high doses in the area peripheral to the target, resulting increase in the integral dose and radiation exposure to the oars.4 the results in our study also showed that the number of mus in the lower energy (6 mv) plans (i.e., seps) were about 9% higher (on average) in comparison to the meps that contained higher energy (16 mv) photon beam. furthermore, the integral dose to the normal tissues was lower in the meps by about 5.5% (on average), and this would also reduce the radiation-induced secondary cancer. 9, 10 the dosimetric differences in the treatment plans from the use of low and high energy photon beams depend on the beam modeling employed within the dose calculation algorithm.11 in this study, we used aaa to calculate the dose in all treatment plans. several studies12-17 have documented the limitation of aaa in estimating the dose more accurately when heterogeneous media are involved along the photon beam path. recently, a number of studies have shown that acuros xb, new dose calculation algorithm employed within eclipse tps, is more accurate than aaa for photon dose calculation, especially in the heterogeneous media.14-17 the dosimetric and radiobiological impact of acuros xb on the prostate cancer treatment plans due to change in photon beam energy will be an interesting topic for future studies. conclusion the preliminary results from this study suggest that use of mixed-energy vmat plan for high-risk prostate cancer could reduce the integral dose and minimize the dose to rectum and bladder, but for the higher femoral head dose. competing interests the authors declare that they have no competing interests. references 1. ncrp. report no, 79: neutron contamination from medical electron accelerators. bethesda, maryland; ncrp: 1987. 2. soderstrom s, eklof a, brahme a: aspects on the optimal photon beam energy for radiation therapy. acta oncol 1999; 38: 179–187. 3. pirzkall a, carol mp, pickett b, xia p, roach m 3rd, verhey lj. the effect of beam energy and number of fields on photon-based imrt for deep-seated targets. int j radiat oncol biol phys 2002; 53: 434–442. 4. subramanian ts. linear accelerators used for imrt should be designed as small field, high intensity, intermediate energy units [for the proposition]. med phys 2002; 29: 2526–28. 5. söderstrom s, eklöf a, brahme a. aspects on the optimal photon beam energy for radiation therapy. acta oncol 1999; 38: 179–187. 6. welsh js, mackie tr, limmer jp. high-energy photons in imrt: uncertainties and risks for questionable gain. technol cancer res treat 2007; 6: 147–149. 7. sun m and ma l. treatments of exceptionally large prostate cancer patients with low-energy intensity-modulated photons. j appl clin med phys 2006;7: 43–49. 8. park jm, choi ch, ha sw, ye sj. the dosimetric effect of mixed-energy imrt plans for prostate cancer. j appl clin med phys 2011;12 :3563. 9. brenner dj, curtis re, hall ej, ron e. second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. cancer 2000; 88: 398-406. 10. hall ej, wuu cs. radiation-induced second cancers: the impact of 3d-crt and imrt. int j radiat oncol biol phys 2003; 56: 83-88. 11. madani i, vanderstraeten b, bral s, et al. comparison of 6 mv and 18 mv photons for imrt treatment of lung cancer. radiother oncol 2007; 82: 63–69. 12. rana sb. dose prediction accuracy of anisotropic analytical algorithm and pencil beam convolution algorithm beyond high density heterogeneity interface. south asian j cancer 2013; 2: 26-30. 13. robinson d. inhomogeneity correction and the analytic anisotropic algorithm. j appl clin med phys 2008; 9: 112-122. 14. rana s, rogers k. dosimetric evaluation of acuros xb dose calculation algorithm with measurements in predicting doses beyond different air gap thickness for smaller and larger field sizes. j med phys 2013; 38: 9-14. 15. bush k, gagne im, zavgorodni s, ansbacher w, beckham w. dosimetric validation of acuros xb with monte carlo methods for photon dose calculations. med phys 2011; 38: 2208-2221. 16. han t, mourtada f, kisling k, mikell j, followill d, howell r. experimental validation of deterministic acuros xb algorithm for imrt and vmat dose calculations with the radiological physics center's head and neck phantom. med phys 2012; 39: 2193-2202. 17. rana s, rogers k, lee t, reed d, biggs c. verification and dosimetric impact of acuros xb algorithm for stereotactic body radiation therapy (sbrt) and rapidarc planning for non-small-cell lung cancer (nsclc) patients. int j med phys clin eng radiat oncol 2013; 2: 6-14. http://dx.doi.org/10.1080/028418699431591 http://dx.doi.org/10.1016/s0360-3016(02)02750-5 http://dx.doi.org/10.1118/1.1513164 http://dx.doi.org/10.1080/028418699431591 http://dx.doi.org/10.1002/(sici)1097-0142(20000115)88:2%3c398::aid-cncr22%3e3.0.co;2-v http://dx.doi.org/10.1016/s0360-3016(03)00073-7 http://dx.doi.org/10.1016/j.radonc.2006.11.016 http://dx.doi.org/10.1016/j.radonc.2006.11.016 http://dx.doi.org/10.4103/2278-330x.105888 http://dx.doi.org/10.4103/0971-6203.106600 http://dx.doi.org/10.1118/1.3567146 http://dx.doi.org/10.1118/1.3692180 http://dx.doi.org/10.4236/ijmpcero.2013.21002 international journal of cancer therapy and oncology www.ijcto.org corresponding author: kr muralidhar; department of radiation physics, american oncology institute nallagandla, lingampally, hyderabad, india. cite this article as: muralidhar kr, rout bk, mallikarjuna a, poornima a, murthy pn. commissioning and quality assurances of the intrabeam intra-operative radiotherapy unit. int j cancer ther oncol 2014; 2(4):020415. doi: 10.14319/ijcto.0204.15 a part of this research was presented at standards, applications and quality assurance in medical dosimetry, which was held in nov 2010 at iaea, vienna commissioning and quality assurances of the intrabeam intra-operative radiotherapy unit kr muralidhar1, birendra kumar rout2, adavala mallikarjuna2, a poornima2, p narayana murthy3 1department of radiation physics, american oncology institute nallagandla, lingampally, hyderabad, india 2department of radiation physics, indo-american cancer institute, hyderabad, india 3department of radiation physics, nagarjuna university, guntur, india received august 20, 2014; revised october 15, 2014; accepted october 19, 2014; published online october 20, 2014 abstract purpose: the authors report comprehensive commissioning and quality assurance (qa) procedures for intrabeam, intra-operative radiotherapy (iort) unit. the intrabeam system miniature x-ray source is a 50 kv and 40 µa unit. methods: the authors’ tests include measurements of output, beam deflection, isotropy, kvp and mas measurements, quality index, isodose, reproducibility, linearity, depth dose verification, and 3d dose distribution. ic ionization chamber and the unidose dosimeter were used for the output commissioning. probe adjuster/ionization chamber holder (paich) was used to check the mechanical straightness of the probe. for radiation tests, nacp parallel plate chamber, standard imaging electrometer, 30 × 30 × 30 cm3 iaea water phantom, solid water slabs, edr-2 films with rit software, and ionization based survey meters were used. unfors xi platinum edition kvp meter was used to measure the kvp and mas. results: in mechanical qa test, x-beam position (-0.09 mm), y-beam position (0.01 mm), and radial position (0.11 mm) errors were within the tolerance level. isotropy test with pda, survey meter, ion chamber, and film measurements also produced results within the specifications. output measurements with paich and external chamber measurements were matched. beam quality, linearity, and reproducibility values were ascertained at 50kv and 40 µa and found to be within limits. isodose, 3d dose distribution, transverse, and horizontal profiles showed the good isotropy of the source. conclusion: the authors’ methodology provides comprehensive commissioning and calibration procedures for the intrabeam system. keywords: iort; intrabeam; x-ray source; isotropy; photo diode array introduction intrabeam system (carl zeiss surgical gmbh, oberkochen, germany) is a mobile unit used for intraoperative radiotherapy (iort), especially for localized tumor irradiation and for sharp fall of dose from the source. the heart of this system is a miniature with high dose rate and low energy x-ray source (xrs) equipped with a 10 cm long (ø 3.2 mm) probe. the tip of the xrs probe is placed into a lesion or a tumor bed. it is a truly flexible system for iort. the intrabeam delivers treatment by a number of methods, including intraoperative, interstitial, intra-cavity, and surface treatments. in iort facility, the quality assurance needs to be more stringent due to miniature x-ray source and its high dose rate.1-2 since intrabeam system installed at our center was the first of its kind in india, various quality assurance procedures and radiation safety issues were to be addressed at the time of commissioning both from regulatory as well as operational standpoints. while a number of reports exist describing the quality assurance for iort, very few papers deal with the qa aspects in detail. these tests (mechanical, dynamic offset, isotropy test with photodiode array (pda), and probe adjuster/ionization chamber holder (paich) output check (dose rate)) are well evaluated as part of the commissioning process; however, there is no discussion about the complementary procedures to ensure its clinical use. in this study, after commissioning the system by measuring the parameters proposed by the manufacturer, a number of procedures have been proposed before the system can be applied in clinical use. these tests (beam quality test, linearity test, and reproducibility test, isotropy test with survey meter and edr-2 film, external kvp and mas measurements, isodose and depth dose measurements with film) were complementary procedures to check the correct installation and calibration. the use of proposed parameters might be helpful to check if doses are correctly delivered from the system measurement using a tank of water. another interesting test is to obtain the original article http://ijcto.org/index.php/ijcto http://ejourpub.com/ http://dx.doi.org/10.14319/ijcto.0204.15 2 muralidhar et al.: commissioning and quality assurances of iort international journal of cancer therapy and oncology www.ijcto.org © muralidhar et al. issn 2330-4049 transverse and horizontal profile information and 3d dose distribution using rit software with edr-2 films. all these tests make sure that the system is within the manufacturer specified values and further improve this technology towards dedicated computerized planning system. the main purpose of this study was to create enough confidence on the intrabeam system by performing additional quality assurances as specified by the authors. methods and materials intrabeam operation this photon radio surgery system (prs) comprises an xrs [figure 1], prs 500 control console, quality assurance tools, and mobile gantry. fig. 1: intrabeam system. the miniature x-ray source [figure 2] is a 50 kvp and 40 µa unit capable of delivering 1.32 mgy/min at 1 meter from the source. fig. 2: x-ray source with internal radiation monitor (irm): (1) xrs-4 cable connector, (2) beam deflector, (3) probe tip, (4) x-ray probe, and (5) irm (courtesy carl zeiss) high voltage is generated by the xrs from the low direct current voltage supplied by the prs 500 control console, and is used to direct an electron beam into the x-ray probe. the electron beam strikes a hemispherical gold target, approximately 1 µm thickness at the end of the x-ray probe, generating x-radiation.3 the x-ray system produces low-energy photons (30-50 kvp) with a steep dose falloff in soft-tissue; hence, no special shielding is required in the room. the production of an x-ray pattern is spherical in shape about the tip of the drift tube. adjustment of beam steering and the angle of precession allow the isotropic distribution to be optimized.4 the probe tip is made of beryllium (be), a material transparent to x-radiation. the exterior surface of the xrs probe is provided with a protective coating. in order to use the xrs, it must be connected to the prs 500 control console with the xrs interface cable. x-radiation produced at the tip of the x-ray probe features a spherical radiation characteristic. as a result, part of the radiation re-enters the xrs through the probe. the irm detects this x-radiation in the xrs. the radiation output measured by the irm is then used during treatment as an indirect measure of radiation delivered at the probe tip. there are few important tests that should be covered prior to clinical use of this unit. these tests typically include the mechanical and radiation measurements. the prs is supplied with a set of components, which facilitate accurate alignment of the xrs probe as well as quality assurance checks.5 mechanical tests mechanical straightness check of the probe is very important. for this test, probe adjuster/ionization chamber holder (paich) can be used. performing this verification step is must if the isotropy verification is unsuccessful or the xrs probe is suspected to be bent. specifically, in order to check the mechanical straightness, the probe should be inserted into the pda (photo diode array), and the paich and the xrs need to be connected to the control console using the appropriate cables. after successful cable connection, rotate the paich completely to 360° or less to measure the highest value of deviation. the plunger is then depressed and released to straighten the xrs probe. this procedure is repeated until the run out value is less than 0.10 mm. radiation tests in our study, inbuilt radiation tests (alignment (probe adjuster), steering (quick check, dynamic offsets), isotropy and irm (pda), output (paich)) were done to check the dynamic offset, isotropy, and dose rate. new quality assurances (beam quality test, linearity test, and reproducibility test, isotropy test with survey meter and edr-2 film, external kvp and mas measurements, isodose and depth dose measurements with film) were done by using film, ionization chamber, survey meter, kvp, and mas meter. dynamic offset this technique is used to align the direction of the electron beam with the mechanical center of the xrs probe by beam deflection adjustment. the xrs and pda photodiode array were aligned with the help of +x and +y markings on them volume 2 • number 4 • 2014 international journal of cancer therapy and oncology 3 www.ijcto.org © muralidhar et al. issn 2330-4049 and were connected to control console using the appropriate cables. in the system calibration procedure, adjustment was performed automatically for the selected xrs source at a specific high voltage. isotropy test with pda the pda was used to measure and, if needed, to adjust the isotropy of the radiation emission from the xrs probe tip. the pda incorporates five photodiodes, placed in a centered position on the four side faces and the top face of a cube, such that all are equidistant from the center of radiation of the xrs probe tip. the signals from the pda were displayed in the screen mask and were used to measure the distribution (isotropy) of x-radiation emitted from the tip of the probe. the isotropy of the radiation field was automatically adjusted on the basis of these measured values. the isotropy adjust procedure was performed using the maximum beam current and the same beam voltage that was selected for the relevant xrs. paich output check (dose rate) this procedure is used to determine the dose rate of the xrs by means of the inbuilt ionization chamber and the unidose dosimeter. the dose rate was checked against a specific expected value from the calibration data given by the manufacturer. to perform this test, the paich was attached to the xrs. ionization chamber was then inserted into the holder of paich and connected to the dosimeter. the output dose rate value indicated in gy/min is the value computed internally. beam quality test dose rates were measured at 5 cm and 3 cm distances from the cone in the water phantom [figure 3] for three days with 0.6 cc ionization chamber (iba dosimetry gmbh, germany). the measured dose rate values were used to verify the energy stability. dose gradients are typically steep within 2 cm distance from the source. in order to avoid the uncertainties, it is always advisable to take the readings at greater than 3 cm. fig. 3: measurements in water phantom. depth dose measurement depth-dose curves were obtained by measuring the ionization chamber output at distances between 1 to 10 cm away from the probe tip in a water phantom of dimensions 30 × 30 × 30 cm3. the ionization chamber was placed at the center of the phantom in the perspex enclosure. the position of the x-ray source is shown in the figure 3. care was taken to maintain the straightness of the probe. the minimum distance away from the probe tip at which the ionization chamber could be positioned was 10 mm from the center of the chamber. we acquired depth dose data in water to reduce the uncertainties involved in converting from an air measurement to the measurement in water. additionally, a comparison was made between the measured depth doses and corresponding values obtained from the manufacturer.1 linearity test the linearity of the intrabeam system was ascertained at 50 kvp and 40 µa for the range of 1 to 5 minutes. measurements were taken at 4 cm distance from the source with parallel plate ionization chamber. reproducibility test reproducibility of the x-ray output was investigated for intrabeam under 10 exposures. each exposure was controlled using a preset timer. a beam voltage of 50 kvp and beam current of 40 µa were used. ten measurements were made for exposures equivalent to 1 minute each at a distance of 4 cm from the surface in water phantom. isotropy test with the survey meter in this study, x-ray radiation was measured in a series of square projections from x-ray source by means of an ion chamber based survey meter. isotropy was estimated with the help of the obtained data. this is one of the simple procedures to check the isotropy of the system. isotropy test with edr-2 film and rit software five edr-2 films were used to test the isotropy of the source. all films were kept at 5 cm from the source in five directions (00, 900, 1800, 2700, and perpendicular to the source). five exposures, each of one minute duration were made. the exposed films were scanned in vidar film scanner and analyzed using radiological imaging technology (rit®) software. this software provides precise qa analysis for images from many different sources (ct, x-ray, etc.). the difference between the horizontal and vertical profiles gives the dose difference at any given point in that particular plane. a good isotropy shows the negligible difference between these two profiles. if the difference is significant (>1%), mechanical test and dynamic offset test should be done to get the good isotropy. 4 muralidhar et al.: commissioning and quality assurances of iort international journal of cancer therapy and oncology www.ijcto.org © muralidhar et al. issn 2330-4049 isodose and depth dose measurements with film isodose measurements were done by exposing the film vertically down from the source. film analysis was done by rit software and percentage depth doses were obtained by normalizing the values at 2 cm depth from the surface where the output was compared with an ionization chamber. external kvp and mas measurements unifors xi platinum edition kvp meter was used to study the kvp measurement. to measure the kvp, the setup was such that the iort cone positioned vertically on the surface of the kvp meter. this kvp meter was connected to the personal computer with loaded software which shows the readings continuously in digital and wave form. measurements were taken with few exposures. results mechanical test distance from the tip of the drift tube was measured and compared with the stated length. geometric accuracy depends upon the variation between these two values. the maximum variation of the drift tube from its longitudinal axis was found to be less than 0.08 mm. this verification test is passed by succeeding in centering the xrs probe to a run out of the maximum deviation of value less than 0.10 mm. radiation tests dynamic offset the x, y, and radial beam position errors were < ± 0.1 mm according to manufacturer recommended value (< 0.1 mm) isotropy test with pda the measurements for the five bars were ranged from 5.7 to 5.75, and these values were within the tolerance level. paich output check (dose rate) readings on the unidos® e dosimeter displayed the dose rate values. the maximum % of variation with the calibrated value was less than 2% observed. beam quality the measured quality indexes for three consecutive days were 0.312, 0.313, and 0.310, respectively, which proved that the system has good energy stability [table 1]. the d5/d3 is the ratio of the meter readings at depth 5 cm and 3 cm, respectively. table 1: quality index intrabeam system. day d5/d3 quality index 1st day 0.714 / 2.286 0.312 2nd day 0.715 / 2.284 0.313 3rd day 0.710 / 2.289 0.310 depth dose measurement sharp dose fall off (approximately 1/r3) in water was observed [figure 4] with respect to the depth. these measurements satisfied the values obtained by carl zeiss3 calibrated values. fig. 4: output measurement. linearity test for all five readings, plot of dose measured versus exposure time was found to be linear [figure 5]. in all the exposures, the ionization chamber distance was 4 cm from the source in the water phantom. fig. 5: linearity test. reproducibility the measurements of reproducibility were carried out for ten measurements as shown in [figure 6]. we observed that the reproducibility was, in terms of mean deviation, better than 0.44%. fig. 6: reproducibility. fig. 7: exposure rate measurements. volume 2 • number 4 • 2014 international journal of cancer therapy and oncology 5 www.ijcto.org © muralidhar et al. issn 2330-4049 fig. 8: isotropy check with edr-2 films and rit software. fig. 9: difference between horizontal and vertical profile. fig. 10: 3d view of the iort dose distribution. isotropy check with survey meter exposure rates in different directions have shown almost similar results. the reading of the survey meter at 5 cm, 50 cm, 100 cm, and 200 cm from the source were taken in four directions and analyzed with graph. figure 7 shows the good isotropy along with the radiation safety in operation theatre itself. isotropy check with edr-2 film the analysis of edr-2 films with rit shows an excellent isotropy. the isodose measured in all directions are at the same distance from the source center. inline and cross line measurements are also shown in the figure 8. with the help of inline and cross line profiles, we can find the dose difference between either sides of the source at the same distance. the difference in dose at 2 cm and 12 cm distance from the center of the exposure were 1.7% and 0.7 %, respectively. in one typical case, the difference between horizontal and vertical profiles were analyzed through rit software as shown in figure 9. the 3d dose distribution also gives us the clear view of the isotropy through rit software as shown in figure 10. fig. 11: analysis of edr2 films after exposing with iort source. 6 muralidhar et al.: commissioning and quality assurances of iort international journal of cancer therapy and oncology www.ijcto.org © muralidhar et al. issn 2330-4049 the figure-11 clearly shows the values which proved that the system displays good isotropy. the maximum % of difference in dose between films in all directions was 4% and the difference between maximum dose deposited on each film was 0.5%. isodose and depth dose measurements with film depth doses and isodoses were derived through film measurements [figure 12]. the dose rate was normalized to 100% at 2 cm depth in the film to simulate the water phantom depth doses, which were used for the output measurements. it was found through film measurements that the beam attenuation varies by 1/r3 as provided by the manufacturer. this concept can be implemented on ct planning in the treatment planning system. fig. 12: isodose curves from film measurements. external kvp and mas measurements reading for one minute exposure was taken for four times and the deviations were observed. these values closely resembles with the value (50 kvp) that was kept inside the console (prs500). the maximum and minimum of variation in percentage were 2% and 0.8%, respectively. discussion in the past ten years, there has been an increasing interest in the iort technique because of the development of mobile accelerators 6-8 producing only electron beams. clinical use of iort, given as a single fraction, was tested using electrons (intraoperative radiotherapy with electrons [eliot])9, brachytherapy10, or low-energy x-rays (targeted intraoperative radiation therapy [targit]).11 it is, however, important to appreciate the different characteristics of the applicators and take advantage of its special features.12 intraoperative radiotherapy is useful for giving high radiation to the tumor, and at the same time, it spares the normal structures with the ability to stop radiation with less penetration because 50 kev energy is increasingly popular, especially among intact breast cases. installation, commissioning, and operation of this equipment are limited across the globe as they have been in use for last few years. we have recently installed this machine. as it is a very delicate apparatus, care should be taken to handle the source and other equipments associated with this device. in built quality assurance procedures should be done to start the exposure.13 this is a very good feature for the accurate treatment. from the radiation safety point of view, there were no issues as it is 50 kev and 40 µa machine, and it is also very easy to handle because the dose decreases steeply with the radial distance, r (approximately proportional to r3). for every month, over one year period, we observed a deviation of baseline values for output, isotropy, and mechanical straightness of the probe to be less than ±1%. this compares favorably with the output constancy of ± 2% recommended by the european commission in 1997.14 conclusion we have summarized the simple qa procedures to test the various parameters of the iort unit (50 kev, 40 µa). the output measurement with ion chamber, kvp meter, isotropy measured with edr films and survey meter were matched perfectly with the inbuilt quality assurance measurements. percent depth dose measurements were found to be in very good agreement with the manufacturer given data after normalization. furthermore, the iort generally comes with manufacturer recommended tests to check the quality of the device. it is very important to verify the isotropy, kvp and mas measurements, quality index, isodose, reproducibility, linearity, depth dose measurements, and 3d dose distribution along with manufacturer recommended tests. in conclusion, uniform irradiation was proved and checked frequently in the sphere of equivalence which defines a novel target volume with low energy x-rays. the measurement techniques presented in this study are helpful to verify the manufacturer recommended values and to implement qa procedures with high accuracy at the institution. conflict of interest the authors declare that they have no conflicts of interest. the authors alone are responsible for the content and writing of the paper. references 1. beatty j, biggs pj, gall k, et al. a new miniature x-ray device for interstitial radiosurgery: dosimetry. med phys 1996; 23:53-62. 2. schneider f, clausen s, thölking j, et al. a novel approach for superficial intraoperative radiotherapy (iort) using a 50 kv x-ray source: a technical and case report. j appl clin med phys 2014; 15:4502. http://dx.doi.org/10.1118/1.597791 http://www.ncbi.nlm.nih.gov/pubmed/24423847 volume 2 • number 4 • 2014 international journal of cancer therapy and oncology 7 www.ijcto.org © muralidhar et al. issn 2330-4049 4. biggs ds, thomson es. radiation properties of a miniature x-ray device for radiosurgery. br j radiol 1996; 69:544-7. 5. armoogum ks, parry jm, souliman sk, et al. functional intercomparison of intraoperative radiotherapy equipment photon radiosurgery system. radiat oncol 2007; 2:11. 6. pimpinella m, mihailescu d, guerra as, laitano rf. dosimetric characteristics of electron beams produced by a mobile accelerator for iort. phys med biol 2007; 52:6197-214. 7. mills md, fajardo lc, wilson dl, et al. commissioning of a mobile electron accelerator for intraoperative radiotherapy. j appl clin med phys 2001; 2:121-30. 8. strigari l, soriani a, landoni v, et al. radiation exposure of personnel during intraoperative radiotherapy (iort): radiation protection aspects. j exp clin cancer res 2004; 23:489-94. 9. veronesi u, orecchia r, luini a, et al. full-dose intraoperative radiotherapy with electrons during breast-conserving surgery: experience with 590 cases. ann surg 2005; 242:101-6. 10. beal k, mccormick b, zelefsky mj, et al. single-fraction intraoperative radiotherapy for breast cancer: early cosmetic results. int j radiat oncol biol phys 2007; 69:19-24. 11. vaidya js, tobias js, baum m, et al. intraoperative radiotherapy for breast cancer. lancet oncol 2004; 5:165–73. 12. lam scp, xu y, ingram g, chong lf. dosimetric characteristics of intrabeam flat and surface applicators. transl cancer res 2014; 3: 106-11. 13. park cc, bevan a, podgorsak mb, pouliot j, yom ss. electronic brachytherapy. evaluation subcommittee of astro’s emerging technology committee; 2008. 14. european commission in radiation protection 91. criteria for acceptability of radiological (including radiotherapy) and nuclear medicine installations. luxembourg: office for official publications of the european communitie; isbn 92-828-1140-9: 1997. available from http://ec.europa.eu/energy/nuclear/radiation_prote ction/doc/publication/091_en.pdf 3. intrabeam system prs 500 with xrs. user manual for the core system. issue 3.0. oberkochen, germany. carl zeiss medical company; 2007. http://www.zeiss.com/meditec/en_de/products---solutions/intraoperative-radiotherapy/intrabeam-for-breast-cancer/intrabeam.html http://dx.doi.org/10.1259/0007-1285-69-822-544 http://dx.doi.org/10.1186/1748-717x-2-11 http://dx.doi.org/10.1088/0031-9155/52/20/008 http://dx.doi.org/10.1120/1.1385128 http://www.ncbi.nlm.nih.gov/pubmed/15595641 http://dx.doi.org/10.1097/01.sla.0000167927.82353.bc http://dx.doi.org/10.1016/j.ijrobp.2007.02.010 http://dx.doi.org/10.1016/s1470-2045(04)01412-3 http://www.thetcr.org/article/view/2100 http://www.astro.org/uploadedfiles/main_site/clinical_practice/best_practices/etcebt.pdf international journal of cancer therapy and oncology www.ijcto.org © ijcto issn 2330-4049 high impact papers from january – march, 2014 high impact papers from a particular issue are selected based on the quality of the article and the number of citations. high impact papers are typically recognized once the issue completes the publication time period of 12 months. following articles are recognized as high impact papers from january-march, 2014: 1. wang h, vassiliev on. microdosimetric characterisation of radiation fields for modelling tissue response in radiotherapy. int j cancer ther oncol 2014; 2(1):020116. doi: 10.14319/ijcto.0201.16 read download citations 2. chaikh a, giraud j, balosso j. a method to quantify and assess the dosimetric and clinical impact resulting from the heterogeneity correction in radiotherapy for lung cancer. int j cancer ther oncol 2014; 2(1):020110. doi: 10.14319/ijcto.0201.10 read download citations 3. rana s. clinical dosimetric impact of acuros xb and analytical anisotropic algorithm (aaa) on real lung cancer treatment plans: review. int j cancer ther oncol 2014; 2(1):02019. doi: 10.14319/ijcto.0201.9 read download citations (high impact papers from april-june, 2014 will be recognized in the next issue of the ijcto) international journal of cancer therapy and oncology www.ijcto.org © ijcto issn 2330-4049 high impact papers from january – march, 2014 high impact papers from a particular issue are selected based on the quality of the article and the number of citations. high impact papers are typically recognized once the issue completes the publication time period of 12 months. following articles are recognized as high impact papers from january-march, 2014: 1. wang h, vassiliev on. microdosimetric characterisation of radiation fields for modelling tissue response in radiotherapy. int j cancer ther oncol 2014; 2(1):020116. doi: 10.14319/ijcto.0201.16 read download citations 2. chaikh a, giraud j, balosso j. a method to quantify and assess the dosimetric and clinical impact resulting from the heterogeneity correction in radiotherapy for lung cancer. int j cancer ther oncol 2014; 2(1):020110. doi: 10.14319/ijcto.0201.10 read download citations 3. rana s. clinical dosimetric impact of acuros xb and analytical anisotropic algorithm (aaa) on real lung cancer treatment plans: review. int j cancer ther oncol 2014; 2(1):02019. doi: 10.14319/ijcto.0201.9 read download citations (high impact papers from april-june, 2014 will be recognized in the next issue of the ijcto) international journal of cancer therapy and oncology www.ijcto.org © ijcto issn 2330-4049 high impact papers from january – march, 2014 high impact papers from a particular issue are selected based on the quality of the article and the number of citations. high impact papers are typically recognized once the issue completes the publication time period of 12 months. following articles are recognized as high impact papers from january-march, 2014: 1. wang h, vassiliev on. microdosimetric characterisation of radiation fields for modelling tissue response in radiotherapy. int j cancer ther oncol 2014; 2(1):020116. doi: 10.14319/ijcto.0201.16 read download citations 2. chaikh a, giraud j, balosso j. a method to quantify and assess the dosimetric and clinical impact resulting from the heterogeneity correction in radiotherapy for lung cancer. int j cancer ther oncol 2014; 2(1):020110. doi: 10.14319/ijcto.0201.10 read download citations 3. rana s. clinical dosimetric impact of acuros xb and analytical anisotropic algorithm (aaa) on real lung cancer treatment plans: review. int j cancer ther oncol 2014; 2(1):02019. doi: 10.14319/ijcto.0201.9 read download citations (high impact papers from april-june, 2014 will be recognized in the next issue of the ijcto) http://dx.doi.org/10.14319/ijcto.0201.16 http://www.ijcto.org/index.php/ijcto/article/view/wang/ijcto.0201.16html http://www.ijcto.org/index.php/ijcto/article/download/wang/ijcto.0201.16pdf http://www.ijcto.org/index.php/ijcto/article/view/chaikh/ijcto.0201.10html http://dx.doi.org/10.14319/ijcto.0201.10 http://www.ijcto.org/index.php/ijcto/article/download/chaikh/ijcto.0201.10pdf http://dx.doi.org/10.14319/ijcto.0201.9 https://scholar.google.com/citations?view_op=view_citation&hl=en&user=aiul49oaaaaj&citation_for_view=aiul49oaaaaj:5nxa0vek-isc https://scholar.google.com/citations?view_op=view_citation&hl=en&user=aiul49oaaaaj&citation_for_view=aiul49oaaaaj:yowf2qjgphmc https://scholar.google.com/citations?view_op=view_citation&hl=en&user=aiul49oaaaaj&cstart=100&pagesize=100&citation_for_view=aiul49oaaaaj:m3ejud6nzc8c http://www.ijcto.org/index.php/ijcto/article/view/rana1/ijcto.0201.9html http://www.ijcto.org/index.php/ijcto/article/download/rana1/ijcto.0201.9pdf http://ijcto.org/index.php/ijcto/issue/view/13 international journal of cancer therapy and oncology www.ijcto.org corresponding author: shanmugam thirumalai swamy; department of radiation oncology, yashoda hospitals, hyderabad, india. cite this article as: thirumalai-swamy s, anuradha c, kathirvel m, arun g, subramanian s. pretreatment quality assurance of volumetric modulated arc therapy on patient ct scan using indirect 3d dosimetry system. int j cancer ther oncol 2014; 2(4):020416. doi:10.14319/ijcto.0204.16 pretreatment quality assurance of volumetric modulated arc therapy on patient ct scan using indirect 3d dosimetry system shanmugam thirumalai swamy1,2, chandrasekaran anuradha2, murugesan kathirvel1, gandhi arun1, shanmuga subramanian1 1department of radiation oncology, yashoda hospitals, hyderabad, india 2school of advanced sciences, vit university, vellore, india received august 29, 2014; revised october 16, 2014; accepted october 18, 2014; published online october 22, 2014 original article abstract purpose: aim of this study is to clinically implement the compass 3d dosimetry system for pretreatment quality assurance of volumetric modulated arc therapy (vmat-rapidarc) treatment plans. methods: for this study, 10 head and neck (h&n) and pelvis vmat plans dose response from linac was measured using compass system along with matrixxevolution and 3d dose reconstructed in the patient computed tomography (ct) scan. dose volume histograms and 3d gamma were used to evaluate difference between the measured and calculated values. in order to validate the compass system, dose response for open fields were acquired for both homogeneous and inhomogeneous phantoms. results: the average dose difference between eclipse treatment planning system (tps) calculated and compass measured (homogenous medium) in normalization region, inner region, penumbra region and buildup region was less than ±2%. in inhomogeneous phantom, there was a maximum difference -3.17% in lung, whereas the difference other densities was within ±2%. the systematic increase in the average 3d gamma between the tps calculated and compass measured for vmat plans with known dose errors and multi-leaf collimator (mlc) offset errors shows that compass system was sensitive enough to find clinical significant errors. the 3d dose parameters (d95, d1, and average dose) of all h&n and pelvis patients were well within the clinically acceptable tolerance level of ±5%. the average 3d gammas for planning target volumes (ptv) and organ at risks (oar) of the patients were less than 0.6. conclusion: the results from this study show that compass along with matrixxevolution can be effectively used for pretreatment verification of vmat plans in the patient anatomy. keywords: compass; vmat; 3d gamma; pretreatment qa introduction in advanced radiotherapy techniques, each patient's treatment plan is customized, to produce high gradient dose distribution to the target and low dose to the critical organs. volumetric modulated arc therapy (vmatrapidarc) produces highly conformal dose distribution by simultaneously changing multi-leaf collimator (mlc) position, dose rate and gantry speed during patient treatment.1-3 complex treatment deliveries demand a comprehensive quality assurance (qa) procedure. american association of physicists in medicine task group (aapm tg)-824 recommends verification of intensity modulated treatment plans with an independent qa method before treatment delivery. traditionally pretreatment qa’s are performed in a phantom using ion chamber, film, 2d array, and electronic portal imaging device (epid). each of these devices has been proven useful but has its own limitations.5-11 position of ion chamber in the high dose gradient area leads to discrepancy between measured and the treatment planning system (tps) calculated dose. film shows excellent spatial resolution; however, problems like chemical processing, scanner readout, and time delay exists. a 2d array shows the dose distribution immediately after the treatment delivery, but their results have limited resolution. also, results provided by them cannot be directly used to identify delivery errors in tumor and normal tissues. benjamin et al.12 showed that there is lack of correlation between gamma passing rates from 2d array and dose differences in critical anatomic regions of interest. to address this issue, alternate qa techniques has been developed to verify the 3d dose distribution by measuring fluence at different gantry angle using ion chamber matrix or epid in a patient computed tomography (ct) scan.13-18 the compass qa system (iba dosimetry, germany) is one such technique which uses matrixxevolution along with gantry http://ijcto.org/index.php/ijcto/index http://ejourpub.com/ http://dx.doi.org/10.14319/ijcto.0204.16 2 thirumalai swamy et al.: 3d pretreatment qa for vmat international journal of cancer therapy and oncology www.ijcto.org © thirumalai swamy et al. issn 2330-4049 angle sensor. it consists of (i) a measurement-based dose reconstruction, and (ii) model-based dose calculation. measurement based dose reconstruction (i) detector dose response is predicted from the patient treatment plan parameters. (ii) measured dose response from the matrixevolution is then compared with predicted dose response. (iii) the difference between the predicted and measured response along with correction kernel was used to derive the reconstruction fluence. finally reconstructed fluence is fed to the dose engine based on collapsed cone model for computation of 3d dose within the patient ct scan. the dose calculated from the reconstructed fluence is referred as “indirectly measured” (compass measured). model based dose calculation compass system can compute dose in patient ct scan using inbuilt beam model. the purpose of the dose computation is to provide an independent cross-verification of tps calculated dose. in addition, compass has a facility to compare the 3d dose distribution and dose volume histograms (dvh) between measured and tps calculated. previous studies have validated the dose reconstruction method of compass system for fixed field imrt against film based qa in phantoms.13, 15, 17 ramesh et al.14 has shown the experimental validation of compass system for rotational imrt in inhomogeneous phantom. this study focuses on pretreatment qa of vmat treatment plan on “measurement based dose reconstruction”. we have evaluated the performance of compass 3d dosimetry system clinically: (i) in open field sizes (10 × 10 cm2 and 20 × 20 cm2) to evaluate the accuracy of beam modeling both in homogeneous and inhomogeneous media, (ii) to check the accuracy of the system in detecting mlc and dose errors and (iii) to implement the system for vmat patient specific qa. methods and materials all measurements were performed using 6 mv photon beam from dual energy clinac-ix (varian medical systems, palo alto, usa). the machine was equipped with millennium 120 mlc, on-board imager (obi) and maximum dose rate of 600 mu/min. conventional pretreatment qa for vmat plans were performed with point dose measurements and 2d planar dosimetry using 0.13 cc ionization chamber in a cube phantom and matrixxevolution in multicube phantom (iba dosimetry) respectively. matrixxevolution contains 1020 parallel plane ion chambers (32 × 32 matrix) with an active area of 24.4 × 24.4 cm2 having 7.62 mm resolution at isocenter of 100 cm. in point dose measurement, percentage dose variation was calculated between the measured dose using ion chamber and the calculated dose in eclipse tps. for 2d planar dosimetry (frontal plane), global gamma analysis was performed using omnipro im’rt software with criteria of 3% dose difference (dd) and 3mm distance to agreement (dta). in this study, compass (v2.1) was used as a pretreatment 3d qa tool to validate vmat plans. dose response from treatment plans was measured using matrixxevolution with 5 cm rw3 buildup plates and gantry angle sensor placed on a gantry holder mount, figure 1 (source to detector distance of 76.2 cm). the dose calculation engine in the compass system is collapsed cone convolution/superposition (ccc/s) algorithm, whereas eclipse tps uses analytical anisotropic algorithm (aaa). since these two algorithms use different approach in dose calculation, simple open field sizes were first validated in both homogeneous and inhomogeneous mediums. fig.1: setup for the pretreatment quality assurance for vmat treatment delivery. matrixxevolution with 5 cm rw3 buildup plates and gantry angle sensor placed on a gantry holder mount with source to detector distance-76.2 cm. open field measurements to verify the accuracy of beam modeling and algorithm difference, the fluence for mlc defined open fields (ranging from 5 × 5 cm2 to 25 × 25 cm2) were acquired by compass system on a homogeneous phantom. average dose calculated and measured by eclipse tps and compass qa system respectively were compared at normalization, inner, outer, penumbra and buildup regions as per aapm tg-53 19 recommendations (figure 2a). average dose had been compared for different hounsfield unit (hu) mediums teflon (990 hu), derlin (340 hu), acrylic (120 hu), polystyrene (-35 hu), ldpe (-100 hu), pmp (-200 hu) and air (-1000 hu) in cat phantom (figure 2b). this average dose comparison was done for two sets of mlc defined open fields (10 × 10 cm2 and 20 × 20 cm2) in an inhomogeneous phantom. volume 2 • number 4 • 2014 international journal of cancer therapy and oncology 3 www.ijcto.org © thirumalai swamy et al. issn 2330-4049 fig.2 (a): homogeneous phantom created in eclipse tps as per aapm tg-53 recommendations. based on beam geometry, phantom was broken into different regions to analyze the agreement between tps calculated and compass measured dose. fig. 2(b): transverse view of cat phantom ct scan with different hu medium. fig. 3: dose distribution and dvh comparison between eclipse tps calculated and compass measured for an h&n patient. intentional error measurements to validate the accuracy of the compass system, vmat plans with known dose error of ±3 and ±5% and mlc errors of 1, 3 and 5 mm due to one side of mlc bank mis-calibration were delivered. for 2d planar dosimetry, dose plane from tps plan without error was used as reference in omnipro im’rt software for gamma analysis. for 3d dosimetry, vmat plan without error was exported to compass system. patient plan evaluation 10 head & neck (h&n) and 10 pelvis vmat plans with two full arcs (181°-179° clock wise / counter clock wise) were chosen for this study. the h&n patients contain three planning target volumes (ptv) with different level of dose prescription (simultaneous integrated boost, figure 3) and single ptv for pelvis patients. vmat plans were optimized in eclipse tps (version 8.9) using progressive resolution optimizer -ii and final dose calculations were performed using aaa with 2.5 mm grid resolution. for pretreatment 3d qa, these vmat plans along with patient’s ct scan, structure set and 3d dose planes were exported to compass in dicom rt format. on treatment machine, matrixxevolution (trigger mode) was used for measuring dose response. compass system calculates predicted dose response using dicom rt plan parameters (gantry angle, mlc position, mu, etc) from tps, detector model and in-built beam model. this predicted dose response was compared against the corresponding measured dose response and the difference was incorporated in dose calculation (figure 4). the final dose distribution was reconstructed on patient ct using ccc/s algorithm with same grid size of 2.5 mm. the average doses for ptv’s and organs 4 thirumalai swamy et al.: 3d pretreatment qa for vmat international journal of cancer therapy and oncology www.ijcto.org © thirumalai swamy et al. issn 2330-4049 at risk (oar’s) in h&n as well as pelvis patients were compared between tps calculated and compass measured. dose to 95% of the ptv volume (d95) and max dose to spinal cord (d1) was also evaluated. the average 3d global gamma was calculated using criteria of 3mm dta and 3% dd. results open fields the percentage difference of average dose between tps calculated and compass measured for different region and hu material were shown in figure 5a and 5b respectively. in order to understand the dose difference arising from the beam modeling, the open field measurements were analyzed. percentage difference of average dose for all open fields in normalization, inner, penumbra and buildup regions was less than aapm tg-53 19 recommended value 0.5%, 1.5%, 10% (2mm) and 20% respectively. for outer region suggested value was 2%, but in our study due to low dose a maximum difference of 8.3% was observed. fig. 4: the predicted dose response by compass system was compared against the corresponding measured dose response from matrixxevolution. the difference in response was incorporated in final dose reconstruction. fig. 5 (a): percentage difference in average dose for different regions of interest in homogeneous phantom for mlc defined open fields size of 5 × 5 cm2, 10 × 10 cm2, 15 × 15 cm2, 20 × 20 cm2 and 25 × 25 cm2 respectively. fig. 5 (b): percentage difference in average dose for different hu material in cat phantom for mlc defined open fields 10 × 10 cm2 and 20 × 20 cm2 intentional errors table 1 shows the gamma agreement index (gai) for known dose and mlc errors between tps calculated and matrixxevolution measured in multicube phantom. gai is defined as percentage of points passing the gamma evaluation criteria. compass system provides the clinical relevance of dose and mlc errors by calculating the average dose difference and 3d gamma for ptv, rectum and bladder. table 1: shows gamma agreement index (gai) for measurements with intentional dose and mlc errors, whereas compass system provides the clinical relevance of errors by calculating the average 3d gamma and dose difference for ptv, rectum and bladder. description gai average 3d gamma % difference in average dose ptv rectum bladder ptv rectum bladder without error 97.5 0.33 0.28 0.25 -0.73 3.11 -2.77 3% dose error 94.8 1.03 0.27 0.55 -3.80 0.56 -5.28 5% dose error 89.9 1.50 0.38 0.69 -5.64 -2.66 -6.96 -3% dose error 92.4 0.58 0.40 0.21 2.04 5.22 0.58 -5% dose error 87.3 1.22 0.61 0.45 4.39 7.62 2.81 1mm mlc error 94.3 0.45 0.28 0.5 -1.06 2.61 -6.53 3mm mlc error 92.95 0.77 0.45 0.41 -1.61 2.18 3.33 5mm mlc error 85.65 1.08 0.61 0.78 -0.96 1.30 7.93 volume 2 • number 4 • 2014 international journal of cancer therapy and oncology 5 www.ijcto.org © thirumalai swamy et al. issn 2330-4049 table 2: 3d gamma and dose volume difference between eclipse tps calculated and compass measured for 10 h&n patients ptv’s and oar's. for same patients, point dose difference from ion chamber and 2d gamma from planar dosimetry were listed. parameters structure pt-1 pt-2 pt-3 pt-4 pt-5 pt-6 pt-7 pt-8 pt-9 pt-10 mean ±sd % of point dose difference 0.97 1.07 -1.11 -0.67 -0.93 -1.29 -2.60 2.09 -2.45 0.63 -0.43 1.56 gamma agreement index 96.1 97.0 97.9 95.1 96.7 95.5 97.9 98.3 98.1 95.1 96.7 1.26 % difference in average dose ptv1 -2.02 -1.53 -2.07 -2.46 -2.09 -1.94 -1.18 -1.25 -0.79 -2.97 -1.83 0.65 ptv2 -2.36 -1.47 -1.98 -2.69 -2.08 -1.36 -1.41 -1.38 -0.96 -2.42 -1.81 0.57 ptv3 -2.56 -0.35 -1.62 -1.88 -2.91 -1.37 -2.62 -2.65 -1.65 -2.71 -2.03 0.81 rt parotid 0.71 -4.00 -3.93 -1.89 4.74 -3.10 -2.75 2.38 -2.05 -4.52 -1.44 3.07 lt parotid -2.42 -2.69 0.33 3.76 3.13 -2.50 1.23 -0.51 -1.28 3.99 0.30 2.62 spinal cord -2.95 -1.12 -2.87 -3.17 -0.83 -1.49 0.23 -1.23 -0.57 -1.18 -1.52 1.13 average 3d gamma ptv1 0.37 0.33 0.49 0.31 0.41 0.57 0.40 0.36 0.27 0.44 0.40 0.09 ptv2 0.39 0.30 0.45 0.36 0.44 0.41 0.36 0.33 0.27 0.48 0.38 0.07 ptv3 0.43 0.24 0.30 0.41 0.46 0.52 0.46 0.56 0.40 0.54 0.43 0.10 rt parotid 0.14 0.30 0.08 0.22 0.25 0.40 0.22 0.11 0.13 0.30 0.22 0.10 lt parotid 0.31 0.26 0.18 0.22 0.29 0.28 0.14 0.09 0.11 0.14 0.20 0.08 spinal cord 0.39 0.11 0.36 0.21 0.20 0.37 0.24 0.15 0.11 0.18 0.23 0.11 % difference in d95 ptv1 -1.95 -2.83 -1.80 -2.22 -2.28 -1.05 -0.26 -0.91 -0.90 -2.50 -1.67 0.84 ptv2 -2.29 -1.10 -1.72 -2.23 -2.36 0.29 -0.99 -1.80 -0.52 -2.24 -1.50 0.89 ptv3 -2.20 0.86 -0.23 -0.84 -2.56 1.85 -1.35 -2.68 -0.16 -2.33 -0.96 1.54 % difference in d1 spinal cord -1.88 -1.00 -3.17 -1.14 -1.37 -2.84 -0.27 -3.60 0.85 -1.96 -1.64 1.36 table 3: 3d gamma and dose volume difference between eclipse tps calculated and compass measured for 10 pelvis patients. parameters structure pt-1 pt-2 pt-3 pt-4 pt-5 pt-6 pt-7 pt-8 pt-9 pt-10 mean ± sd % of point dose difference 0.16 2.71 0.32 1.6 -0.91 0.1 0.93 0.16 -1.07 -1.11 0.29 1.22 gamma agreement index 98.4 97.2 98.6 99.1 95.1 96.4 97.7 96.3 97.0 97.9 97.4 1.22 % difference in average dose ptv -1.82 -1.27 -0.42 -0.83 -1.29 -1.52 -0.16 -0.60 -1.49 0.82 -0.86 0.79 rectum 0.43 0.50 1.64 2.35 0.40 0.18 3.49 0.39 -3.45 1.13 0.71 1.81 bladder -3.75 -1.97 0.02 -2.03 -1.93 -1.63 -2.38 -2.61 1.06 0.78 -1.44 1.56 bowel -3.19 -0.68 13.1 15.5 0.16 -0.53 17.6 3.34 -0.87 -2.46 4.20 7.99 average 3d gamma ptv 0.50 0.40 0.18 0.28 0.41 0.44 0.42 0.26 0.33 0.33 0.36 0.10 rectum 0.33 0.27 0.20 0.21 0.34 0.14 0.27 0.15 0.12 0.27 0.23 0.08 bladder 0.40 0.34 0.12 0.24 0.41 0.26 0.23 0.18 0.06 0.23 0.25 0.11 bowel 0.28 0.23 0.11 0.18 0.26 0.18 0.2 0.25 0.19 0.20 0.21 0.05 % difference in d95 ptv 0.34 -0.41 0.23 0.07 -0.20 -0.64 -2.43 -0.78 -0.43 -1.43 -0.57 0.84 vmat plans in table 2, 10 h&n patients percentage difference of average dose, percentage difference of d95 and d1 and average 3d gamma between eclipse tps calculated and compass measured for ptv's and critical oar's were listed. also, percentage variation of point dose measurement and gai was listed. table 3 summarizes the percentage difference of average dose, percentage difference of d95 and average 3d gamma for ptv, rectum, bladder and bowel for 10 pelvis patients. discussion advantage of compass 3d dosimetry system over other qa systems is its capability of performing 3d dose reconstruction on patient ct scan using beam modeling, detector measurement and treatment plan. the dose calculation algorithm in an inhomogeneous medium was completely different in eclipse tps and compass 3d dosimetry system. the compass uses ccc/s algorithm, where the dose calculation is based primarily on a point source dose spread array. the eclipse tps uses aaa wheredose calculation is based on a pencil beam in association with lateral density scaling. in ccc/s, the dose at a point from a point source of given terma (total energy released per unit mass) to the dose at another location in a patient can be calculated by scaling both primary and scatter. point to point density scaling of this kind is not feasible by the pencil beam kernel method. the point spread kernel based method allows greater flexibility in dealing with 3d inhomogeneous medium than pencil beam kernel. due to this, maximum average dose difference of 3.2% in air was observed.14, 20 open field measurements provide vital information for fine tuning of beam 6 thirumalai swamy et al.: 3d pretreatment qa for vmat international journal of cancer therapy and oncology www.ijcto.org © thirumalai swamy et al. issn 2330-4049 modeling and help to understand the efficiency of dose reconstruction, especially in the buildup, air and penumbra region, so that one can set the tolerance level when oar falls in region of interest. for example, in h&n patients lips lie in surface (build-up), trachea lies in air and cochlea lies in the field border (penumbra). for ptv in table 1, there was a systematic decrease in gai and increase in average 3d gamma with respect to increase in treatment delivery errors. however, 2d planar dosimetry does not provide any clinically relevant information about the results,12 whereas compass system provides the significance of error in ptv and as well as in oar’s. the information provided by traditional 1d point dosimetry and 2d planar devices cannot easily be translated onto dose deviations in the tumor and/or at oar's. dvh based evaluation will be a good alternative since it allows physicist and physician to accept or reject the treatment plan based on the dose difference in ptv and oar's. measurements based dose reconstruction of compass enables us to verify the treatment delivery with acceptable accuracy (±5%). ptv in table 1 shows there was a systematic increase and decrease in the percentage difference of average dose with respect to known dose delivery errors, and an increase in average 3d gamma with planned mlc errors.16,21 in the compass system, the difference between predicted and measured response is into two components.16 the first component is a scaling correction (acorr) factor, which is used to find dose errors (incorrect mu) and the second component is the remaining residual response, which is used to reconstruct mlc errors. the calculation grid resolution used in the tps and compass affects the accuracy of the dose distribution calculated. literatures have reported that a 2.5 mm isotropic grid produces an accuracy of about 1% in the high-dose gradient region of an imrt plan consisting of multiple fields.23 benedict et al.23 and park et al.24 have recommend grid size less than 3 mm for stereotactic treatments. in both eclipse tps and compass qa system grid size resolution can be varied from 1 mm to 5 mm, for our study we have chosen 2.5 mm grid size. although smaller grid size can yield more accurate results, 2.5 mm grid size was chosen by optimizing the accuracy and computational time. the results show that 3d dose parameters were well within the clinically acceptable tolerance level of ±5%.22 the average 3d gamma for ptv's and oar’s for twenty patients used in this study were less than the recommended value of 0.6 by visser et al.17 in three pelvis cases due to low dose of bowel, the percentage difference of average dose was more than 10%. dvh in compass provides many statistical tools; however, we cannot judge plan quality by choosing one criteria, as the percentage difference in average dose, dose at volume and volume at dose will be too high for structure lying in low dose region. for higher deviation of fluence over small distances there are limitations due to the reconstruction capabilities of compass and chamber resolution of matrixxevolution. so compass may slightly underestimate and/oroverestimate the actual delivered dose for oar's.14 despite local inaccuracies in the dose reconstruction, godart et al.16 have proven that compass can be used to perform pretreatment verification of imrt treatment plans. compass can compute dose in patient ct scan using only inbuilt beam model (without measurements). this model based dose calculation, function as an independent secondary tps verification. compass have dose calculation engine (ccc/s) similar to tps, it not only verify the plan parameters (mu) but also provides anatomically localized qa dose information. kunnanchath et al.25 have showed good agreement in comparison of eclipse tps calculated vs compass calculated with average dose difference less than 1% and average gamma less than 0.5 for ptv and oar’s of 10 head and neck and 10 pelvis imrt plans. previous studies have shown that measurement (matrixxevolution) based dose reconstruction in phantom images were in excellent agreement with the ion chamber results and planar dosimetry (film).13-15 our study shows that compass is a better system than point and 2d planar dosimetry by providing the 3d dose discrepancies in the region of interest in patient anatomy. conclusion traditionally qa methods are performed in a phantom and it is often difficult to quantify and interpret the results in patient anatomy. the ability of the compass software to reconstruct the 3d dose distribution on patient ct from the measurements, provides a unique perspective for medical physicist and radiation oncologist to evaluate the patient’s qa plan. the results from this study show that the compass along with matrixxevolution can be effectively used for pretreatment verification of vmat plans and it is good enough to find clinical significant errors in dose delivery. conflict of interest the authors declare that they have no conflicts of interest. the authors alone are responsible for the content and writing of the paper. references 1. vanetti e, clivio a, nicolini g, et al. volumetric modulated arc radiotherapy for carcinomas of the oro-pharynx, hypo-pharynx and larynx: a treatment planning comparison with fixed field imrt. radiother oncol 2009; 92:111-7. 2. rana s, pokharel s, zheng y, et al. treatment planning study comparing proton therapy, rapidarc and intensity modulated radiation therapy for a synchronous bilateral lung cancer case. int j cancer ther oncol 2014; 2:020216. http://dx.doi.org/10.1016/j.radonc.2008.12.008 http://dx.doi.org/10.14319/ijcto.0202.16 volume 2 • number 4 • 2014 international journal of cancer therapy and oncology 7 www.ijcto.org © thirumalai swamy et al. issn 2330-4049 3. subramanian s, srinivas c, ramalingam k, et al. volumetric modulated arc-based hypofractionated stereotactic radiotherapy for the treatment of selected intracranial arteriovenous malformations: dosimetric report and early clinical experience. int j radiat oncol biol phys 2012; 82:1278-84. 4. ezzell ga, galvin jm, low d, et al. guidance document on delivery, treatment planning, and clinical implementation of imrt: report of the imrt subcommittee of the aapm radiation therapy committee. med phys 2003; 30:2089-115. 5. dong l, antolak j, salehpour m, et al. patient-specific point dose measurement for imrt monitor unit verification. int j radiat oncol biol phys 2003; 56:867-77. 6. masi l, casamassima f, doro r, francescon p. quality assurance of volumetric modulated arc therapy: evaluation and comparison of different dosimetric systems. med phys 2011; 38: 612-22. 7. herzen j, todorovic m, cremers f, et al. dosimetric evaluation of a 2d pixel ionization chamber for implementation in clinical routine. phys med biol 2007; 52:1197-208. 8. fenoglietto p, laliberte b, ailleres n, et al. eight years of imrt quality assurance with ionization chambers and film dosimetry: experience of the montpellier comprehensive cancer center. radiat oncol 2011; 6:85. 9. charland pm, chetty ij, yokoyama s, fraass ba. dosimetric comparison of extended dose range film with ionization measurements in water and lung equivalent heterogeneous media exposed to megavoltage photons. j appl clin med phys 2003; 4: 25-39. 10. howell rm, smith ip, jarrio cs. establishing action levels for epid-based qa for imrt. j appl clin med phys 2008; 9: 162721. 11. nicolini g, vanetti e, clivio a, et al. the glaas algorithm for portal dosimetry and quality assurance of rapidarc, an intensity modulated rotational therapy. radiat oncol 2008; 3:24. 12. nelms be, zhen h, tomé wa. per-beam, planar imrt qa passing rates do not predict clinically relevant patient dose errors. med phys 2011; 38:1037-44. 13. boggula r, jahnke l, wertz h, et al. patient-specific 3d pretreatment and potential 3d online dose verification of monte carlo-calculated imrt prostate treatment plans. int j radiat oncol biol phys 2011; 81:1168-75. 14. boggula r, lorenz f, mueller l, et al. experimental validation of a commercial 3d dose verification system for intensity-modulated arc therapies. phys med biol 2010; 55:5619-33. 15. korevaar ew, wauben dj, van der hulst pc, et al. clinical introduction of a linac head-mounted 2d detector array based quality assurance system in head and neck imrt. radiother oncol 2011; 100:446-52. 16. godart j, korevaar ew, visser r, et al. reconstruction of high-resolution 3d dose from matrix measurements: error detection capability of the compass correction kernel method. phys med biol 2011; 56:5029-43. 17. visser r, wauben dj, de groot m, et al. efficient and reliable 3d dose quality assurance for imrt by combining independent dose calculations with measurements. med phys 2013; 40:021710. 18. venkataraman s, malkoske ke, jensen m, et al. the influence of a novel transmission detector on 6 mv x-ray beam characteristics. phys med biol 2009; 54:3173-83. 19. fraass b, doppke k, hunt m, et al. american association of physicists in medicine radiation therapy committee task group 53: quality assurance for clinical radiotherapy treatment planning. med phys 1998; 25:1773-829. 20. hasenbalg f, neuenschwander h, mini r, born ej. collapsed cone convolution and analytical anisotropic algorithm dose calculations compared to vmc++ monte carlo simulations in clinical cases. phys med biol 2007; 52:3679-91. 21. fredh a, scherman jb, fog ls, rosenschöld pm. patient qa systems for rotational radiation therapy: a comparative experimental study with intentional errors. med phys 2013; 40:031716. 22. thwaites d. accuracy required and achievable in radiotherapy dosimetry: have modern technology and techniques changed our views? j phys 2013; 444: 012006. 23. park jy, kim s, park hj, et al. optimal set of grid size and angular increment for practical dose calculation using the dynamic conformal arc technique: a systematic evaluation of the dosimetric effects in lung stereotactic body radiation therapy. radiat oncol 2014; 9:5. 24. benedict sh, yenice km, followill d, et al. stereotactic body radiation therapy: the report of aapm task group 101. med phys 2010; 37:4078-101. 25. kunnanchath j, majumdar skd, tharmarnadar g, et al. validation of compass qa system and the independent verification of dose calculation algorithm for imrt patient specific plans. transworld medical journal 2014; 2:170-5. http://dx.doi.org/10.1016/j.ijrobp.2011.02.005 http://dx.doi.org/10.1118/1.1591194 http://dx.doi.org/10.1016/s0360-3016(03)00197-4 http://dx.doi.org/10.1118/1.3533900 http://dx.doi.org/10.1088/0031-9155/52/4/023 http://dx.doi.org/10.1186/1748-717x-6-85 http://dx.doi.org/10.1120/1.1522990 http://dx.doi.org/10.1120/1.1522990 http://www.ncbi.nlm.nih.gov/pubmed/18716584 http://dx.doi.org/10.1186/1748-717x-3-24 http://dx.doi.org/10.1118/1.3544657 http://dx.doi.org/10.1016/j.ijrobp.2010.09.010 http://dx.doi.org/10.1088/0031-9155/55/19/001 http://dx.doi.org/10.1016/j.radonc.2011.09.007 http://dx.doi.org/10.1088/0031-9155/56/15/023 http://dx.doi.org/10.1118/1.4774048 http://dx.doi.org/10.1088/0031-9155/54/10/014 http://dx.doi.org/10.1118/1.598373 http://dx.doi.org/10.1088/0031-9155/52/13/002 http://dx.doi.org/10.1118/1.4788645 http://dx.doi.org/10.1088/1742-6596/444/1/012006 http://dx.doi.org/10.1186/1748-717x-9-5 http://dx.doi.org/10.1118/1.3438081 http://www.tmjournals.com/pdf/validation%20of%20compass%20qa%20system%20and%20the%20independent%20verification%20of%20dose%20calculation%20algorithm%20for%20imrt%20patient%20specific%20plans.pdf international journal of cancer therapy and oncology www.ijcto.org corresponding author: carmen salvador coloma; department of medical oncology, hospital universitari i politècnic la fe, valencia, spain. cite this article as: salvador-coloma c, bennis m, díez-langhetée l, niño-gómez o, reche-santos e, juan-vidal o. intestinal pseudo-obstruction: an important diagnostic challenge. int j cancer ther oncol 2015; 3(3):339. doi: 10.14319/ijcto.33.9 [a part of this research was presented at desafío oncológico-2014, which was held from march 12april 12, 2014 in valencia, spain] © salvador-coloma et al. issn 2330-4049 intestinal pseudo-obstruction: an important diagnostic challenge carmen salvador coloma1, mohamed hassan bennis2, lydia díez langhetée3, óscar niño gómez1, encarnación reche santos1, óscar juan vidal1 1department of medical oncology, hospital universitari i politècnic la fe, valencia, spain 2department of medical oncology, hospital de xativa, valencia, spain 3department of internal medicine, hospital universitari i politècnic la fe, valencia, spain received april 12, 2015; revised may 12, 2015; accepted may 17, 2015; published online june 09, 2015 case report abstract we present the case of a 72-year-old patient admitted on various occasions with symptoms of intestinal pseudo-obstruction. extensive diagnostic tests eventually found that the patient had small-cell lung cancer associated with high anti-hu antibody titres, which pointed to a probable paraneoplastic intestinal obstruction syndrome associated with small-cell lung cancer. a paraneoplastic syndrome causing abnormal changes in gastrointestinal motility can be the first signs of small cell lung cancer. these syndromes improve with treatment of the underlying disease, as seen in our patient, who stopped having episodes of i ntestinal pseudo-obstruction after administration of chemotherapy. keywords: lung cancer; small-cell lung cancer; anti-hu; paraneoplastic syndrome; intestinal obstruction introduction a 72-year-old patient with a number of cardiovascular risk factors (hypertension, diabetes, dyslipidaemia, obesity and smoking, with a history of 120 pack-years) and chronic obstructive pulmonary disease on treatment with insulin, antihypertensive drugs, lipid-lowering drugs and bronchodilators. he came to accident and emergency department with a three-day history of nausea, vomiting, intolerance of oral diet and generalised abdominal pain associated with not having passed wind or moved his bowels for eight days. the patient’s general condition was fair. haemodynamically was stable. heart and lung sounds were normal. abdomen was distended. tympanic percussion was observed. no bowel sounds were detected. diffuse pain on abdominal palpation was observed. no relevant findings on rectal examination and the rest of examination were found. additional tests were done: normal blood test results except creatinine 1.53 mg/dl; urea 71 mg/dl; crp 89 mg/l; transaminases and bilirubin within normal limits; haemoglobin 11.2 g/dl; mcv 74 fl; mch 22.9 pg; leucocytes 10.2×103 per ul (differential normal); quick’s test 72%. the x-ray abdomen showed small bowel loops greatly dilated and no gas observed in colon, even distally. erect, there areair-fluid levels and more than three levels. images suggestive of small bowel obstruction (figure 1). the ct abdomen-pelvis scan manifested a distension of stomach and jejunum as far as right iliac fossa, where change in lumen visible although with no evidence of obstructive cause. no other relevant findings (figure 2). fig. 1: image suggestive of small bowel obstruction. http://www.ijcto.org/ http://www.ejourpub.com/ http://dx.doi.org/10.14319/ijcto.33.9 2 salvador-coloma et al.: paraneoplastic syndrome international journal of cancer therapy and oncology www.ijcto.org © salvador-coloma et al. issn 2330-4049 fig. 2: distension of stomach and jejunum as far as right iliac fossa, where change in lumen visible although with no evidence of obstructive cause. table 1: intestinal pseudo-obstruction causes. autoimmune diseases infectious diseases endocrine diseases neurological diseases oncological disease myopathy granulomatous diseases drugs other causes lesa hivc hypoparathyroidism d.ng pheo-chromo cytoma mmj tuberculosis antidepressants ehlers-danlos crohn disease cmvd hypothyroidism stroke multiple myeloma duchenne sarcoidosis antiparkisonian radiation enteritis celiac disease vzve hyperthyroidism m.sh m.dk wegener vincristine eosinophilic gastroenteritis scleroderma vebf paraneoplastic dofl churg strauss diltiazem lymphoid infiltration dmb kawasaki sc injuryi nifedipine sickle-cell anemia chagas amyloidosis narcotics diverticulosis parkinson abbreviations: ales: systemic lupus erythematosus, bdm: diabetes mellitus, chiv: human immunodeficiency virus, dcmv: cytomegalovirus, evzv: varicella zoster, fveb: epstein barr virus, g d.n: diabetic neuropathy, hm.s: multiple sclerosis, ispinal cord injury, jmm: mitochondrial myopathy, km.d: myotonic dystrophy, loculopharyngeal dystrophy. in view of the above, an exploratory laparotomy was performed, but no obstructive component was found, only a dilation of small bowel loops from the ligament of treitz to the terminal ileum with dilation of the caecum without signs of obstructive cause. following the intervention, the patient was transferred to the recovery unit and once he had sufficiently recovered, a ct scan of the chest/abdomen/pelvis was ordered which showed lymphadenopathy-type mediastinal masses in virtually all the node spaces, in addition to ischaemia with pneumatosis intestinalis in the caecum and part of the ascending colon, along with pneumoperitoneum, which was possibly secondary to microperforation. the patient was eventually discharged once normal bowel function was restored, with conservative treatment and follow-up at respiratory medicine outpatients. two weeks after being discharged, the patient had a further episode of abdominal pain, vomiting and diarrhoea lasting a week, with deterioration in his general condition, and had to be re-admitted. suspecting dysentery, tests were ordered for rotavirus and adenovirus antigens, clostridium toxin, parasites in faeces, stool cultures and human immunodeficiency virus (hiv) serology, all of which were negative. a drug-related cause was ruled out. the symptoms were not suggestive of either food poisoning or food allergy. thyroid hormones and transglutaminase antibodies were normal. a colonoscopy was performed showing ulceration of the right colon/caecum; biopsies were taken but results came back as normal. having made good progress, the patient was discharged with the diagnosis of suspected ischemic colitis and an appointment for follow-up at gastrointestinal medicine outpatients. over the following four weeks, he was admitted on two more occasions for partial obstruction which, like the previous episodes, simulated intestinal obstruction but in the absence of any anatomical obstruction. the main causes of intestinal pseudo-obstruction were ruled out (table 1): autoimmune (for not meeting criteria; anas, enas, ancas negative; absence of skin manifestations and normal colonoscopy), endocrine-metabolic (hormones negative), myopathy (biopsy negative), infectious causes (serology negative). at the end of this process, the differential diagnosis was between granulomatous, neurological and oncological diseases. we then ordered a positron-emission tomography (pet) volume 3 • number 3 • 2015 international journal of cancer therapy and oncology 3 www.ijcto.org © salvador-coloma et al. issn 2330-4049 scan, endobronchial ultrasound (ebus) with bronchoalveolar lavage, electromyogram (emg), anti-hu antibodies, mantoux test and tumour markers. the pet showed abnormal uptake in a number of different lymph node regions with suv (standardized uptake value) ranging from 4.8 to 11.3. the mantoux test was negative and tumour markers and angiotensin-converting enzyme (eca) were normal. the pathology results were compatible with small cell lung cancer. at the same time, the lymph node samples were subjected to flow cytometry analysis, ruling out lymph node cell proliferation. with the diagnosis of small cell lung cancer with disease limited to the thorax, the patient was started on cisplatin/etoposide-based chemotherapy with concomitant radiotherapy. we received the positive anti-hu anti-neuronal antibody results after starting the treatment. after five cycles of chemotherapy, the patient’s general condition is good and he has had no further admissions for new episodes of partial bowel obstruction. discussion a paraneoplastic syndrome causing abnormal changes in gastrointestinal motility can be the first signs of small cell lung cancer.2, 3 paraneoplastic syndromes can affect any organ or tissue, including both the central nervous system (cns) and the peripheral nervous system. the latter type occurs in less than 1% of all cancer patients. the cause of the majority of paraneoplastic neurological syndromes is unknown, but it is thought that the pathogenesis is immune-mediated due to fact that the expression of neuronal antigens by the tumour triggers an immune response against it and the immune response, in turn, affects the nervous system.3, 4 paraneoplastic autonomic neuropathy normally occurs as a component of other disorders, but it is very rare for it to be the predominant sign.1 these patients may develop life-threatening complications such as gastrointestinal paresis, cardiac arrhythmias and postural hypotension. they are frequently associated with small cell lung cancer (sclc), cancer of the pancreas, carcinoid tumours and lymphoma. anti-hu antibodies are seen in single or multiple (combined forms) paraneoplastic syndromes, such as sensory-motor neuropathy, neuropathy, cerebellar degeneration and gastrointestinal pseudo-obstruction.5-6 the production of hu antigens by sclc is not fully understood. in normal tissues, hu antigen production is restricted to the tissues of the nervous system. this antigen is found in the majority of sclc cases. although the neuroendocrine origin of sclc is widely accepted, only 50% of neuroblastomas and very few neuroendocrine tumours express the hu antigen.7 we have presented the case of a patient with chronic intestinal pseudo-obstruction as the first sign of his cancer. pseudo-obstruction is defined as recurrent or persistent episodes of obstructed bowel symptoms in the absence of any mechanical obstruction. in the majority of reported cases, this complication is associated with sclc and thymoma. nguyen-tat et al. detected in 1 patient, four months earlier of the diagnosis of sclc, a symptomatic paraneoplastic gastroparesis with high anti-hu antibody titres.3 our patient was anti-hu antibody positive and the finding of high anti-hu antibody titres suggests a clear influence of these antibodies on the development of our patient’s disease. however, low titres have been detected in 16% of patients with sclc without paraneoplastic syndrome.8 these antibodies exhibit reactivity against mesenteric plexus neurons producing inflammatory changes at these levels.9 the average time between the development of neurological paraneoplastic syndromes and diagnosis of cancer is four months;1-3 in our case, there was a gap of four and a half months between the onset of symptoms and the histological diagnosis. based on the assumption that paraneoplastic neuropathies are autoimmune disorders, several studies have been carried out with steroids, immuno-suppressants and even plasmapheresis, but with no clinical benefit being found.3-10-11 these syndromes improve with treatment of the underlying disease, as seen in our patient, who stopped having episodes of intestinal pseudo-obstruction after administration of chemotherapy. clinicians should consider paraneoplastic neuropathies, as chronic intestinal pseudo-obstruction, as a differential diagnosis for gastrointestinal dysmotility. identification of paraneoplastic gastroparesis can lead to earlier diagnosis of a malignancy, and, in some cases, better prognosis. conflict of interest the authors declare that they have no conflicts of interest. the authors alone are responsible for the content and writing of the paper. references 1. dalmau j, graus f, rosenblum mk, posner jb. anti-hu--associated paraneoplastic encephalomyelihttp://dx.doi.org/10.1097/00005792-199203000-00001 4 salvador-coloma et al.: paraneoplastic syndrome international journal of cancer therapy and oncology www.ijcto.org © salvador-coloma et al. issn 2330-4049 tis/sensory neuronopathy. a clinical study of 71 patients. medicine (baltimore). 1992;71:59-72. 2. jun s, dimyan m, jones kd, ladabaum u. obstipation as a paraneoplastic of small cell lung cancer: case report and literature review. neurogastroenterology motil. 2005;17:16-22. 3. nguyen-tat m, pohl j, günter e, et al. severe paraneoplastic gastroparesis associated with anti-hu antibodies preceding the manifestation of small-cell lung cancer. z gastroenterol. 2008;46:274-8. 4. abeloff m, armitage j, niederhuber j, et al. síndromes neurológicos paraneoplásicos. oncología clínica. 2005; 1:993. 5. heidenreich f, schober r, brinck u, hartung hp. multiple paraneoplastic syndromes in a patient with antibodies to neuronal nucleoproteins (anti-hu). j neurol. 1995;242:210-6. 6. cuillerier e, coffin b, potet f, et al. paraneoplastic intestinal pseudo-obstruction revealing small cell lung carcinoma: "the anti-hu syndrome". gastroenterol clin biol. 1998; 22: 346-8. 7. dalmau j, furneaux hm, cordon-cardo c, posner jb. the expression of the hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues. am j pathol. 1992;141:881-6. 8. lennon va, sas df, busk mf, scheithauer b. enteric neuronal antibodies in pseudoobstruction with small-cell lung carcinoma. gastroenterology. 1991;100:137-42. 9. altermatt hj, rodriguez m, scheithauer b, lennon va. paraneoplastic anti-purkinje and type 1 anti-neuronal autoantibodies bind selectively to central peripheral and autonomic nervous system cells. lab invest. 1991; 65:412-20. 10. thirkill ce, fitzgerald p, sergutt rc. cancer-associated retinopathy (car syndrome) with antibodies reacting with retinal, optic nerve and cancer cells. n england journal of medicine. 1989; 321: 1589-94. 11. bell ce, seetharam s. expression of endodermally derived and neural crest-derived differentiation antigens by human lung and colon tumors. cancer. 1979; 44:13-8. http://dx.doi.org/10.1097/00005792-199203000-00001 http://dx.doi.org/10.1111/j.1365-2982.2004.00608.x http://dx.doi.org/10.1055/s-2007-963429 http://dx.doi.org/10.1007/bf00919593 http://www.ncbi.nlm.nih.gov/pubmed/97622211415481 http://www.ncbi.nlm.nih.gov/pubmed/97622211845756 http://dx.doi.org/10.1056/nejm198912073212307 http://dx.doi.org/10.1002/1097-0142(197907)44:1<13::aid-cncr2820440103>3.0.co;2-b http://www.ncbi.nlm.nih.gov/pubmed/9762221 http://www.ncbi.nlm.nih.gov/pubmed/97622211921331