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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 pre- and 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 pre- and 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 pre- and 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.

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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 pre- andpost-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.



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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%)



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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).



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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.



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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



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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.
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