DR [page 130] [Dermatology Reports 2011; 3:e57] Combined cetuximab and volumetric modulated arc-radiotherapy in advanced recurrent squamous cell carcinoma of the scalp Uwe Wollina,1 Andreas Schreiber,2 Knut Merla,2 Gunter Haroske3 1Department of Dermatology and Allergology, 2Department of Radiology, and 3Institute of Pathology Georg Schmorl, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany Abstract A 77-year old male patient presented with an ulcerated exophytic tumor (T2, N0, M0) with three macroscopically visible satellite metas- tases in the right temporo-occipital region. Mohs surgery could not control the disease due to lymphangiosis carcinomatosa and perineur- al infiltration, and recurrence of satellite skin metastases. Re-staging demonstrated a T2, N1, M0 profile (stage III, AJCC). Chemotherapy was limited by the patient’s co-morbidities. Therefore, we used targeted therapy with mon- oclonal anti-epidermal growth factor receptor antibody cetuximab in combination with volu- metric modulated arc- radiotherapy (VMAT). Cetuximab was well tolerated except for the loading dose when the patient developed fever chills. To verify the correct application of VMAT, it was applied to a 3-dimensional meas- uring phantom prior to the patient’s first treat- ment session. To minimize these tolerances, patient set-up was checked and corrected by orthogonal fluoroscopic images recorded daily by the on-board imager used in our Varian accelerator. The average daily beam time was 6 min (6 arcs, 767 monitor units); the total treat- ment time including patient set-up and set-up correction was less than 20 min. Combined therapy was well tolerated and complete remis- sion was achieved. Introduction Squamous cell carcinoma (SCC) is one of the most important non-melanoma skin can- cers (NMSC) because of its frequency and because it has a more aggressive course than basal cell carcinoma (BCC), the most common NMSC. SCC development has been linked to chronic UV exposure with an Odds Ratio of 1.77.1 Patient related incidence rates for cuta- neous SCC in Germany has been estimated at 9.7 for females and 17.4 for males.2 Higher incidence rates in Europe have been reported for Scotland (34.7)3 and Spain.4 Diagnosis of SCC depends on clinical data and histopathology. Tumor staging is depend- ent on tumor diameter, invasion into cranial bone, tumor thickness and invasion level, dif- ferentiation, perineural invasion and anatomic location. Furthermore, regional lymph nodes and distant metastases have to be considered.5 The standard treatment of SCC of the head and neck area is Mohs surgery or delayed Mohs. For advanced SCC, radiation therapy is anoth- er therapeutic option.6,7 Since conventional chemotherapy in head and neck SCC (HNSCC) of the mucous mem- branes is associated with significant toxicity, alternatives for cutaneous SCC have emerged. A phase III trial with bleomycin versus other chemotherapy protocols, and prospective observational studies using bleomycin, cis- platin, doxorubicin or oral 5-fluorouracil (5- FU), had low rates of complete responses (0- 33%) but significant adverse effects.8 Interferon in combination with capecitabine (an oral prodrug of 5-FU) is effective in SCC of the head and neck region9 and in the reduction of SCC developing in transplant recipients.10 Response rates of 100% and complete respons- es of up to 50% have been reported.9,10 Advanced SCC shows numerical aberrations in the epidermal growth factor-receptor (EGFR) gene and overexpression of EGF/EGFR.11-14 Therefore, targeted therapy against EGF-receptor (EGFR) would be another option. Recently, monoclonal antibodies against EGFR have become available, includ- ing gefitinib, erlotinib, cetuximab and panitu- mumab.15 Cetuximab is a 152 kDA chimeric IgG1 mon- oclonal antibody of 65% human and 35% murine origin. It specifically binds to EGFR at an extracellular epitope in the ligand-binding domain.16 Pharmacokinetics of single and mul- tiple doses have been extensively evaluated. The drug half-life is 70-100 h.17 There are encouraging data from HNSCC using cetuximab in the treatment of recurrent or metastatic tumors, either alone or in combi- nation with radiation or chemotherapy. Response rates vary between 10-71%. Since 2006, cetuximab is approved for use in combi- nation with radiotherapy in patients with local- ly advanced HNSCC.18-22 There are limited data available for cetux- imab therapy in advanced cutaneous SCC of the head and neck region.23-27 We present a patient who was successfully treated by cetux- imab combined with radiation for locally advanced cutaneous SCC of the scalp. Case Report A 77-year old male patient presented with a large tumor of the scalp that had grown over a period of more than 24 months. He suffered from arterial hypertonia, hyperlipidemia, hype- ruricemia, and liver cirrhosis. On examination, we observed an ulcerated exophytic tumor (approx. 4 cm in diameter) with three macroscopically visible satellite metastases in the right temporo-occipital region (Figure 1). We performed delayed Mohs surgery for both the tumor and the metastases. The defect was covered by large transposition flaps leaving a central area that was closed with a full thickness skin graft. Healing was unremarkable and complete (Figure 2). Histological examination of the species revealed a moderately differentiated SCC (T2, N0, M0; stage II, American Joint Committee on Cancer (AJCC)) with lymphangiosis carcino- matosa, and perineural infiltration and satelli- tosis (Figure 3). Because of the age of the patient and his co-morbidities, we decided against further surgery but initiated a closer follow up. Eight weeks later, the patient presented with ulcerated satellitosis in the frontal and right fronto-temporal area of the scalp. Re- staging demonstrated a T2, N1, M0 profile (stage III, AJCC). The situation was not controllable by sur- gery. Chemotherapy was limited by the patient’s co-morbidities. Therefore, we decid- ed to use targeted therapy with monoclonal anti-epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux®; Bristol-Meyers Sqibb) in combination with radiotherapy. After the loading dose of 400 mg/m2, the patient Dermatology Reports 2011; volume 3:e57 Correspondence: Uwe Wollina, Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Friedri - chstrasse 41, 01067 Dresden, Germany. E-mail: wollina-uw@khdf.de. Key words: advanced squamous cell carcinoma, cetuximab, volumetric modulated arc-therapy Conflict of interest: the authors have no conflict of interest. Received for publication: 20 October 2011. Accepted for publication: 22 October 2011. This work is licensed under a Creative Commons Attribution NonCommercial 3.0 License (CC BY- NC 3.0). ©Copyright U. Wollina et al., 2011 Licensee PAGEPress, Italy Dermatology Reports 2011; 3:e57 doi:10.4081/dr.2011.e57 No n- co mm er cia l u se on ly [Dermatology Reports 2011; 3:e57] [page 131] received 250 mg/m2 once a week for six weeks. Pre-medication consisted of 100 mg pred- nisolone i.v., 4 mg dimetindene maleate i.v., 50 mg ranitidine i.v. and 8 mg ondansetron p.o. Cetuximab was well tolerated except for the loading dose when the patient developed fever chills. We gave him dimetinden maleate intra- venously and lowered the infusion speed. There was a fast recovery within a couple of hours. From the second infusion onwards, no further adverse effects of this kind were observed. Within the first week of monoclonal antibody treatment, the patient developed rosacea-like pustules on facial and neck skin. The reaction was scored grade II according to the NCI-CTC scoring system.28 These cuta- neous lesions were treated with metronidazole gel and there was a marked improvement with- in two weeks. The tumor response was visible within the first two weeks of treatment. Nodules became flat and no new nodules developed. The lymph node swelling disappeared. There was an almost complete clinical response at the end of cetuximab therapy. After two weeks of monotherapy, radiothera- py was added. Irradiation was realized by volu- metric modulated arc-therapy (VMAT). In this irradiation technique, the gantry of the accel- erator moves 360° around the patient. Due to the use of a dynamic multileaf collimator, vari- able dose rates and variable gantry speeds, this technique allows the generation of a very com- plex dose distribution in one or two optimized arcs around the patient. Through continuously modulating the applied dose, high doses to the entire tumor volume can be delivered while at the same time sparing normal healthy tissue. Another major advantage of VMAT is the dra- matically shorter treatment time compared to all existing methods, including tomotherapy. In the application of this technique, the exact and reproducible set-up of the patient during every treatment session is of crucial importance. We used a custom-formed 1 cm thick thermoplastic head-mask for immobiliza- tion and fixation. This mask was lined inside with bolus material to shift the dose maximum in the superficial treatment area. The physical treatment plan was designed according to a proposal of Skinner29 consisting of 3 non-coplanar arcs. This technique pro- vides homogeneous dose distribution and tar- get coverage but still results in a relevant dose to brain (mean dose 28 Gy) and eyes. We modified this approach in order to improve the protection of brain and eyes: both Article Figure 1. Initial presentation of cutaneous squamous cell carcinoma of the scalp with satellitosis. Figure 2. Clinical presentation nine days after after Mohs surgery. Figure 3. Histological evaluation demon- strates (A) lymphatic and (B) perineural invasion (hematoxylin-eosin, x20). Figure 4. Improved treatment technique is based on 2 coplanar and 4 non-coplanar arcs. Figure 5. Image of one partial non-copla- nar arc demonstrating the dose deposition mainly in a tangential direction to the tar- get volume. A B Figure 6. Image of one partial non-copla- nar arc demonstrating the dose deposition mainly in a tangential direction to the tar- get volume. No n- co mm er cia l u se on ly [page 132] [Dermatology Reports 2011; 3:e57] the non-coplanar arcs were divided into two partial arcs (Figure 4). In summary, the dose deposition in the target volume is built up mainly by tangential irradiation (Figure 5) and optimal sparing of all organs at risk is achieved (Table 1, Figure 6). To verify the correct appli- cation of this treatment plan, it was applied to a 3-dimensional measuring phantom (ArcCheck, Sun Nuclear Corp., Melbourne/FL, USA) prior to the patient’s first treatment ses- sion. This showed good agreement between calculated and measured dose distributions [gamma (3%, 3 mm) = 95.4]. Additional checks were carried out to investigate influ- ences of deviations in daily patient set-up or bolus attachment on the dose distribution, in target volume and organs at risk. All results demonstrated that a safe application of this treatment plan is guaranteed, taking account of the tolerance levels achievable in daily routine clinical practce. To minimize these tolerances, patient set-up was checked and corrected by orthogonal fluoroscopic images recorded daily by the on-board imager (OBI) used in our Varian accelerator. Average daily beam time was 6 min (6 arcs, 767 monitor units). Total treatment time, including patient set-up and set-up correction, was less than 20 min. Radiotherapy was well tolerated and the patient achieved complete remission (Figure 7). Discussion Advanced cutaneous SCC has a risk of metastases and relapse. In a prospective analy- sis of 653 patients, tumor thickness more than 2mm and tumor size more than 6 mm are the major risk factors for these phenomena. Other features characterizing high-risk cutaneous SCC include poor differentiation, perineural or lympho-vascular infiltration, and bone inva- sion.5,30,31 Article Table 1. Main values characterizing dose distribution in planning target volume and organs of risk. PTV Volume > 95 % dose 92% Brain maximum dose 17.2 Gy Spinal cord maximum dose 34.3 Gy Optic nerves (left/right) maximum dose 16.4/22.0 Gy Chiasma maximum dose 7.3 Gy Eyes (left/right) maximum dose 11.1/28.2 Gy Eye lenses (left/right) maximum dose 4.1/9.0 Gy Table 2. Case reports of cutaneous Squamous cell carcinoma treated with cetuximab. Patients Tumor site Treatment Outcome References 1. 92 yrs, male Forehead Cetuximab weekly CR for at least Kim et al. 201123 for 3 months 10 months 2. 79 yrs, male Back 3 cycles of cetuximab CR for at least Miller et al. 201024 weekly for 4 weeks 26 months 3. 73 yrs, male Scalp Weekly cetuximab CR Baumann et al. 200725 4. 71 yrs, female Nose Weekly cetuximab Almost cleared 5. 67 yrs, male Ear 7 weeks cetuximab CR, 3 months Giacchero et al. 201127 and radiotherapy 6. 69 yrs, female Nose 32 weeks cetuximab PR, > 18 months and radiotherapy 7. 72 yrs, male Ear 7 weeks cetuximab CR, 5 months and radiotherapy 8. 79 yrs, male Scalp 16 weeks cetuximab CR, >21 months and radiotherapy 9. 82 yrs, female infra-orbital 46 weeks cetuximab SD, 11 months 9. 69 yrs, male temple 11 weeks cetuximab PD 10. 57 yrs, male sacrum 9 weeks cetuximab PR, 6 months and radiotherapy 11. 78 yrs, male scalp 7 weeks cetuximab PR, not reported and radiotherapy 12. 24 yrs, female arm 12 weeks cetuximab PR; > 3 months Arnold et al. 200926 12. 77 yrs, male scalp 6 weeks cetuximab CR, > 3 months Present and radiotherapy Figure 7. Treatment course with cetuximab and radiotherapy. (A) Relapse with multi- ple ulcerated satellites eight weeks after Mohs surgery. (B) At the end of radiother- apy. Ulcers were tumor free. (C) After three months. A B C No n- co mm er cia l u se on ly [Dermatology Reports 2011; 3:e57] [page 133] We report a successful treatment of advanced cutaneous SCC with regional lym- phnode involvement of the scalp with the anti- EGFR drug cetuximab and radiation after pri- mary surgery. There are limited data available in this indication for cutaneous SCC despite approval for HNSCC23-27 (Table 2). A single phase II trial performed in France has only been published as an abstract. Thirty-six patients with advanced cutaneous SCC were involved. Cetuximab therapy alone was able to control the disease in 69% of patients making this well tolerated treatment of interest for eld- erly patients with SCC.32 HNSCC and cutaneous SCC over-express EGFR, a 170 kDa transmembrane protein, linked to tumor progression and autonomous tumor cell growth. EGFR signaling in the cell is mediated by three major pathways: RAS-MAP kinases, PI3K-AKTC, and SCR-STAT. Response to cetuximab in these tumors has been associ- ated to overexpression of signal transducers and activators of transcription (STAT) gene STAT5A and ephrin receptor gene EPHA2.33 Cetuximab demonstrated in vitro antiprolifer- ative activity, direct cytotoxicity, and the poten- tiation of chemo- or radiotherapy18,19 in HNSCC. In vitro studies using cell lines derived from cutaneous SCC further substanti- ated these results. Xenograft tumor models gave evidence for the anti-angiogenic, apoptot- ic and anti-proliferative activity of cetuximab.34 A great advantage of cetuximab compared to traditional chemotherapy is the fact that there is no additional hepatotoxicity.35 EGFR- inhibitors can induce skin reactions like papu- lopustular rash or periungual inflammation, compromised hair growth, skin dryness and itching. These types of adverse effects have been linked to better outcome in patients with colorectal cancer and targeted therapy against EGFR.36 In a recent investigation, 49% of patients with HNSCC developed a grade III to IV radia- tion dermatitis with concurrent cetuximab.37 A possible explanation is the reduction of a major anti-oxidant enzyme, i.e. glucose-6- phosphate dehydrogenase by cetuximab.38 In the present case, however, severe radiation dermatitis was not observed. Other EGFR inhibitors have been developed, such as erlotinib and gefitinib, but there are limited reports of experience with these drugs in cuta- neous SCC.8,33 Radiotherapy was added with intention to cure. Given this, a total dose of at least 60 Gy in six weeks based on daily doses of 2.0 Gy is nec- essary when using percutaneous irradiation.27 Traditionally these lesions were treated by two different methods:39 by afterloaded Iridium-192 skin moulds. Unfortunately, this technique is very time- consuming in terms of preparation, plan- ning, quality assurance and implementa- tion. Additionally, it results in high doses to brain and optical structures, and the actually delivered dose may vary from the planned dose; most commonly combined photon-electron plans are used. This is technically very com- plex due to necessary shiftings of match- lines between different fields during the treatment course, and results in less confor- mal plans with large dose gradients in the target volume. Therefore, studies using the application of helical tomotherapy were initiated to over- come these problems.40 In recent publications, volumetric modulated arc-therapy (VMAT) has also been demonstrated to be an alternative option; it is clinically acceptable and compara- ble to tomotherapy.41 It provides significantly more homogeneous dose distribution and reduces high-dose regions in the brain to a larger degree than all conventional methods. An additional advantage is the short treatment time. In conclusion, the present case report and other reports from the literature (Table 2) sug- gest that the combination of monoclonal EGFR antibody and radiotherapy is effective in con- trolling advanced cutaneous SCC with or with- out metastases in analogy to HNSCC. The recent advances in radiotherapy offer an effec- tive and well tolerated treatment option. In summary, VMAT is an excellent method for total scalp irradiation comparable to helical tomotherapy. The treatment achieved a com- plete stable remission without major toxici- ties. References 1. Schmitt J, Seidler A, Diepgen TL, Bauer A. Occupational ultraviolet light exposure increases the risk for the development of cutaneous squamous cell carcinoma: a systematic review and meta-analysis. Br J Dermatol 2011;164:291-307. 2. Stang A, Ziegler S, Büchner U, et al. Malignant melanoma and nonmelanoma skin cancers in Northrhine-Westphalia, Germany: a patient- vs. diagnosis-based incidence approach. Int J Dermatol 2007; 46:564-570. 3. Brewster DH, Bhatti LH, Inglis JH, et al. Recent trends in incidence of non- melanoma skin cancer in the East of Scotland, 1992-2003. Br J Dermatol 2007; 156:1295-300. 4. Revenga Arranz F, Paricio Rubio JF, Mar Vásquez Salvado M, del Villar Sordo V. Decriptive epidemiology of basal cell carci- noma and cutaneous squamous cell carci- noma in Soria (north-east Spain) 1998- 2000: a hospital-based survey. J Eur Acad Dermatol Venereol 2004;18:137-41. 5. Farasat S, Yu SS, Neel VA, et al. A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: Creation and rationale for inclusion of tumor (T) characteristics. J Am Acad Dermatol 2011;64:1051-9. 6. Ho T, Byrne PJ. Evaluation and initial man- agement of the patient with facial skin cancer. Facial Plast Surg Clin North Am 2009;17:301-7. 7. Jambusaria-Pahlajani A, Miller CJ, Quon H, et al. Surgical monotherapy versus sur- gery plus adjuvant radiotherapy in high- risk cutaneous squamous cell carcinoma: a systematic review of outcomes. Dermatol Surg 2009;35:574-85. 8. Cranmer LD, Engelhardt C, Morgan SS. Treatment of unresectable and metastatic cutaneous squamous cell carcinoma. Oncologist 2010;15:1320-8. 9. Wollina U, Hansel G, Koch A, Köstler E. Oral capecitabine plus subcutaneous interferon alpha in advanced squamous cell carcinoma of the skin. J Cancer Res Clin Oncol 2005;131:300-4. 10. Jirakulaporn T, Endrizzi B, Lindgren B, et al. Capecitabine for skin cancer preven- tion in solid organ-transplanted recipi- ents. Clin Transplant 2010;doi:10.1111/j. 1399-0012.2010.01348.x. 11. Wollina U, Prochnau D, Hoffmann A, et al. Vasoactive intestinal peptide and epider- mal growth factor: co-mitogens or inhibitors of keratinocyte proliferation in vitro? Int J Mol Med 1998;2:725-30. 12. Maubec E, Duvillard P, Velasco V, et al. Immunohistochemical analysis of EGFR and HER-2 in patients with metastatic squamous cell carcinoma of the skin. Anticancer Res 2005;25:1205-10. 13. Schlauder SM, Calder KB, MoodyP, Morgan MP. HER2 and EGFR expression in cuta- neous spindle squamous cell carcinoma. Am J Dermatopathol 2007;29:559-63. 14. Toll A, Salgado R, Yèbenes M, et al. Epidermal growth factor receptor gene numerical aberrations are frequent in actinic keratoses and invasive cutaneous squamous cell carcinoma. Exp Dermatol 2010;19:151-3. 15. Amini S, Viera MH, Valins W, Berman B. Nonsurgical innovations in the treatment of nonmelanoma skin cancer. J Clin Aesthetic Dermatol 2010;3:20-34. 16. Goldstein NI, Prewett M, Zuklys K, et al. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1995;1:1311-8. 17. Humbert Y. Cetuximab: an IgG1 monoclon- al antibody for the treatment of epidermal growth factor receptor-expressing tumours. Expert Opin Pharmacother 2004; Article No n- co mm er cia l u se on ly [page 134] [Dermatology Reports 2011; 3:e57] 5:1621-33. 18. Specenier P, Vermorken JB. Cetuximab in the treatment of squamous cell carcinoma of the head and neck. Expert Rev Anticancer Ther 2011;11:511-4. 19. Harrington KJ, Kazi R, Bhide SA, et al. Novel therapeutic approaches to squa- mous cell carcinoma of the head and neck using biologically targeted agents. Indian J Cancer 2010;47:248-59. 20. Tejani MA, Cohen RB, Mehra R. The con- tribution of cetuximab in the treatment of recurrent and/or metastatic head and neck cancer. Biologics Targets Therapy 2010;4:173-85. 21. Dequanter D, Shala M, Paulus P, Lothaire P. Cetuximab in the treatment of head and neck cancer: preliminary results outside clinical trials. Cancer Management Res 2010;2:165-8. 22. Ho C. Cetuximab in locally advanced head- and-neck cancer: defining the population. Curr Oncol 2010;17:48-51. 23. Kim S, Eleff M, Nicolaou N. Cetuximab as primary treatment for cutaneous squa- mous cell carcinoma to the neck. Head Neck 2011;33:286-8. 24. Miller K, Sherman W, Ratner D. Complete clinical response to cetuximab in a patient with metastatic cutaneous squamous cell carcinoma. Dermatol Surg 2010;36:2069- 74. 25. Bauman JE, Eaton KD, Martins RG. Treatment of recurrent squamous cell car- cinoma of the skin with cetuximab. Arch Dermatol 2007;143:889-92. 26. Arnold AW, Bruckner-Tuderman I, Zuger C, Itin PH. Cetuximab therapy of metastasiz- ing cutaneous squamous cell carcinoma in a patients with severe recessive dystrophic epidermolysis bullosa. Dermatology 2009;219:80-3. 27. Giacchero D, Barrière J, Benezery K, et al. Efficacy of cetuximab for unresectable or advanced cutaneous squamous cell carci- noma - a report of eight cases.Clin Oncol (R Coll Radiol) 2011; 23: 716-8. 28. National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_ 4 . 0 2 _ 2 0 0 9 - 0 9 - 1 5 _ Q u i c k Reference_8.5x11.pdf pages 73-74. 29. Skinner M. 2010. Available at: http://my.varian.com/files/Varian%20AAPM % 2 0 U s e r s % 2 0 M e e t i n g % 2 0 2 0 1 0 % 2 0 - %20Skinner.pdf 30. Brantsch KD, Meisner C, Schönfisch B, et al. Analysis of risk factors determining prognosis of cutaneous squamous-cell car- cinoma: a prospective study. Lancet Oncol 2008;9:713-20. 31. Jennings L, Schmults CD. Management of high-risk cutaneous squamous cell carci- noma. J Clin Aesthet Dermatol 2010;3:39- 48. 32. Maubec E, Petrow P, Duvillard P, et al. Cetuximab as first-line monotherapy in patients with unresectable squamous cell carcinoma: final results of a phase II mut- licenter study [abstract]. J Clin Oncol 2010;28:8510. 33. Kotoula V, Lambaki S, Televantou D, et al. STAT-related profiles are associated with patient response to targeted treatments in locally advanced SCCHN. Translation Oncol 2011;4:47-58. 34. Galer CE, Corey CL, Wang Z, et al. Dual inhibition of epidermal growth factor receptor and insulin-like growth factor receptor I: reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma. Head Neck 2011;33:189-98. 35. Pessaux P, Panaro F, Casnedi S, et al. Targeted molecular therapies (Cetuximab and bevacicumab) do not induce addition- al hepatotoxicity: preliminary results of a case-control study. Eur J Surg Oncol 2010:36:575-82. 36. Lacouture ME, Melosky BL. Cutaneous reactions to anticancer agents targeting the epidermal growth factor receptor: a dermatology-oncology perspective. Skin Therapy Lett 2007;12:1-5. 37. Giro C, Berger B, Bölke E, et al. High rate of severe radiation dermatitis during radi- ation therapy with concurrent cetuximab in head and neck cancer: results of a sur- vey in EORTC institutes. Radiother Oncol 2009;90:166-71. 38. Skvortsova I. Oxidative damage and cuta- neous reactions during radiotherapy in combination with cetuximab. Radiother Oncol 2009;90:281-2. 39. Wojcicka JB, Lasher DE, McAfee SS, Fortier GA. Dosimetric comparison of three different techniques in extensive scalp lesion irradiation. Radiother Oncol 2009;91:255-60. 40. Mallik S, Master Z, Gupta T, et al. Brain sparing whole skull/scalp radiotherapy: unique application of helical tomotherapy [abstract]. Int J Radiation Oncol Biol Physics 2009;75:729. 41. Agazaryan N, Tenn S, Chow P, et al. Total scalp irradiation: comparison between vol- umetric modulated arc therapy, helical tomotherapy and conventional electron and photon field combination. Med Physics 2010;37:3319. Article No n- co mm er cia l u se on ly