Hypofractionated palliative radiotherapy for advanced head and neck cancer: The IHF2SQ regimen

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1 ORIGINAL ARTICLE Hypofractionated palliative radiotherapy for advanced head and neck cancer: The IHF2SQ regimen Laurie Monnier, MD, 1 * Emmanuel Touboul, MD, PhD, 1 Catherine Durdux, MD, 2 Philippe Lang, MD, 3 Jean Lacau St Guily, MD, PhD, 4 Florence Huguet, MD, PhD 1 1 Department of Radiation Oncology, Tenon Hospital, Assistance Publique Hôpitaux Universitaires Paris Est, University Pierre et Marie Curie Paris VI, Paris, France, 2 Department of Radiation Oncology, Georges Pompidou Hospital, Assistance Publique Hôpitaux de Paris, University Paris V, Paris, France, 3 Department of Radiation Oncology, Pitie Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, University Paris VI, Paris, France, 4 Departement of Otorhinolaryngology and Head and Neck Surgery, Tenon Hospital, Assistance Publique Hôpitaux de Paris, Cancerest, University Paris VI, Paris, France. Accepted 1 October 2012 Published online 29 January 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Standard treatment for unresectable advanced head and neck squamous cell carcinoma is chemoradiotherapy, which can be toxic, particularly among patients with coexisting medical conditions. We report our experience with the hypofractionated radiotherapy regimen Irradiation HypoFractionnee 2 Seances Quotidiennes (IHF2SQ). Methods. We retrospectively reviewed 78 patients treated with the IHF2SQ regimen. Radiotherapy was administrated as 2 fractions of 3 Gy per day (days 1 and 3), during the first, third, fifth, and seventh week of treatment with concurrent platinum-based chemotherapy. Results. Tolerance was excellent. Forty-one patients had complete or partial response. Median overall survival (OS) was 12.9 months and median progression-free survival (PFS) was 10.3 months. One-year OS, specific survival (SS), and PFS were 58%, 71%, 51.5%, respectively. Independent predictive factors increasing the PFS were response to chemoradiotherapy, male sex, and laryngeal tumor location. Conclusions. This regimen is an alternative to conventional chemoradiotherapy with good response rates and acceptable toxicity for selected patients. VC 2013 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: head and neck cancer, palliation, hypofractionated radiotherapy, chemoradiotherapy, cetuximab *Corresponding author: L. Monnier, Service d Oncologie Radiotherapie, Hôpital Tenon, 4 rue de la Chine, Paris, France. laurie.monnier@tnn.aphp.fr Introduction Head and neck cancer is the fifth most common cancer in terms of incidence in France with 14,350 new cases in 2009 and 5343 deaths. 1 At diagnosis, approximately 60% of patients present with advanced disease (stage Union for International Cancer Control III and IV), for which the prognosis is poor. 2 For these patients, extensive surgery and radiation therapy are used in sequence unless the patient is unable to undergo surgery or has unresectable disease. 3 For many years, external radiation therapy has been the treatment of choice for unresectable disease, resulting in 5-year survival rates below 20%. More recently, additional benefit has been obtained with alteredfractionation radiotherapy (ie, accelerated fractionation or hyperfractionated radiotherapy) and with chemoradiotherapy. 4,5 However, the benefit of chemoradiotherapy is counterbalanced by increased and often prohibitive toxicity, particularly among patients with coexisting medical conditions and decreased performance status. Indeed, in the head and neck cancer population, a significant minority of patients is unsuited for aggressive definitive treatment because of medical comorbidities, distant metastatic disease, very advanced locoregional disease, or a combination of these factors, but still requires some form of treatment for their locoregional disease. For these patients, conventional chemoradiotherapy does not seem reasonable. An effective palliation regimen is one that generates symptom reduction with minimal treatment side effects. Hypofractionated/split-course regimens are frequently used in elderly patients, especially the most fragile, in order to minimize the burden of a relatively long treatment, which generally is associated with tiring daily transportation. Several prospective studies reported an association between the use of hypofractionated regimens and clinical benefit in the management of head and neck cancer. 6 9 Baillet et al 10 at Pitie Salpêtrière Hospital, Paris, set out in the early 1990s to develop a palliative regimen that would be simple to administer and that would provide worthwhile tumor regression and symptom control with minimal acute toxicity. The Irradiation HypoFractionnee avec 2 Seances Quotidiennes (IHF2SQ) regimen proposed palliative hypofractionated radiation therapy with concurrent radiosensitizing chemotherapy. 10 In the present study, we review our 10-year experience with 78 patients with advanced head and neck squamous cell carcinoma (HNSCC) treated with the IHF2SQ regimen in 3 Parisian Radiation Oncology departments. The purpose of this study was to evaluate the efficacy and tolerance of this regimen in patients with short life expectancy not eligible for conventional treatment. HEAD & NECK DOI /HED DECEMBER

2 MONNIER ET AL. PATIENTS AND METHODS Patients Between March 1997 and April 2008, 78 patients initiated therapy for advanced HNSCC with the IHF2SQ regimen at Georges Pompidou, Pitie Salpêtrière, and Tenon Hospitals in Paris. The purpose of this study was to assess the safety and efficacy of the IHF2SQ regimen. The medical records of the 78 patients were retrospectively reviewed. All patients had a pathological diagnosis of HNSCC. Nasopharynxgeal and paranasal sinus tumors were excluded. Advanced disease was defined as the American Joint Committee on Cancer Staging Manual and International Union Against Cancer classification stage III and IV (seventh edition, 2010). Four patients had an incomplete tumor resection before chemoradiation. Patients with recurrent disease could be treated with this regimen if they had not received radiation therapy before. The hospital s institutional review board approved this study. Treatment plan Radiotherapy. Radiotherapy was administrated as 2 fractions of 3 Gy per day (with at least a 6-hour interval between the fractions) on days 1 and 3, during the first, third, fifth, and seventh weeks of treatment. The patients received 12 Gy per week of treatment. Each week of treatment was followed by a week of rest (Figure 1). Some variations could occur with fractions of 2.5 Gy instead of 3 Gy during the fifth and seventh weeks. Thirty-four patients (44%) were treated with conventional radiation therapy and 44 (56%) with 3-dimensional conformal radiation therapy. For patients treated with 3-dimensional conformal radiation therapy, a planning CT scan was required to define target volumes. The following volumes were based on the International Commission on Radiation Units 50 report: the gross tumor volumes (GTVs) included the primary tumor and involved neck lymph nodes; the clinical target volume 1 (CTV1) was defined as the GTVs and drainage lymph nodes; the planning target volume 1 included the CTV1 plus a safety margin of 1 cm in all directions. After 24 Gy, the reduced CTV2 was limited to the GTVs and the involved neck nodes plus a safety margin of 1 cm in all directions; the planning target volume 2 included the CTV2 plus a safety margin of 1 cm in all directions. Organ-at-risk was the spinal cord. Radiation therapy was delivered by use of 4-MV or 6-MV photons. Customized blocks or multileaf settings were used to minimize the radiation dose to the normal tissues. Chemotherapy Sixty-three patients (81%) underwent induction chemotherapy (ICT) before radiation therapy. Thirty-four patients (54%) received 5-fluorouracil (5-FU) combined with cisplatin, 11 patients (18%) received 5-FU combined with cisplatin and docetaxel, 7 patients (11%) received 5-FU combined with carboplatin, and the remaining 11 patients (17%) received taxane-based therapy. They received a median number of 3 cycles of ICT before chemoradiotherapy (range, 1 8 cycles). FIGURE 1. The Irradiation HypoFractionnee 2 Seances Quotidiennes (IHF2SQ) regimen. D, day. Most of the patients (94%) received chemotherapy concurrently with radiotherapy. Chemotherapy was administrated on days 1 to 3, during the first, third, fifth, and seventh weeks of treatment. Thirty-five patients (48%) received a combination of platinum (cisplatin or carboplatin) and 5-FU, 25 patients (34%) received concurrent carboplatin, 7 patients (10%) received concurrent taxane, and 6 patients (8%) received cetuximab. Assessment of safety and efficacy Acute radiation toxicity was evaluated by the clinician and graded during each week of radiotherapy according to the Common Terminology Criteria for Adverse Events version 3.0. Late radiation toxicity was assessed by reviewing notes of clinicians seeing the patients in follow-up and graded using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale. 11 Tumor response was assessed by clinical examination, endoscopy, and CT scan in all patients using Response Evaluation Criteria in Solid Tumors at 2 months after the completion of the chemoradiotherapy, and then at 2-month intervals. Statistical analysis The endpoints assessed were response to chemoradiotherapy, overall survival (OS), progression-free survival (PFS), specific survival (SS), and tolerance. The Kaplan Meier method was used to estimate the OS, PFS, and SS, which were calculated from the day of treatment initiation until the date of disease progression or death. Statistical differences in OS were tested by the 2-tailed log-rank test. When suitable, the chi-square or Fisher exact test was used to compare qualitative data. Multiple regression analysis was used to study prognostic factors. Variables with p values <.05 on univariate analysis were considered candidates for the multiple regression analysis. A forward selection procedure was used to determine the 1684 HEAD & NECK DOI /HED DECEMBER 2013

3 PALLIATIVE RADIOTHERAPY IN HEAD AND NECK CANCER independent prognostic factors. Differences were assumed to be significant when p <.05. RESULTS Patient characteristics From March 1997 to April 2008, 78 patients were treated for advanced HNSCC with the IHF2SQ regimen. Their characteristics are reported in Table 1. The median age was 64 years (range, years). The sex ratio (men/women) was 5.5. One third of patients presented with comorbid conditions (diabetes, cardiac, neurological, and hepatic morbidities). By World Health Organization (WHO) classification, most patients had a performance status of 1 or 2 (90%). Fifty-eight patients (74%) had nutritional support, among which 32 had a feeding tube. The most frequent tumor location was the oropharynx (45%). In most cases, patients had advanced tumors with T4 tumors in 65% of cases and nodal involvement in 82% of cases. Twenty patients (26%) had distant metastatic disease at diagnosis. Two patients presented with a synchronous second primary cancer (lung and esophagus). Tolerance Sixty-six patients (85%) completed the prescribed course of radiation. Radiotherapy was stopped after 3 weeks of treatment for 6 patients and after 5 or 6 weeks for 6 patients (1 because of early death, 4 because of TABLE 1. Patient characteristics. Characteristic No. of patients (%), n ¼ 78 Age, y Mean 6 SD Median 64 Range Sex Male 66 (84.5) Female 12 (15.5) WHO Performance Status 0 5 (6) 1 49 (63) 2 21 (27) 3 3 (4) Location Oral cavity 14 (18) Oropharynx 35 (45) Hypopharynx 22 (28) Larynx 7 (9) Center Georges Pompidou Hospital 26 (33) Pitie Salpetrière Hospital 17 (22) Tenon Hospital 35 (45) Comorbidities Yes 23 (29.5) No 55 (70.5) AJCC staging III 6 (8) IVA 35 (45) IVB 37 (47) Abbreviations: SD, standard deviation; WHO, World Health Organization; AJCC, American Joint Committee on Cancer. TABLE 2. Acute treatment-related toxicity according to Common Terminology Criteria for Adverse Events version 3.0. No. (%) by toxicity grade Toxicity (CTCAE) Grade 1 Grade 2 Grade 3 Mucositis 23 (29) 41 (53) 1 (1) Skin 30 (38) 13 (17) 1 (1) Fatigue 1 (1) 23 (29) 0 Xerostomia 4 (5) 24 (31) 1 (1) Weight loss 13 (17) 10 (13) 2 (3) Abbreviation: CTCAE, Common Terminology Criteria for Adverse Events. disease progression, 1 because of poor tolerance, and 6 because of refusal of treatment). The median overall treatment time was 45 days (range, days). Acute toxicities are summarized in Table 2. Fifteen patients (31%) required treatment breaks with a median period of 3 days (range, 1 16 days), mainly because of low blood counts (thrombocytopenia grade 3, n ¼ 6; neutropenia grade 3, n ¼ 3), which were all attributed to the chemotherapy. Three patients were given a treatment break because of fever. The overall incidence of severe (grade 3 4) acute toxicity was low (4%). Hematologic toxicity has not been reported. On univariate and multivariate analysis of the relationship between potential predictors and acute toxicity, larynx location was predictive of better tolerance (odds ratio, 5.9; 95% confidence interval [CI], ; p ¼.03). Fifteen patients (12%) presented with severe (grade 3 4) late toxicity: 9 patients had severe cervical fibrosis and 6 patients had grade 3 to 4 xerostomia. Ten patients (13%) needed long-term nutritional support. Treatment outcome Sixty-three patients (81%) received ICT and response to ICT was evaluated on CT scan, clinical examination, and endoscopy before the start of chemoradiation. Three patients (5%) had complete response, 30 (48%) had partial response, 20 (31%) had stable disease, and 10 (16%) had progressive disease. The objective tumor response to chemoradiation was assessed 2 months after the completion of chemoradiation by clinical examination, endoscopy, and CT scan. Regarding the primary tumor, 11 patients (14.5%) achieved a complete response, 30 (39.5%) achieved a partial response, 30 (39.5%) had stable disease, and 5 (6.5%) experienced progressive disease. Regarding the neck nodes, 7 patients (11%) achieved a complete response, 35 (53%) achieved a partial response, 20 (30%) had stable disease, and 4 (6%) experienced progressive disease. On univariate analysis of the relationship between potential predictors and chemoradiation response, WHO performance status (WHO 0 1 vs2 3), tumor location (larynx vs other locations), and response to ICT (complete/partial response vs stable/progressive disease) were predictive of response to chemoradiation. Multivariate analysis showed that a good performance status (odds ratio, 3.7; 95% CI, ; p ¼.01) and a response to ICT (odds ratio, 50.2; 95% CI, ; p ¼.0007) were significantly associated with response to chemoradiation. HEAD & NECK DOI /HED DECEMBER

4 MONNIER ET AL. FIGURE 2. Kaplan Meier progression-free survival (Black) and specific survival (Dotted line) curves for the 78 patients. The median follow-up time was 13 months (range, 1 37 months) and 4 patients have been lost to follow-up. At the time of analysis, there have been 71 deaths, 44 attributable to cancer, 33 locoregional failures, and 11 distant recurrences. The median PFS was 9.9 months (Figure 2). The 1-year and 2-year actuarial PFS rates were 51.5%, and 14.3%, respectively. Univariate analysis showed that patients with either a complete or partial response to radiotherapy or male sex had a significantly longer survival time without disease progression (p ¼.002). Multivariate analysis using Cox regression showed that response to radiotherapy (odds ratio, 3.3; 95% CI, ; p ¼.002), male sex (odds ratio, 3.2; 95% CI, 1.5 7; p ¼.002), and laryngeal location (odds ratio,3.3;95%ci, ; p ¼ 0.02) were significantly associated with longer survival time without progression. The median OS was 12.9 months. The 1-year and 2-year actuarial OS rates were 58% and 12%, respectively. The 1-year and 2-year actuarial SS rates were 71% and 26%, respectively. Univariate analysis showed that patients with a complete or partial response to chemoradiotherapy were associated with a significantly longer SS time. Multivariate analysis showed that a response to chemoradiotherapy was significantly associated with longer SS time (odds ratio, 3.5; 95% CI, 1.7 7; p ¼.0005). DISCUSSION The standard treatment for locally advanced head and neck cancer is surgery and/or concurrent chemoradiotherapy. 2 Patients with untreated advanced HNSCC have a median survival of approximately 100 days. 12 These patients have been shown to benefit from a locoregional palliative treatment regimen. 13 The optimal palliative radiotherapy schedule is unknown but would provide tumoral response with minimal toxicity. From a radiobiological, economic, and logistical perspective, a hypofractionated schedule would be the most suitable option. The purpose of this study was to assess the hypofractionated IHF2SQ regimen in terms of tolerance and efficacy in patients not eligible for conventional chemoradiotherapy. The IHF2SQ regimen was well tolerated. Eighty-five percent of patients received the full-prescribed dose of radiation. Only 4% of the patients experienced grade 3 toxicities and no grade 4 toxicity was reported, indicating that this hypofractionated regimen is safe and feasible when combined with chemotherapy. This good tolerance could be explained by the hypofractionation and the pauses between the different treatment phases, allowing for recuperation of healthy tissues. With conventional chemoradiotherapy, a higher level of grade 3 to 4 toxicity is reported in the literature, ranging from 65% to 78%. 14 In our study, the median OS was 12.9 months and the 1-year and 2-year actuarial OS rates were 58% and 12%, respectively. The 1-year and 2-year actuarial SS rates were 71% and 26%, respectively. In the study by Baillet et al, 10 in which this regimen was first described, patients with similar characteristics had a median survival of 13 months and 1-year, 2-year, and 3-year OS of 58%, 40%, and 35%, respectively. Several randomized trials including patients with locally advanced tumors treated with chemoradiotherapy reported 2-year OS rates between 38% and 51% and 2-year PFS rates around 45% versus 12% and 14.3% in our study, respectively. 15 The lower 2- year survival rates in our study could be explained by the large proportion of patients with very advanced disease (47% of stage IVB). Furthermore, among the patients who received ICT, the response rate is lower than usual (53%) indicating the selection of many patients refractory to chemotherapy. Finally, it seems that patients with laryngeal tumors benefit from the use of IHF2SQ regimen more than the others. Patients with laryngeal tumors tolerated treatment better and had a longer PFS. Although all patients in our study were treated with the same radiotherapy regimen, our study was retrospective and thus hypothesis generating, which precludes drawing any definitive conclusions. Few patients were included with heterogeneous characteristics. They had in common a short life expectancy, secondary to disease extension and/or medical condition. Although radiation therapy was homogeneously administered, the chemotherapy approach was more heterogeneous. Eighty percent of patients had ICT with at least 4 different combinations. There is a lack of prospective studies assessing the role of palliative radiotherapy in patients with incurable HNSCC (Table 3). One randomized trial evaluated normofractionated versus hypofractionated palliative radiotherapy for patients with advanced HNSCC. It compared 60Gyto70Gyin6to7weeksversus40Gyto48Gy in 2 to 3 weeks in 64 patients. No differences were noted in tumor control, acute side effects, or long-term sequelae. 6 In a phase II study, the value of hypofractionated radiotherapy was examined in patients with previously untreated HNSCC. The "Quad Shot" regimen consisted of 14 Gy in 4 fractions given twice per day for 2 consecutive days, repeated at 4-week intervals for an additional 2 courses if there was no tumor progression. The median survival was 5.7 months, and quality of life improvements were documented in 44% of patients. 8 In another phase II study, more than 500 patients with stage IV head and neck cancer were treated with palliative radiotherapy to 20 Gy in 5 fractions in 1 week. Patients who had regression of at least 50% in their tumor size went on to receive additional radiotherapy on a more standard fractionation scheme up to a total of HEAD & NECK DOI /HED DECEMBER 2013

5 PALLIATIVE RADIOTHERAPY IN HEAD AND NECK CANCER TABLE 3. Overview of published studied on palliative radiotherapy in head and neck cancers. Author Year Type of Study No. Dose and Fractionation Overall Response Rate, % Grade 3 4 Acute Toxicity, % Median OS, (months) Weissberg III Gy in 6 7 weeks vs 88 Mucositis Gy in 2 3 weeks 83 Mucositis 70 - Mohanti II Gy in 5 fractions and 1 week 37 Mucositis Dermatitis 56 Corry II Gy in 12 fractions and 12 weeks 53 Mucositis Dermatitis 0 Porceddu II Gy in 5 fractions and 2.5 weeks 80 Mucositis Dysphagia 17 Dermatitis 11 Agarwal R Gy in 16 fractions and 3.5 weeks 73 Mucositis 66 - Dermatitis 14 Al-Mamgani R Gy in 16 fractions and 3.5 weeks 73 Mucositis Dermatitis 45 Kancherla R Gy in 10 fractions and 4 weeks 72 Mucositis 6 9 Dysphagia 9 Dermatitis 3 Current study 2011 R Gy in 16 fractions and 8 weeks 54 Mucositis Dermatitis 1 Abbreviations: No. pts, number of patients; R, retrospective; OS, Overall Survival. Gy. Thirty percent of patients received the full 70 Gy dose and had a median survival of 13 months, whereas the less responsive group that was limited to 20 Gy had a median survival of approximately 6 months. 7 In another phase II trial, the "Hypo Trial," 35 patients were planned to receive 30 Gy in 5 fractions at 2 weeks. Thirteen patients reported an improvement in their quality of life. The median time to progression and death was 3.9 and 6.1 months, respectively. 9 Recently, several retrospective studies have also shown a benefit and good tolerance with hypofractionated schedules in this population of patients As such, the IHF2SQ regimen is an effective and well-tolerated treatment, which can be an alternative to conventional chemoradiotherapy in patients with a limited life expectancy. However, this regimen could be modified to improve its efficiency. In a phase III trial, Bonner et al 19 have shown that cetuximab, an epidermal growth factor receptor inhibitor, combined with radiotherapy is superior to radiotherapy alone in increasing both the duration of locoregional disease control and survival in locoregionally advanced HNSCC. This regimen seems well tolerated and represents a new therapeutic option. The TREMPLIN trial included patients with laryngeal and hypopharyngeal tumors. 20 They were treated with Docetaxel, cisplatin and 5-FU ICT and then randomized to either cisplatin with radiation or to cetuximab with radiation. Only 40% of the patients on the cisplatin arm were able to successfully complete their treatment versus 70% of patients on the cetuximab arm. The 3- month laryngeal preservation rate was the same in the 2 arms. It could be interesting to combine cetuximab with the IHF2SQ regimen. Few patients in this series received concomitant cetuximab, but their numbers are not sufficient to formulate a conclusion. It seems unethical to consider a phase III trial comparing conventional CRT to the IHF2SQ in this population of patients. A phase II trial with concurrent cetuximab in combination with radiotherapy has to be considered. The hypofractionated IHF2SQ regimen combined with chemotherapy is an alternative to conventional chemoradiotherapy in patients with locally advanced head and neck cancer and a short life time expectancy. REFERENCES 1. Guerin S, Hill C. Cancer epidemiology in France in 2010, comparison with the USA. [Article in French] Bull Cancer 2010;97: Seiwert TY, Cohen EE. State-of-the-art management of locally advanced head and neck cancer. Br J Cancer 2005;92: Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993;328: Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368: Pignon JP, le Maître A, Maillard E, Bourhis J; MACH-NC Collaborative Group. 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