INAS I. ABDELHALIM, M.D.; NAWAL M. ELSAID, M.D.; ELSAID M. ALI, M.D. and BASHEER S. ATA, M.Sc.

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1 Med. J. Cairo Univ., Vol. 81, No. 1, December: , Neoadjuvant Docetaxel (Taxotere) Plus Cisplatin and 5-Flurouracil Followed by Concomitent Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck INAS I. ABDELHALIM, M.D.; NAWAL M. ELSAID, M.D.; ELSAID M. ALI, M.D. and BASHEER S. ATA, M.Sc. The Departments of Clinical Oncology & Nuclear Medicine, Faculty of Medicine, Mansoura University Abstract Background: Concomitent chemoradiotherapy (CRT) has become the standard of care for patients with inoperable head and neck squamous cell carcinoma (HNSCC). More recently, induction chemotherapy (IC) has been adopted as an approach in the management of these patients. The primary objective of this study is to evaluate PFS (progression-free survival) after sequential therapy, (taxotere, cisplatin, and 5-FU induction therapy followed by concomitant CRT) in patients with locally advanced HNSCC. Secondary objectives include; overall response rate (ORR) to treatment, duration of response, overall survival (OS) and safety profile. Patients and Methods: 30 patients with stage III-IV M0 HNSCC, Eastern Cooperative Oncology Group performance status (ECOG PS) of zero to one were prospectively treated with 3 courses of TPF induction chemotherapy followed by concomitant CRT. IC consisted of Docetaxel (Taxotere) 75mg/m 2 day 1 followed by cisplatin 75mg/m 2 day 1 and 5- Flurouracil 750mg/m 2 day 1-5 continuous infusion, given every 3 weeks. Concomitent CRT started 4 weeks after the last cycle of chemotherapy with the goal of delivering a total dose of 66Gy concomitant with cisplatin 80mg/m 2 for 2 cycles during RT. Results: At a median follow-up period of 18 months (ranging from 8 to 30m), the median PFS was 15 months, the PFS was 46.7% and the OS was 53.3% while the median OS was not reached. The one year PFS and OS were 70% and 90% respectively. The overall response rate to treatment was 90%. Median duration of CR was 20 months and median duration of ORR was 15 months. The most common grade III toxicity during IC was neutropinic fever (13.3%). Conclusions: Induction TPF is active, feasible, well tolerated, with acceptable toxicity and does not compromise the delivery of subsequent CRT in patients with ECOG PS of 0-1. Key Words: Induction chemotherapy Concomitant chemoradiation Head and neck cancer. Introduction TUMORS arising from the head and neck are the seventh most common neoplasms worldwide. In 2010, an estimate of 634,760 new cases were Correspondence to: Dr. Basheer S. Ata Bashir2002@hotmail.com. diagnosed and 356,705 deaths occurred secondary to these tumors globally [1,2]. Most (about 90%) of these cases are squamous cell carcinomas (SCC) that arise from the upper aerodigestive tract [3]. The most important risk factors are tobacco and alcohol consumption and the combined exposure to alcohol and tobacco has a synergistic effect on carcinogenesis [4]. Other risk factors for oral cancer are snuff or chewing tobacco and chronic use of betel nut (paan). Marijuana use is also considered to be a potential risk factor [5]. Human papilloma virus (HPV) is a recently appreciated cause of head and neck squamous-cell carcinoma (HNSCC). It encompasses many different subtypes, with HPV-16 and HPV-18 being the most common oncogenic variants in HNSCC [6]. About two-thirds of patients with HNSCC present with advanced stage disease, commonly involving regional lymph nodes. Distant metastases at initial presentation are uncommon, arising in only 10% of patients [7]. The low overall cure rate in combination with a poor functional outcome in a significant percentage of patients with locally advanced HNSCC has led to alternative strategies of management. Historically, this has consisted of surgery and postoperative radiotherapy (RT) or RT alone for unresectable disease. These efforts yielded low locoregional control rates and 5-year survival rates from 10% to 40% [8]. The addition of chemotherapy to locoregional treatment has revolutionized the treatment of patients with locally advanced HNSCC. In the early 1990s, the focus shifted to administering chemotherapy concomitantly with radiation, to take advantage of the radiation enhancing properties of cytotoxics active in HNSCC. Evidence from a large 887

2 888 Neoadjuvant Docetaxel (Taxotere) Plus Cisplatin & 5- Flurouracil meta-analysis of individual patient data from randomized trials demonstrated that adding chemotherapy led to a real survival advantage of around 4% at 5 years over that seen with locoregional treatment alone [9,10]. More recently, efforts have focused on testing induction chemotherapy followed by concurrent chemoradiation (CRT) to improve organ preservation rates, reduce locoregional and distant failure and improve overall survival. Cisplatin-based induction chemotherapy doublets have been generally used as induction chemotherapy, and cisplatin plus 5-fluorouracil (5-FU), PF, has become a common treatment standard. The addition of a taxane to induction chemotherapy, in the form of a cisplatin-taxane doublet, or, more frequently, a taxane, cisplatin, and 5-FU triplet, has improved the activity of induction chemotherapy. Several trials have shown very promising results and confirmed the superiority of the triplet docetaxel, cisplatin, and 5-FU (TPF) regimen over PF, followed by RT or CRT, in terms of response rate (RR), overall survival (OS) and progression free survival (PFS) [11-13]. These data are supported by a meta-analysis of randomized clinical trials, in which a direct comparison showed an overall and progressionfree survival advantage for docetaxel and cisplatinbased induction chemotherapy over PF induction chemotherapy [14]. However, all of these randomized trials compared two different induction regimens and were not designed to compare induction therapy or sequential treatment to chemoradiation alone. Many large randomized phase III trials comparing TPF induction chemotherapy followed by chemoradiation to chemoradiation alone are currently planned or underway. GSTTC, (the Gruppo di Studio sui Tumori della Testa e del Collo) conducted a randomized phase II trial of induction TPF followed by CRT or CRT alone. CR rates (primary end point) were higher with TPF (50% versus 21.2%, p=0.004). Median progression-free survival and overall survival were also higher with TPF (30.4 vs 19.7 and 39.6 vs 33.3 months respectively). Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms [15]. The primary objective of this study is to evaluate PFS after sequential therapy, (taxotere, cisplatin, and 5-FU induction therapy followed by concomitant CRT) in patients with locally advanced HNSCC. Secondary objectives include; overall response rate to treatment, duration of response, overall survival and safety profile. Patients and Methods This study was conducted at Clinical Oncology and Nuclear Medicine Department, Faculty of Medicine, Mansoura University over the period from August 2010 to April Patients aged years were eligible if they had histological or cytological proven stage III- IV M0; inoperable SCC of the head and neck (oral cavity, oropharynx, nasopharynx, hypopharynx, larynx or nasal/paranasal); one or more measurable lesion; Eastern Cooperative Oncology Group performance status (PS) of zero to one [16] ; adequate hematologic, hepatic, and renal function; and no prior chemotherapy, radiotherapy, or surgery for HNSCC. Inoperability criteria were technical unresectability (tumor fixation/invasion to either base of the skull, cervical vertebrae, nasopharynx, or fixed lymph nodes), low surgical curability (T3- T4, N2-N3 excluding T1 N2) as assessed by an experienced surgeon, and organ preservation. Exclusion criteria include; pregnant or lactating women; previous or other malignancies at other sites; any prior treatment with radiotherapy or chemotherapy; symptomatic peripheral neuropathy or altered hearing >grade 2; patients with contraindications to use of prednisone and patients with other serious illness or medical conditions such as unstable cardiac disease, history of significant neurological or psychiatric disorders, active uncontrolled infection, and acute peptic ulcer. Patients were required to provide oral informed consent before inclusion in the study. Treatment plan: After complete diagnosis and staging work-up, patients started IC (TPF) Taxotere 75mg/m 2 (1 hour IV infusion, D1) followed by cisplatin 75mg/m 2 (30-minutes IV infusion with adequate hydration, D1) and 5-FU 750mg/m 2 /day (continuous IV infusion, D1-5, starting after cisplatin) repeated every 3 weeks-up to a total of 3 cycles followed by concomitant RT 66Gy (using twodimensional conventional techniques in two phases, 200cGy/F) and cisplatin 80 mg/m 2 D1& D28 (2 cycles during the radiotherapy course) with a minimum interval of 4 weeks after the last cycle of induction chemotherapy. During IC, the dose of the next cycle was reduced by 25% in patients with grade III-IV toxicities. G-CST (100 µg/day) was given for grade III-IV nuetropenia or febrile neutropenia. Patients was considered evaluable for response if he or she received 2 cycles of induction chemotherapy and all his or her baseline lesions have been assessed. Patients with progression

3 Inas I. Abdelhalim, et al. 889 before cycle 2 will be evaluable as early progression. Tumor assessment to IC was done clinically and radiologically just before CRT. All patients received the following premedications: 5-HT3 (5-hydroxytryptamine) antagonists and H2 (histamine 2) blockers 30 minutes before chemotherapy; dexamethasone 8mg/12 hours, IV for 3 days, one day before and 2 days after docetaxel infusion; adequate hydration with normal saline solution three liters on day1; calcium gluconate, magnesium sulphate and potassium chloride ampoules before cisplatin infusion (IV); and mannitol 20% 200cc IV push after cisplatin infusion. Antibiotic prophylaxis (oral ciprofloxacin 500mg twice daily) was given after each cycle (days 5-15). Patients then followed clinically every 2 months in the 1 st year and every 3 months in the 2 nd year (including endoscopy). CT scan or MRI was performed every 3-6 months (unless suspicion of progression) up to the time of documented progression, death or lost follow-up. End points (objectives): The primary objective of this study is to evaluate PFS after sequential therapy (TPF followed by concomitant CRT) in patients with locally advanced HNSCC. Secondary objectives include, overall response rate, duration of response, overall survival and safety profile. PFS was calculated from the date of inclusion to the date of progression or date of death whichever occurs first. OS was calculated from the date of inclusion to the date of death. Response rate was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) [17]. Clinical examination and toxicities will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE, v3.0) [18]. Statistical analysis: At the end of follow-up, the patients clinicopathological and outcome data were collected, and subjected to statistical analysis using IBM SPSS advanced statistics version 20 (SPSS Inc., Chicago, IL). Numerical data of scores were expressed as mean and standard deviation or median and range as appropriate. Qualitative data were expressed as frequency and percentage. Chi-square test (Fisher s exact test) was used to examine the relation between qualitative variables. Survival analysis was done using Kaplan-Meier method and comparison between two survival curves was done using logrank test. Univariate cox regression was done to calculate the hazard ratio for the different prognostic factors. Binary logistic regression was used to determine significant predictors for the outcome. A p-value<0.05 was considered significant. Results Patient characteristics: Thirty patients with histologically confirmed diagnosis of locally advanced HNSCC presented to Clinical Oncology and Nuclear Medicine Department at Mansoura University Hospital over the period from August 2010 to January 2012 were included in this study. Baseline clinicopathological characteristics of the patients are shown in (Table 1). The median age for all patients was 52 years (ranged from 20-65) with a mean value ( ±SD) of (± 14.66) years and male to female ratio of 5:1. Table (1): Baseline clinicopathologic characteristics of the study population. Characteristic No=30 % (frequency) (100) Age (years): Mean±SD 49.63± Median (range) 52.0 (20-65) Sex: Male Female PS: Smoking: + ve ve Site: Nasopharynx Hypopharynx Larynx Oropharynx Nasal/paranasal Grade: G I G II G III Undiffentiated Stage G: III IV A IV B Response to treatment and survival: After IC, 5 patients (16.7%) had complete response (CR), 20 patients (66.6%) had partial response (PR) and 5 patients (16.7%) had stable disease (SD). Overall response rate (PR+CR) to IC was 83.3%. Following IC/CRT, 11 more patients went into CR making a total of 16 patients (53.3%) in CR.

4 890 Neoadjuvant Docetaxel (Taxotere) Plus Cisplatin & 5- Flurouracil Eleven patients (36.7%) had PR and 3 patients (10%) had SD. Pathological CR was confirmed in 3 patients. The overall response rate at the end of the protocol was 90%. Median duration of CR was 20 months (ranged from months) and median duration of ORR was 15 months (ranged from 8-30 months). Response to treatment (CR, PR, and SD) after IC/CRT for tumors in different sites in head and neck is summarized in (Table 2). All cases of oropharyngeal SCC had PR, progressed locally, died in the first 9-14 months of follow-up and had the worst prognoses than other sites. Table (2): Response to treatment for tumors in different sites in head and neck. Primary site of tumor CR PR SD Total Nasopharynx Hypopharynx Larynx Oropharynx Nasal/paranasal Total/% 17/ /33.3 3/10 30/100 At a median follow-up period of 18 months (ranging from 8 to 30 months), the median PFS was 15 months, mean PFS was months (95% CI of ) and the overall PFS was 46.7% (Fig. 1). At the end of the study there were 16 patients alive and 14 patients died. The OS was 53.3%, mean OS was (95% CI of ) while the median OS was not reached (Fig. 2). The one year PFS and OS were 70% and 90% respectively. Cum Survival Censored PFS time (months) Fig. (1): PFS curve of the whole group. Cum Survival OS_ time (months) Fig. (2): OS curve of the whole group. Toxicity: During induction TPF, 27 patients (90%) completed all planned there cycles of IC while 3 patients (10%) received only 2 cycles (these 3 patients developed NF and refused to receive the 3 rd cycle). Grade III toxicities were seen in 26.7% (8 patients) and include neutropinic fever 13.3% (4 patients), mucositis 10% (3 patients) and diarrhea 6.7% (2 patients). Age of the patients was an important factor in determining the toxicity to IC. In this study 13 patients (44.3%) were >_60 years and had grade III toxicities more than patients <60 years with Odds ratio of 6.43, 95% CI 1.03 to and a significant p-value of During CRT, all patients completed the scheduled total dose of radiation therapy (66 Gy/33 F, 5F/w). Grade III toxicities include mucositis which were seen in 3 patients (10%). As a late toxicity, grade III laryngeal oedema was seen 1 patient (3.3%). Univariate analysis of different factors affecting out-comes: The following factors: Age, P.S (0 vs 1), grade, stage, IC dose reduction, IC interruption, interruption of RT period and response to treatment were analyzed and statistically evaluated in relation to RR and PFS. RR: When analyzing those factors using Chi-Square test and OR (Odds Ratio); factors associated with a statistically significant impact on RR include tumor stage and interruption of RT period (Table 3). Patients with stage III disease showed higher CR rate than patients with stage IV disease with +

5 Inas I. Abdelhalim, et al. 891 an odds ratio of 0.005, 95% CI of and a significant p-value of < Also patients with no RT delay showed higher CR rate than patients with RT delay with an odds ratio of 0.018, 95% CI of and a significant p-value of < PFS: When analyzing those factors using Kaplan- Meier Log-Rank test and Cox regression analysis, factors associated with a statistically significant impact on PFS include also tumor stage and interruption of RT period in addition to CR response to treatment. Patients with CR to treatment (IC/CRT) had a better PFS than patients with PR or SD with odds ratio of , 95% CI of and a significant p-value of (Table 4). Other factors including; age, ECOG PS (0 vs 1), grade, IC dose reduction and IC delay had no significant impact on RR and PFS. Logistic regression for predictors of disease progression: Binary logistic regression model was used to determine the predictors of disease progression. The dependent variable was the progression (progressed or non-progressed) while the independent variables were: age, ECOG PS (0 vs 1), grade, stage, IC dose reduction, IC interruption, interruption of RT period and RR to treatment. Table (3): Univariate analysis of different factors affecting RR (CR vs no CR). RR Factor Odds R 95% CI p-value CR No CR Age: <60y vs 60y 11 (64.7%) 6 (35.3%) (38.5%) 8 (61.5%) ECOG PS: 0 vs 1 15 (57.7%) 11 (42.3%) (25%) 3 (75%) Grade: low G (I, II) vs high G (III, undifferentiated) 6 (35.3%) 11 (64.7%) (76.9%) 3 (23.1%) Stage: III vs IV 15 (93.8%) 1 (6.2%) < (7.1%) 13 (92.9%) IC dose reduction: 3 vs 2 cycles 14 (51.9%) 13 (48.1%) (66.7%) 1 (33.3%) IC interruption (delay): No delay vs delay 12 (50%) 12 (50%) (66.7%) 2 (33.3%) RT delay: No delay vs delay 13 (92.9%) 1 (7.1%) < (18.8%) 13 (81.2%) Table (4): Unvariate analysis of different factors affecting PFS. Factor Odds R 95% CI p-value Age: <60y vs >_60y ECOG PS: 0 vs Grade: Low ( G I, II) vs High G (III, Undifferentiated) Stage: III vs IV IC dose reduction: 3 cycles vs 2 cycles IC interruption (delay): No delay vs Delay RT delay: Yes vs No RR to treatment: CR vs PR, SD Table (5): Binary logistic regression analysis for predicting disease progression. Factor Score p-value Age: <60y vs >_60y ECOG PS: 0 vs Grade: Low G: I, IIvs High G: III, Undifferentiated Stage: III vs IV <0.001 IC dose reduction: 3 cycles vs 2 cycles IC interruption (delay): No delay vs Delay RT delay: Yes vs No <0.001 RR to treatment: CR vs PR, SD <0.001

6 892 Neoadjuvant Docetaxel (Taxotere) Plus Cisplatin & 5- Flurouracil The results showed that the significant predictors of progression include tumor stage, RT delay and RR to treatment (Table 5). Discussion Adding IC to concurrent CRT, otherwise known as sequential chemoradiotherapy, remains controversial due to lack of published randomized Phase III data demonstrating its superiority over concurrent CRT. However, encouraging results from the TAX 323 and TAX 324 studies have generated renewed interest in the use of IC in HNSCC [12, 13]. There are concerns that the toxic effects of IC may compromise or even preclude the delivery of subsequent RT [19,20]. Prolongation of RT duration through treatment interruption and failure to complete definitive RT have a significant adverse impact on locoregional tumour control and survival in HNSCC [21]. Multiple phase III randomized trials investigated the addition of taxane to PF as IC before definitive treatment also reported higher response rate with the addition of taxane. In Spanish Head and Neck Cooperative Group trial [11], the CR rate and ORR after induction PCF (Paclitaxel, cisplatin and 5- FU) were 33 and 80%. After IC/CRT, they were 88 and 98% respectively. In the Tax 323 [12] and Tax 324 [13] trials the ORR in induction-tpf/crt arms was 72% for each trial although, Tax 323 trial used RT with altered fractionation and no concurrent chemotherapy and Tax 324 trial used weekly carboplatin during RT. In our study, the radiologic CR after TPF induction chemotherapy was 16.7%, PR was 66.6% and stable disease was 16.7%. The radiologic ORR was 83.3%. After induction-tpf/crt, CR was 53.3%, PR was 36.7% and stable disease was 10%. The radiologic ORR at the end of treatment was 90%. In this trial, at a median follow-up period of 18 months (ranging from 8 to 30 months), 16 patients (53.3%) were progressed or died. Of these patients, 11 progressed locally and 3 patients developed distal metastases. The remaining 2 patients died without decommended recurrence. The median PFS was 15 months and the overall PFS was 46.7%. The one year PFS was 70% (Fig. 1). In the sequential therapy arm (TPF followed by CRT) of Italian Collaborative Group Sudy [15], the 2 years PFS was 55.6% which was better than that in this study (46.7%). This may be due to smaller size of population in our study (30 vs 50 patients) or more RT delay. In our study the median duration of RT delay was 7 days ranging from 7-21 days; while in Paccagnella et al trial the median duration of of RT delay in TPF sequential arm was 7 days ranging from 3-10 days. In addition the survival advantage in Paccagnella et al trial may be due to surgical intervention. Radical surgery was used in case of residual disease after IC/CRT and prophylactic neck dissection for patients with initial stage of N2-N3. The one year OS rate was 90% which was nearly equal to 1-year survival result of TPF arm obtained by Italian Collaborative Group study [15] which was 86%. Survival at 18m in our study was dropped to 53.3% while, at Italian Collaborative Group Study dropped to 61% at 2 years indicating a better survival out come in Italian Collaborative Group Study possibly due to causes mentioned above. Prophylactic G-CSF was not given during IC in this study like some other trials and grade III toxicities were seen in 26.7% (8 patients of all 30). NF was the most common and developed in all neutropinic patients; 13.3% (4 patients) followed by mucositis; 10% (3 patients) and diarrhea; 6.7% (2 patients). During CRT, grade III toxicities include mucositis 10% (3 patients) and sever laryngeal edema as a late toxicity in 3.3% (one patient). In Italian Collaborative Group trial [15], the most common grade 3-4 toxicity during IC was neutropenia (52%; 26 of 44 assessable patients), with 8% (n=4) experiencing febrile neutropenia followed by alopecia (18%), stomatitis/mucositis (6.0%), and nausea (4.3%). During CRT, Grade III toxicities include mucositis/stomatitis (27.7%), skin toxicity (18.6%), and dysphagia (20.7%). Conclusions: Induction chemotherapy using TPF followed by CRT is active, feasible, well tolerated, with manageable toxicities and provide a higher overall response rate in patients with locally advanced SCC of the head and neck. References 1- FERLAY J., SHIN H. R., BRAY F., et al.: Estimates of worldwide burden of cancer in: Globocan Int. J. Cancer, 127 (12): , JEMAL A., SIEGEL R., XU J., et al.: Cancer statistics, CA Cancer J. Clin., 60 (5): , DUVVURI U. and MYERS J.N.: Cancer of the head and neck is the sixth most common cancer worldwide. Curr. Probl. Surg., 46 (2): , 2009.

7 Inas I. Abdelhalim, et al PELUCCHI C., GALLUS S., GARAVELLO W., et al.: Alcohol and tobacco use, and cancer risk for upper aerodigestive tract and liver. Eur. J. Cancer Prev., 17 (4): , NEVILLE B.W. and DAY T.A.: Oral cancer and precancerous lesions. CA Cancer J. Clin., 52 (4): , CHUNG C.H. and GILLISON M.L.: Human papillomavirus in head and neck cancer: Its role in pathogenesis and clinical implications. Clin. Cancer Res., 15 (22): , COOPER J.S., PORTER K., MALLIN K., et al.: National Cancer Database report on cancer of the head and neck: 10-year update. Head Neck., 31 (6): , VOKES E.E., WEICHSELBAUM R.R., LIPPMAN S.M., et al.: Head and neck cancer. N. Engl. J. Med., 328 (3): , PIGNON J.P., LE MAITRE A., BOURHIS J., et al.: Meta-Analyses of Chemotherapy in Head and Neck Cancer (MACH-NC): An update. Int. J. Radiat. Oncol. Biol. Phys., 69 (2 Suppl): S , PIGNON J.P., LE MAITRE A., MAILLARD E., et al.: Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17, 346 patients. Radiother. Oncol., 92 (1): 4-14, HITT R., LOPEZ-POUSA A., MARTINEZ-TRUFERO J., et al.: Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J. Clin. Oncol., 23 (34): , VERMORKEN J.B., REMENAR E., VAN HERPEN C., et al.: Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N. Engl. J. Med., 357 (17): , POSNER M.R., HERSHOCK D.M., BLAJMAN C.R., et al.: Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N. Engl. J. Med., 357 (17): , HITT R., POSNER M., CUCHERAT M., et al.: Docetaxel-cisplatin based induction chemotherapy (ICT) in locally advanced head and neck cancer (LAHNC): A meta-analysis of randomized controlled trials (RCT) using indirect comparisons. Ann. Oncol., 19: 695, PACCAGNELLA A., GHI M. G., LOREGGIAN L., et al.: Concomitant chemoradiotherapy versus induction docetaxel, cisplatin and 5 fluorouracil (TPF) followed by concomitant chemoradiotherapy in locally advanced head and neck cancer: a phase II randomized study. Ann. Oncol., 21 (7): , OKEN M.M., CREECH R.H., TORMEY D.C., et al.: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol., 5 (6): , THERASSE P., ARBUCK S.G., EISENHAUER E.A., et al.: New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl. Cancer Inst., 92 (3): , TROTTI A., COLEVAS A.D., SETSER A., et al.: CTCAE v3.0: Development of a comprehensive grading system for the adverse effects of cancer treatment. Semin. Radiat. Oncol., 13 (3): , EISBRUCH A.: Commentary: Induction chemotherapy for head and neck cancer: Hypothesis-based rather than evidence-based medicine. Oncologist, 12 (8): , BEITLER J.J. and COOPER J.S.: Seduction by induction? J. Clin. Oncol., 27 (1): 9-10, FESINMEYER M.D., MEHTA V., TOCK L., et al.: Completion of radiotherapy for local and regional head and neck cancer in medicare. Arch. Otolaryngol Head. Neck. Surg., 135 (9): , 2009.