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Background: Previous results from our phase 3 randomised trial showed that adding cetuximab to primary radiotherapy increased overall survival in patients with locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN) at 3 years. Here we report the 5-year survival data, and investigate the relation between cetuximab-induced rash and survival., Methods: Patients with LASCCHN of the oropharynx, hypopharynx, or larynx with measurable disease were randomly allocated in a 1:1 ratio to receive either comprehensive head and neck radiotherapy alone for 6-7 weeks or radiotherapy plus weekly doses of cetuximab: 400 mg/m(2) initial dose, followed by seven weekly doses at 250 mg/m(2). Randomisation was done with an adaptive minimisation technique to balance assignments across stratification factors of Karnofsky performance score, T stage, N stage, and radiation fractionation. The trial was un-blinded. The primary endpoint was locoregional control, with a secondary endpoint of survival. Following discussions with the US Food and Drug Administration, the dataset was locked, except for queries to the sites about overall survival, before our previous report in 2006, so that an independent review could be done. Analyses were done on an intention-to-treat basis. Following completion of treatment, patients underwent physical examination and radiographic imaging every 4 months for 2 years, and then every 6 months thereafter. The trial is registered at www.ClinicalTrials.gov, number NCT00004227., Findings: Patients were randomly assigned to receive radiotherapy with (n=211) or without (n=213) cetuximab, and all patients were followed for survival. Updated median overall survival for patients treated with cetuximab and radiotherapy was 49.0 months (95% CI 32.8-69.5) versus 29.3 months (20.6-41.4) in the radiotherapy-alone group (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p=0.018). 5-year overall survival was 45.6% in the cetuximab-plus-radiotherapy group and 36.4% in the radiotherapy-alone group. Additionally, for the patients treated with cetuximab, overall survival was significantly improved in those who experienced an acneiform rash of at least grade 2 severity compared with patients with no rash or grade 1 rash (HR 0.49, 0.34-0.72; p=0.002)., Interpretation: For patients with LASCCHN, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash., Funding: ImClone Systems, Merck KGaA, and Bristol-Myers Squibb., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Purpose: The feasibility of combining concomitant boost-accelerated radiation regimen (AFX-C) with cisplatin was previously demonstrated in this Phase II trial. This article reports the long-term toxicity, relapse patterns, and survival in patients with advanced head and neck carcinoma., Methods and Materials: Between April and November 2000, 84 patients with Stage III-IV HNC were enrolled, and 76 patients were analyzable. Radiation consisted of 72 Gy over 6 weeks. Cisplatin dose was 100 mg/m(2) on Days 1 and 22. Tumor and clinical status were assessed, and acute-late toxicities were graded., Results: The median follow-up for surviving patients is 4.3 years. The 2- and 4-year locoregional failure rates were 33% and 36%, respectively, and the 2- and 4-year survival rates were 70% and 54%, respectively. The worst overall late Grade 3 or 4 toxicity rate was 42%. The prevalence rates of a gastrostomy at any time during follow-up, at 12 months, and at 48 months were 83%, 41%, and 17%, respectively. Five of 36 patients (14%) alive and without disease at last follow-up were gastrostomy-tube dependent., Conclusion: These data of long-term follow-up of patients treated with AFX-C with cisplatin show encouraging results with regard to locoregional disease control and survival, with few recurrences after 2 years. The late toxicity rates are relatively high. However, although prolonged dysphagia was noted in our preliminary report, its prevalence does decreased over time. A Phase III trial comparing AFX-C plus cisplatin against standard radiation plus cisplatin has completed accrual.

Purpose: To assess the safety of long-term cevimeline treatment of radiation-induced xerostomia in patients with head-and-neck cancer; and to assess the efficacy of cevimeline in these patients., Methods and Materials: A total of 255 adults with head-and-neck cancer who had received more than 40 Gy of radiation 4 months or more before entry and had clinically significant salivary gland dysfunction received cevimeline hydrochloride 45 mg t.i.d. orally for 52 weeks. Adverse events (AEs), their severity, and their relationship to the study medication were assessed by each investigator. The efficacy assessment was based on subjects' global evaluation of oral dryness on a scale of 0 (none) to 3 (severe)., Results: Overall, 175 subjects (68.6%) experienced expected treatment-related AEs, most mild to moderate. The most frequent was increased sweating (47.5%), followed by dyspepsia (9.4%), nausea (8.2%), and diarrhea (6.3%). Fifteen subjects (5.9%) experienced Grade 3 treatment-related AEs, of which the most frequent was increased sweating. Eighteen subjects (7.1%) reported at least one serious AE, and 45 subjects (17.6%) discontinued study medication because of an AE. The global efficacy evaluation at the last study visit showed that cevimeline improved dry mouth in most subjects (59.2%). Significant improvement was seen at each study visit in the mean change from baseline of the numeric global evaluation score (p < 0.0001)., Conclusions: Cevimeline 45 mg t.i.d. was generally well tolerated over a period of 52 weeks in subjects with xerostomia secondary to radiotherapy for cancer in the head-and-neck region.

Objectives: To assess whether microvessel density (MVD), an immunohistochemical marker for tumor vascularity, predicts for radiotherapy (RT) outcome in locally advanced HNSCC patients., Methods: A total of 459 patients, enrolled on the RTOG 90-03 trial, had biopsy specimens submitted, and a value for MVD determined, prior to definitive RT. 450 patients were analyzable for this study. Tumor microvessels were stained for factor VIII-related antigen using a standard immunoperoxidase method. The mean number of stained microvessel profiles, from three x200 fields containing the highest MVD (hot spot), was recorded as the MVD. A prospective value of >or=60 was chosen as the threshold for high MVD, tumor vascularity., Results: The median follow-up for the analyzable patients with MVD assessment was 22.0 months and 79.1 months for all living patients. There were no differences concerning the pretreatment characteristics between those RTOG 90-03 patients with a value for MVD and those without a value for MVD. Thus, the present study cohort possessed comparable characteristics with the entire RTOG 90-03 population. MVD values ranged from 5 to 80, with a median value of 30. Only 37 of 450 (8.2%) patients possessed an MVD >or=60. There were no outcome differences for patients with MVD <60 versus >or=60 on multivariate analysis for time to local-regional failure (P = 0.89), time to distant metastasis (P = 0.80), disease-free survival (P = 0.46), and overall survival (P = 0.39)., Conclusions: In this large, correlative study, a MVD >or=60, ie, high tumor vascularity, did not predict for outcome in locally advanced head and neck squamous cell carcinoma patients treated with radiotherapy.

Purpose: To study the efficacy and safety of cevimeline in two double-blind trials (Studies 003 and 004) enrolling patients with head and neck cancer in whom xerostomia developed after radiotherapy., Methods and Materials: Subjects were randomly assigned to receive cevimeline, 30 mg three times daily, or placebo for 12 weeks, with the possibility of dose escalation to 45 mg three times daily at 6 weeks. The primary efficacy endpoint was the patient's final global evaluation of oral dryness; change in unstimulated salivary flow was a secondary endpoint., Results: Five hundred seventy subjects (284 in Study 003 and 286 in Study 004) were randomized. Significantly more cevimeline-treated subjects than placebo recipients (47.4% vs. 33.3%, p = 0.0162) in Study 003 reported improvement in dry mouth in the final global evaluation of oral dryness. No significant difference between groups in the final global evaluation was seen in Study 004, in which a high placebo response rate of 47.6% was observed. In both studies, cevimeline-treated subjects had significantly greater increases in the objective measure of unstimulated salivary flow than placebo recipients (p = 0.0093 [Study 003] and p = 0.0215 [Study 004]), whereas no significant differences in stimulated salivary flow were observed. The most frequent adverse event was increased sweating., Conclusion: Cevimeline was well tolerated by patients with xerostomia after radiotherapy for head and neck cancer, and oral administration of 30-45 mg of cevimeline three times daily increased unstimulated salivary flow.

Objective: The purpose of this study was to determine if radiographic response correlates with survival for patients treated patients with malignant gliomas treated on Radiation Therapy Oncology Group (RTOG) protocol 90-06. This study compared patients treated with hyperfractionated radiation and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to standard fractionation and BCNU., Methods: There were 453 patients evaluable. Histology included anaplastic astrocytoma (60) (AA), and glioblastoma multiforme (312) (GBM). All scans were forwarded to the RTOG central office and evaluated by a single reviewer without knowledge of outcome. Response at 4 months post initiation of therapy was evaluated by computed tomography or magnetic resonance image and compared with overall survival., Results: For patients with no tumor on the 4 month scan the median survival was 20.3 months and the 2 year survival 43%. Patients with partial or minor response had a median survival of 18.1 and 14.2 months and 2 year survival of 37% and 29%. Patients with progression had a median survival of 8.6 months and 2 year survival of 10%., Conclusions: Response rates were similar in both arms.

Purpose: To investigate the feasibility of combining concomitant boost accelerated radiation regimen (AFX-C) with cisplatin and to assess its toxicity and the relapse pattern and survival in patients with advanced head and neck carcinoma (HNC)., Patients and Methods: Between April and November of 2000, 84 patients with stage III to IV HNC who met the eligibility criteria were enrolled; 76 of these patients were analyzable. Radiation consisted of 72 Gy in 42 fractions over 6 weeks (daily for 3.5 weeks, then twice a day for 2.5 weeks). Cisplatin dose was 100 mg/m(2) on days 1 and 22. Tumor and clinical status were assessed, and acute late toxicities were graded., Results: Sixty-five patients (86%) received both radiation and chemotherapy per protocol or with minor variations. The estimated 2-year locoregional relapse and distant metastasis rates were 34.7% and 16.1%, respectively. The estimated 2-year overall survival and disease-free survival rates were 71.6% and 53.5%, respectively. Three patients (4%) died of complications, 19 patients (25%) had acute grade 4 toxicity, and 49 patients (64%) had acute grade 3 toxicity. The 2-year cumulative incidence of late grade 3 to 5 toxicities was 51.3%., Conclusion: These data showed that it was feasible to combine AFX-C with cisplatin. The compliance to therapy was high, and the locoregional control and survival rates achieved compared favorably with AFX-C alone or other concurrent chemoradiation regimens tested by the Radiation Therapy Oncology Group. A phase III trial comparing AFX-C plus cisplatin against standard radiation plus cisplatin is ongoing to determine whether the use of AFX-C in the concurrent chemoradiation setting further improves outcome.

Purpose: In a previous retrospective study, p105 AD, a proliferation-associated nuclear antigen density (AD), was found to be an independent prognostic factor for patients irradiated for locally advanced head-and-neck cancer. We sought to confirm this finding by analyzing patients entered on RTOG 9003, a Phase III randomized trial of altered fractionation radiotherapy., Methods and Materials: Paraffin blocks of pretreatment biopsies of the primary tumor of patients with Stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, or supraglottic larynx, or Stage II squamous cell carcinoma of the hypopharynx or base of tongue entered on RTOG 9003 were prospectively collected at patient entry. From these paraffin blocks, areas of tumor were selected based on histologic examinations and sectioned. Nuclear suspensions were then prepared and processed for p105 antibody and DNA staining. Flow cytometric quantification of p105 labeling indices and DNA content were then performed for correlation with local-regional control and survival., Results: Paraffin blocks of tumor biopsies from 457 of 1073 patients entered were available for p105 determination. There was no significant difference in pretreatment characteristics between patients who had paraffin blocks available or not available. The median (range) of p105 labeling index (LI-C), p105 labeling index of cells in S phase (p105 LI-S), and p105 AD were 56 (range: 6-99), 8.255 (range: 0.913-23), and 67 (range: 5-364), respectively. Multivariate analysis of prognostic factors showed that T stage, N stage, Karnofsky performance status, and fractionation schedule were significant for local-regional control (p < 0.0001, 0.0011, <0.0001, and 0.007, respectively) and T stage, N stage, Karnofsky performance status, and tumor grade were significant for survival (p = 0.018, 0.002, <0.0001, and 0.0058, respectively). Neither p105 LI-C nor p105 LI-S nor p105 AD nor DNA ploidy was significant for local-regional control or survival., Conclusion: p105 labeling indices, antigen density, and DNA ploidy do not predict the outcome of patients irradiated for advanced squamous cell carcinomas of the head and neck.

To examine combination cisplatin and twice-daily accelerated irradiation (RT) after aggressive transurethral resection of bladder tumor (TURBT) in an attempt to preserve the bladder and to determine the likelihood that patients who complete this regimen could then complete three cycles of methotrexate, cisplatin, vinblastine (MCV) chemotherapy. Between 1998 and 2000, 52 patients with Stage T2-T4aN0M0 disease, from 17 institutions, were entered into the trial. Forty-seven patients were deemed eligible; the planned accrual was 40. Of the 46 patients, 68% were >60 years old, 70% were men, and 96% had a Karnofsky score >/=90. The clinical T stage was T2 in 66%, T3a in 25%, and T3b in 9%. The median follow-up at the time of analysis was 26 months. The protocol required TURBT within 6 weeks of the initiation of induction therapy. Induction treatment involved 13 days of concomitant boost RT, 1.8 Gy to the pelvis in the morning followed by 1.6 Gy to the tumor 4-6 h later. For sensitization, cisplatin (20 mg/m(2)) was given on the first 3 days of each treatment week. Three to four weeks after induction, patients were evaluated cystoscopically for residual disease. Patients whose biopsies and cytologic evaluations showed no disease completed consolidation chemoirradiation. Patients with residual tumor went on to cystectomy. After either consolidation or cystectomy, patients were to complete three cycles of MCV chemotherapy. Of the 47 patients, 45% completed all phases of the protocol treatment with minor, or no, deviations. Five patients refused either the postinduction evaluation or cystectomy and 6 refused adjuvant chemotherapy. The CR rate after induction therapy was 74%. For 2 patients, residual disease after induction was limited to positive cytologic findings, and for 8 patients, biopsy of the primary site revealed persistence. Of the 8 cystectomy patients, 2 had no evidence of disease in the bladder at pathologic review of the surgery specimen. Grade 3 toxicity related to chemotherapy was observed in 11% of patients during both induction and consolidation, and in 41% during adjuvant chemotherapy. A total of 8 patients (36% of those receiving adjuvant chemotherapy) went on to develop Grade 4 neutropenia or thrombocytopenia during additional adjuvant chemotherapy. Grade 3 toxicity due to RT was seen in 4% and 0% of patients during induction and consolidation, respectively. One patient developed Grade 4 hydronephrosis during consolidation. The projected 36-month value for locoregional failure, distant metastasis, overall survival, and bladder-intact survival was 27%, 29%, 61%, and 48%, respectively. After aggressive TURBT, twice-daily accelerated RT initiated in concomitant-boost format is well tolerated and results in a rate of complete response (74%) similar to that in previous bladder-sparing trials. The projected 2-year values for locoregional control, bladder-intact survival, and overall survival were also consistent with previously reported trials of bladder-sparing treatment. With only 45% of patients completing three cycles of MCV, this form of adjuvant chemotherapy appears to be poorly tolerated by most patients.

Purpose: To (1) measure radiation therapy costs for patients in randomized controlled clinical trials, (2) compare measured costs to modeling predictions, (3) examine cost distributions, and (4) assess feasibility of collecting economic data within a cooperative group., Methods: The Radiation Therapy Oncology Group conducted economic pilot studies for two Phase III studies that compared fractionation patterns. Expected quantities of Current Procedural Terminology (CPT) codes and relative value units (RVU) were modeled. Institutions retrospectively provided procedure codes, quantities, and components, which were converted to RVUs used for Medicare payments. Cases were included if the radiation therapy quality control review judged them to have been treated per protocol or with minor variation. Cases were excluded if economic quality review found incomplete economic data., Results: The median and mean RVUs were within the range predicted by the model for all arms of one study and above the predicted range for the other study., Conclusion: The model predicted resource use well for patients who completed treatment per protocol. Actual economic data can be collected for critical cost items. Some institutions experienced difficulty collecting retrospective data, and prospective collection of data is likely to allow wider participation in future Radiation Therapy Oncology Group economic studies.

This paper reports the results of a preliminary study designed to evaluate swallowing function in 20 patients 1 year after successful treatment of head and neck carcinomas with radiotherapy. The timing of swallowing events was evaluated by videofluoroscopy. The mean values for each measure were compared to the normative data from 60 control subjects. The radiotherapy patients demonstrated prolonged pharyngeal bolus transit and a delay of laryngeal closure. Hyoid bone elevation began late relative to the onset of bolus movement. A strong trend toward a delay in hyoid elevation relative to bolus movement was demonstrated. The time required for the hyoid bone to reach maximal elevation did not differ from that in normals, but the hyoid was held in an elevated position for a longer period of time. As a result of changes in hyoid movement, the upper esophageal sphincter tended to open early relative to the arrival of the bolus. In conclusion, changes in deglutition occur after radiotherapy, presumably as an adaptation to changes in tissue compliance.

Purpose: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation., Methods and Materials: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1. 2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive., Results: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control (p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival (p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects., Conclusions: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

Purpose: The recursive partitioning analysis (RPA) classes for malignant glioma patients were previously established using data on over 1500 patients entered on Radiation Therapy Oncology Group (RTOG) clinical trials. The purpose of the current analysis was to validate the RPA classes with a new dataset (RTOG 90-06), determine the predictive power of the RPA classes, and establish the usefulness of the database norms for the RPA classes., Patients and Methods: There are six RPA classes for malignant glioma patients that comprise distinct groups of patients with significantly different survival outcome. RTOG 90-06 is a randomized Phase III study of 712 patients accrued from 1990 to 1994. The minimum potential follow-up is 18 months. The treatment arms were combined for the purpose of this analysis. There were 84, 13, 105, 240, 150, and 23 patients in the RPA Classes I-VI from RTOG 90-06, respectively., Results: The median survival times (MST) and 2-year survival rates for the six RPA classes in RTOG 90-06 are compared to those previously published. The MST and 2-year survival rates for the RTOG RPA classes were within 95% confidence intervals of the 90-06 estimates for Classes I, III, IV, and V. The RPA classes explained 43% of the variation (squared error loss). By comparison, a Cox model explains 30% of the variation. The RPA classes within RTOG 90-06 are statistically distinct with all comparisons exceeding 0.0001, except those involving Class II. A survival analysis from a prior RTOG study indicated that 72.0 Gy had superior outcome to literature controls; analysis of this data by RPA classes indicates the survival results were not superior to the RTOG database norms., Conclusion: The validity of the model is verified by the reliability of the RPA classes to define distinct groups with respect to survival. Further evidence is given by prediction of MST and 2-year survival for all classes except Class II. The RPA classes explained a good portion of the variation in survival outcome in the data. Lack of correlation in RPA Class II between datasets may be an artifact of the small sample size or an indication that this class is not distinct. The validation of the RPA classes attests to their usefulness as historical controls for the comparison of future Phase II results.