Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer.

PURPOSE: To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91-11 study evaluating the contribution of chemotherapy added to radiation therapy (RT) for larynx preservation. PATIENTS AND METHODS: Patients with stage III or IV glottic or supraglottic squamous cell cancer were randomly assigned to induction cisplatin/fluorouracil (PF) followed by RT (control arm), concomitant cisplatin/RT, or RT alone. The composite end point of laryngectomy-free survival (LFS) was the primary end point. RESULTS: Five hundred twenty patients were analyzed. Median follow-up for surviving patients is 10.8 years. Both chemotherapy regimens significantly improved LFS compared with RT alone (induction chemotherapy v RT alone: hazard ratio [HR], 0.75; 95% CI, 0.59 to 0.95; P = .02; concomitant chemotherapy v RT alone: HR, 0.78; 95% CI, 0.78 to 0.98; P = .03). Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR, 1.25; 95% CI, 0.98 to 1.61; P = .08). Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT (HR, 0.58; 95% CI, 0.37 to 0.89; P = .0050) and over RT alone (P < .001), whereas induction PF followed by RT was not better than treatment with RT alone (HR, 1.26; 95% CI, 0.88 to 1.82; P = .35). No difference in late effects was detected, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% v 20.8% with induction chemotherapy and 16.9% with RT alone). CONCLUSION: These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS. Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone. New strategies that improve organ preservation and function with less morbidity are needed.

Retinoblastoma and phosphate and tensin homolog tumor suppressors: impact on ductal carcinoma in situ progression.

BACKGROUND: A subset of patients with ductal carcinoma in situ (DCIS) will progress to invasive breast cancer. However, there are currently no markers to differentiate women at high risk from those at lower risk of developing invasive disease. METHODS: The association of two major tumor suppressor genes, retinoblastoma (RB) and phosphatase and tensin homolog (PTEN), with risk of any ipsilateral breast event (IBE) or progression to invasive breast cancer (IBC) was analyzed using data from 236 DCIS patients treated with breast conserving surgery with long-term follow-up. RB and PTEN expression was assessed with immunohistochemistry. The functional effects of RB and/or PTEN loss were modeled in MCF10A cells. Hazard ratios (HRs) were estimated with univariate and multivariable Cox regression models. All statistical tests were two-sided. RESULTS: Loss of RB immunoreactivity in DCIS was strongly associated with risk of IBE occurrence (HR = 2.64; 95% confidence interval [CI] = 1.64 to 4.25) and IBC recurrence (HR = 4.66; 95% CI = 2.19 to 9.93). The prognostic power of RB loss remained statistically significant in multivariable analyses. PTEN loss occurred frequently in DCIS but was not associated with recurrence or progression. However, patients with DCIS lesions that were both RB and PTEN deficient were at further increased risk for IBEs (HR = 3.39; 95% CI = 1.92 to 5.99) and IBC recurrence (HR = 6.1, 95% CI = 2.5 to 14.76). Preclinical modeling in MCF10A cells demonstrated that loss of RB and PTEN impacted proliferation, motility, and invasive properties. CONCLUSIONS: These studies indicate that RB and PTEN together have prognostic utility and could be used to target aggressive treatment for patients with the greatest probability of benefit.

Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck.

PURPOSE: Previous analysis of this Intergroup trial demonstrated that with a median follow-up among surviving patients of 45.9 months, the concurrent postoperative administration of cisplatin and radiation therapy improved local-regional control and disease-free survival of patients who had high-risk resectable head-and-neck carcinomas. With a minimum of 10 years of follow-up potentially now available for all patients, these results are updated here to examine long-term outcomes. METHODS AND MATERIALS: A total of 410 analyzable patients who had high-risk resected head-and-neck cancers were prospectively randomized to receive either radiation therapy (RT: 60 Gy in 6 weeks) or identical RT plus cisplatin, 100 mg/m(2)i.v. on days 1, 22, and 43 (RT + CT). RESULTS: At 10 years, the local-regional failure rates were 28.8% vs 22.3% (P=.10), disease-free survival was 19.1% vs 20.1% (P=.25), and overall survival was 27.0% vs 29.1% (P=.31) for patients treated by RT vs RT + CT, respectively. In the unplanned subset analysis limited to patients who had microscopically involved resection margins and/or extracapsular spread of disease, local-regional failure occurred in 33.1% vs 21.0% (P=.02), disease-free survival was 12.3% vs 18.4% (P=.05), and overall survival was 19.6% vs 27.1% (P=.07), respectively. CONCLUSION: At a median follow-up of 9.4 years for surviving patients, no significant differences in outcome were observed in the analysis of all randomized eligible patients. However, analysis of the subgroup of patients who had either microscopically involved resection margins and/or extracapsular spread of disease showed improved local-regional control and disease-free survival with concurrent administration of chemotherapy. The remaining subgroup of patients who were enrolled only because they had tumor in 2 or more lymph nodes did not benefit from the addition of CT to RT.

Hyperfractionated or accelerated radiotherapy for head and neck cancer.

BACKGROUND: Several trials have studied the role of altered fractionation radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. OBJECTIVES: The aim of this individual patient data (IPD) meta-analysis was to assess whether this type of radiotherapy could improve survival. SEARCH STRATEGY: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; CENTRAL (2010, Issue 3); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and unpublished trials. The date of the most recent search was 8 August 2010. SELECTION CRITERIA: We identified randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic head and neck squamous cell carcinomas and grouped trials into three pre-specified treatment categories: hyperfractionated, accelerated and accelerated with total dose reduction. Trials were eligible if they began recruitment after 1969 and ended before 1998. DATA COLLECTION AND ANALYSIS: We obtained updated individual patient data. Overall survival was the main outcome measure. The secondary outcome measures were local or regional control rates (or both), distant control rates and cause-specific mortality. MAIN RESULTS: We included 15 trials with 6515 patients. The median follow up was six years. Tumour sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (UICC 2002). There was a significant survival benefit with altered fractionation radiotherapy, corresponding to an absolute benefit of 3.4% at five years (hazard ratio (HR) 0.92, 95% CI 0.86 to 0.97; P = 0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at five years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at five years, P = 0.02). There was a benefit in locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at five years; P < 0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (under 50 year old) (HR 0.78, 95% CI 0.65 to 0.94), 0.95 (95% CI 0.83 to 1.09) for 51 to 60 year olds, 0.92 (95% CI 0.81 to 1.06) for 61 to 70 year olds, and 1.08 (95% CI 0.89 to 1.30) for those over 70 years old; test for trends P = 0.007). AUTHORS' CONCLUSIONS: Altered fractionation radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation provides the greatest benefit. An update of this IPD meta-analysis (MARCH 2), which will increase the power of this analysis and allow for other comparisons, is currently in progress.

Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation Therapy Oncology Group trial 90-03.

PURPOSE: To validate lysyl oxidase (LOX), a hypoxia-related protein, as a marker for metastasis in an independent head and neck cancer (HNC) patient group enrolled onto a prospective trial. PATIENTS AND METHODS: We performed traditional immunohistochemical (IHC) staining and automated quantitative analysis (AQUA) for LOX expression in 66 HNC patients from one institution. We also performed AQUA staining for LOX in 306 of 1,113 patients treated on a phase III trial comparing four radiation fractionation schedules in locally advanced HNC (RTOG 90-03). Pretreatment characteristics and outcome were similar between patients with and without LOX assessment. We correlated AQUA LOX expression with time to metastasis (TTM), time to progression (TTP), and overall survival (OS). RESULTS: LOX expression from both staining methods predicted for TTM in the first 66 patients. Multivariate analysis, controlling for significant parameters including nodal stage and performance status, revealed tumor LOX expression, as a continuous variable, was an independent predictor for TTM (hazard ratio [HR], 1.21; 95% CI, 1.10 to 1.33; P = .0001), TTP (HR, 1.06; 95% CI, 1.02 to 1.10; P = .0069), and OS (HR, 1.04; 95% CI, 1.00 to 1.07; P = .0311) in RTOG 90-03 patients. This translates into a 259% increase in metastatic risk for a patient at the 75th percentile of LOX compared with one at the 25th percentile. CONCLUSION: AQUA LOX expression was strongly associated with increased metastasis, progression, and death in RTOG 90-03 patients. This study validates that LOX is a marker for metastasis and survival in HNC.

Surrogate endpoints for overall survival in locally advanced head and neck cancer: meta-analyses of individual patient data.

BACKGROUND: The gold standard endpoint in randomised trials of locally advanced head and neck squamous-cell carcinoma (HNSCC) is overall survival. Our objective was to study whether duration of locoregional control or event-free survival (EFS) could be considered as surrogate endpoints to estimate the effect of radiotherapy and chemotherapy on overall survival. This would allow a reduction in the duration and cost of the development of new treatments. METHODS: Individual patient data from 104 trials (22 744 patients), with 116 treatment-control comparisons, from four meta-analyses on hyperfractionated or accelerated radiotherapy and concomitant, induction, or adjuvant chemotherapy were analysed. Duration of locoregional control was defined as the time from randomisation to the first locoregional event and EFS as the time to any first event (ie, locoregional relapse, distant recurrence, or death). At the individual level, a rank correlation coefficient between the surrogate endpoint and overall survival was used to assess surrogacy; at the trial level, a correlation coefficient R between treatment effects was used. FINDINGS: At the individual level, overall survival was more strongly correlated with EFS (range of correlations 0.82-0.90) than with locoregional control (0.65-0.76). For radiotherapy, treatment effects on both locoregional control and EFS were strongly correlated with those on overall survival (R=0.94 and 0.98, respectively). For chemotherapy, the correlations between treatment effects on EFS and overall survival were stronger than those between locoregional control and overall survival (range of R 0.79-0.93 vs 0.53-0.84, respectively). INTERPRETATION: EFS is a better correlate with overall survival than locoregional control and could be used as a surrogate for overall survival to assess the treatment effect of radiotherapy and chemotherapy in randomised trials of locally advanced HNSCC.

Pretreatment quality of life predicts for locoregional control in head and neck cancer patients: a radiation therapy oncology group analysis.

PURPOSE: To analyze the prospectively collected health-related quality-of-life (HRQOL) data from patients enrolled in two Radiation Therapy Oncology Group randomized Phase III head and neck cancer trials (90-03 and 91-11) to assess their value as an independent prognostic factor for locoregional control (LRC) and/or overall survival (OS). METHODS AND MATERIALS: HRQOL questionnaires, using a validated instrument, the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N), version 2, were completed by patients before the start of treatment. OS and LRC were the outcome measures analyzed using a multivariate Cox proportional hazard model. RESULTS: Baseline FACT-H&N data were available for 1,093 patients and missing for 417 patients. No significant difference in outcome was found between the patients with and without baseline FACT-H&N data (p = 0.58). The median follow-up time was 27.2 months for all patients and 49 months for surviving patients. Multivariate analyses were performed for both OS and LRC. Beyond tumor and nodal stage, Karnofsky performance status, primary site, cigarette use, use of concurrent chemotherapy, and altered fractionation schedules, the FACT-H&N score was independently predictive of LRC (but not OS), with p = 0.0038. The functional well-being component of the FACT-H&N predicted most significantly for LRC (p = 0.0004). CONCLUSIONS: This study represents, to our knowledge, the largest analysis of HRQOL as a prognostic factor in locally advanced head and neck cancer patients. The results of this study have demonstrated the importance of baseline HRQOL as a significant and independent predictor of LRC in patients with locally advanced head and neck cancer.

Emotional well-being does not predict survival in head and neck cancer patients: a Radiation Therapy Oncology Group study.

BACKGROUND: The objective of the current study was to examine whether emotional well-being predicted survival in a large sample of patients with head and neck cancer who were participating in multicenter clinical trials. METHODS: Participants were enrolled in 2 Radiation Oncology Group (RTOG) clinical trials (RTOG 9003 and RTOG 9111) and completed a baseline measure of quality of life (the Functional Assessment of Cancer Therapy-General [FACT-G]), which included an Emotional Well-Being subscale. The outcome measure was overall survival. Main statistical analyses included overall survival rates, which were estimated by using the Kaplan-Meier method with univariate comparisons analyzed using the log-rank test. A multivariate Cox proportional hazards model was used to determine whether emotional well-being had prognostic impact on survival after accounting for tumor-related and sociodemographic variables. Additional exploratory analyses examined possible subgroup effects. RESULTS: No statistically significant univariate or multivariate effects were observed for emotional well-being, and there were no effects limited to subgroups. These results stand in sharp contrast to the prognostic value of a variety of demographic and clinical variables. CONCLUSIONS: The current results add to the weight of the evidence that emotional functioning is not an independent predictor of survival in cancer patients. The study had the advantage of a large number of deaths to be explained in a sample with the uniformity of treatment and quality of care that is required in clinical trials.

Microvessel density >or=60 does not predict for outcome after radiation treatment for locally advanced head and neck squamous cell carcinoma: results of a correlative study from the Radiation Therapy Oncology Group (RTOG) 90-03 Trial.

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.

Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: a randomized trial of the Radiation Therapy Oncology Group (RTOG 99-03).

PURPOSE: To determine whether the addition of recombinant human erythropoietin (Epo) could improve the outcomes of anemic patients receiving definitive radiotherapy for squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Eligible patients had SCCHN, with a plan for continuous-course definitive radiotherapy (66-72 Gy) with or without chemotherapy. Patients with Stage III or IV SCCHN were required to undergo concurrent chemoradiotherapy and/or accelerated fractionation radiotherapy. Preradiotherapy hemoglobin was required to be between 9.0 g/dL and 13.5 g/dL (12.5 g/dL for women). Patients randomized to Epo received 40,000 U once weekly, starting 7-10 days before start of radiotherapy. RESULTS: A total of 148 patients were enrolled; 141 were evaluable. Median pretreatment hemoglobin was 12.1 g/dL. Hemoglobin levels at 4 weeks rose by an average of 1.66 g/dL in the Epo arm, compared with an average 0.24 g/dL decrease in the control arm (p = 0.0001). Median follow-up was 2.5 years (3.1 years for surviving patients). There was no statistically significant difference in the primary endpoint of local-regional failure (LRF) rate between the treatment arms. The 3-year LRF rate was 36% for control and 44% for Epo (p = 0.56). There were also no significant differences in local-regional progression-free survival (LRPFS), patterns of failure, overall survival, or toxicity. The 3-year LRPFS rate was 52% for control and 47% for Epo. The overall survival rate was 57% and 56%, respectively. CONCLUSIONS: The addition of Epo to definitive radiotherapy for SCCHN did not improve outcomes. The study was not specifically designed to detect a potential negative association between Epo and tumor progression/survival.

TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group.

BACKGROUND: We aimed to examine deficiencies in established methods of summarising adverse events, and to create a new reporting system (TAME) for summarising the toxicity burden of cancer treatment. TAME consolidates traditional adverse-event data into three risk domains: short-term (acute) Toxicity (T), Adverse long-term (late) effects (A), and Mortality risk (M) generated by a treatment programme (E=End results); and assigns treatments to risk classes for each risk domain. METHODS: We examined formally an established method for summarising adverse events (the max-grade method) in five trials of patients with head and neck cancer done between September, 1991, and August, 2000, by the Radiation Therapy Oncology Group (RTOG) that involved 13 treatment groups (2304 patients). We calculated TAME summary metrics that included time and multiplicity factors in the same patient groups. We compared relative T values with relative values for toxic effects from the max-grade approach. We also calculated the range of individual patient T scores in two groups from one of the trials (the laryngeal-preservation trial). RESULTS: The max-grade method systematically excluded 29-70% of total reported high-grade (grade 3-4) acute adverse events, contained progressive bias, and favoured higher toxicity programmes. Relative T values in the 13 treatment programmes tested showed an increase of almost 500% in acute toxicity burden (100-590) between treatment groups compared with a 170% increase (100-270) between treatment groups by use of the max-grade method. The difference between these two summary systems was statistically significant (mean difference -102 [95% CI -167 to -37], p=0.005, t test for paired differences). Four risk classes were designated for acute and relative late effects: low (100-140), moderate (150-390), high (400-490), and extreme (>or=500). The distribution of individual patient T scores showed that 82 (60%) patients who received concurrent platinum-radiotherapy for larynx preservation reported two or more high-grade events, and 34 (20%) reported four or more high-grade events; these findings differed significantly from the distribution of individual patient T scores for patients who received radiotherapy alone, in which 32 (19%) reported two or more high-grade events and 3 (3%) reported four or more high-grade events (p<0.0001). The max-grade method also systematically excluded 26-48% of high-grade (grade 3-4) late adverse events. However, less variation was noted in the relative risk of late events (100-270) by the TAME method for late effects. INTERPRETATION: Traditional methods for summarising adverse events systematically exclude important data, giving an inaccurate impression of the toxicity burden in complex multimodality trials. By contrast, T values use data on all high-grade adverse events. T values are proportional to the intensity of treatment, showing a 500% increase between treatment groups in acute toxicity burden in RTOG trials of head and neck cancer done during this study interval. TAME reporting provides a concise and uniform method to compare relative risk among treatment options. Future studies should include testing the performance of the TAME system in additional datasets (from different research organisations and disease sites), prospective correlation of TAME endpoints with predefined outcome measures, and assessment of its usefulness in clinical decision making.

Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis.

BACKGROUND: Several trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this meta-analysis was to assess whether this type of radiotherapy could improve survival. METHODS: Randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction. FINDINGS: 15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86-0.97; p=0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at 5 years, p=0.02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at 5 years; p<0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0.78 [0.65-0.94] for under 50 year olds, 0.95 [0.83-1.09] for 51-60 year olds, 0.92 [0.81-1.06] for 61-70 year olds, and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007). INTERPRETATION: Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.

Disadvantage of men living alone participating in Radiation Therapy Oncology Group head and neck trials.

PURPOSE: This study evaluated whether males without partners were disadvantaged for survival in Radiation Therapy Oncology Group (RTOG) head and neck cancer clinical trials. METHODS: Patients treated on three RTOG trials were studied. The Cox proportional hazards model was used to determine if sex and the interaction between sex and marital/partner status were independent prognostic variables for overall survival controlling for Karnofsky performance status, tumor stage, nodal stage, primary site, and protocol treatment. RESULTS: A total of 1,901 patients (1,509 men) were entered onto the three RTOG trials, with 1,822 (1,438 men) analyzable patients. Prognostic variables independent of disease-related variables for survival in multivariate analyses restricted to men were age, marital/partner status, and income. CONCLUSION: The apparent disadvantage of unpartnered men is striking, even after controlling for disease and other demographic variables. Possible explanations could easily be tested in observational studies, leading to evaluation of simple interventions to improve their outcome.

Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients.

BACKGROUND: Isotretinoin (13-cis-retinoic acid) is a synthetic vitamin A derivative, or retinoid, widely used in the treatment of cystic acne. Preclinical and clinical studies of high-dose isotretinoin in patients with head and neck squamous cell cancer (HNSCC) have produced encouraging results. We conducted a phase III randomized trial of low-dose isotretinoin versus placebo in early-stage HNSCC patients to assess its effect on second primary tumor incidence and survival. METHODS: We randomly assigned 1190 patients who had been treated for stage I or II HNSCC to receive either low-dose isotretinoin (30 mg/day) or placebo for 3 years. The patients were monitored for up to 4 more years. Survival was analyzed by the Kaplan-Meier method, and Cox proportional hazards models were used for multivariable survival analysis. All statistical tests were two-sided. RESULTS: Isotretinoin did not statistically significantly reduce the rate of second primary tumors (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 0.83 to 1.35) or increase survival (HR = 1.03, 95% CI = 0.81 to 1.32) compared with placebo in patients with early-stage HNSCC. Current smokers had a higher rate of second primary tumors than that of never (HR = 1.64, 95% CI = 1.08 to 2.50) or former (HR = 1.32, 95% CI = 1.01 to 1.71) smokers. The hazard ratio of death from any cause for current smokers versus never smokers was 2.51 (95% CI = 1.54 to 4.10) and for current smokers versus former smokers was 1.60 (95% CI = 1.23 to 2.07). Major sites of second primary tumors (n = 261) included lung (31%), oral cavity (17%), larynx (8%), and pharynx (5%). CONCLUSIONS: Low-dose isotretinoin was not effective in reducing the rate of second primary tumors or death or smoking-related disease. Smoking statistically significantly increased the rate of second primary tumors and death. Ongoing trials are testing higher doses of isotretinoin as part of combination bioadjuvant therapeutic methods for patients with locally advanced HNSCC.

Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.

BACKGROUND: Despite the use of resection and postoperative radiotherapy, high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed. We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control. METHODS: Between September 9, 1995, and April 28, 2000, 459 patients were enrolled. After undergoing total resection of all visible and palpable disease, 231 patients were randomly assigned to receive radiotherapy alone (60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks) and 228 patients to receive the identical treatment plus concurrent cisplatin (100 mg per square meter of body-surface area intravenously on days 1, 22, and 43). RESULTS: After a median follow-up of 45.9 months, the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone (hazard ratio for local or regional recurrence, 0.61; 95 percent confidence interval, 0.41 to 0.91; P=0.01). The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group, as compared with 72 percent in the radiotherapy group. Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group (hazard ratio for disease or death, 0.78; 95 percent confidence interval, 0.61 to 0.99; P=0.04), but overall survival was not (hazard ratio for death, 0.84; 95 percent confidence interval, 0.65 to 1.09; P=0.19). The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group (P<0.001). Four patients who received combined therapy died as a direct result of the treatment. CONCLUSIONS: Among high-risk patients with resected head and neck cancer, concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival. However, the combined treatment is associated with a substantial increase in adverse effects.

A multinational, randomized phase III trial of iseganan HCl oral solution for reducing the severity of oral mucositis in patients receiving radiotherapy for head-and-neck malignancy.

PURPOSE: Oral mucositis (OM) causes significant morbidity during the course of radiotherapy (RT) treatment of head-and-neck cancer. It is hypothesized that infection plays a role in the development of OM. We tested the efficacy of iseganan HCl (iseganan), a synthetic peptide with broad-spectrum antimicrobial activity, for preventing RT-associated OM. METHODS: A multinational, randomized, double-blind, controlled trial was performed on patients receiving primary RT, primary chemoradiotherapy or postoperative RT. Patients were randomized to receive iseganan oral solution plus standard-of-care oral hygiene (SOC), placebo plus SOC, or SOC alone throughout the RT administration period. The severity of OM was assessed by NCI-CTC scoring and clinical symptoms by patient questionnaire. RESULTS: A total of 545 patients were randomized to the study. Nine percent of the patients in both the iseganan and placebo groups did not develop ulcerative OM (Grades 2, 3, 4) (p = 0.998) whereas only 2% of the patients receiving SOC alone remained free of oral ulceration (p = 0.049). The maximum severity of mouth pain and difficulty swallowing did not differ in patients treated with iseganan or placebo. However, patients in both intervention groups reported less mouth pain and difficulty swallowing than did patients receiving SOC alone. Nausea was the only adverse event that occurred with >/=5% increased frequency in the iseganan group than in either the placebo or SOC groups (51% vs. 42% vs. 46%). Adverse events leading to study drug discontinuation and death did not differ significantly between groups. CONCLUSION: Iseganan oral solution was safe but did not reduce the risk for developing ulcerative OM relative to placebo. Intensified oral hygiene or the administration of the vehicle used to deliver study drug in this trial appears to have reduced the risk and severity of OM. Our results suggest that antimicrobial intervention may not meaningfully affect the pathogenesis of radiation-induced OM.

Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer.

BACKGROUND: Induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the standard alternative to total laryngectomy for patients with locally advanced laryngeal cancer. The value of adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown. METHODS: We randomly assigned patients with locally advanced cancer of the larynx to one of three treatments: induction cisplatin plus fluorouracil followed by radiotherapy, radiotherapy with concurrent administration of cisplatin, or radiotherapy alone. The primary end point was preservation of the larynx. RESULTS: A total of 547 patients were randomly assigned to one of the three study groups. The median follow-up period was 3.8 years. At two years, the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin (88 percent) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy (75 percent, P=0.005) or radiotherapy alone (70 percent, P<0.001). The rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin (78 percent, vs. 61 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 56 percent with radiotherapy alone). Both of the chemotherapy-based regimens suppressed distant metastases and resulted in better disease-free survival than radiotherapy alone. However, overall survival rates were similar in all three groups. The rate of high-grade toxic effects was greater with the chemotherapy-based regimens (81 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 82 percent with radiotherapy with concurrent cisplatin, vs. 61 percent with radiotherapy alone). The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy. CONCLUSIONS: In patients with laryngeal cancer, radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control.

Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02.

PURPOSE: Radiation Therapy Oncology Group (RTOG) Protocol 92-02 was a randomized trial testing long-term (LT) adjuvant androgen deprivation (AD) after initial AD with external-beam radiotherapy (RT) in patients with locally advanced prostate cancer (PC; T2c-4) and with prostate-specific antigen level less than 150 ng/mL. PATIENTS AND METHODS: Patients received a total of 4 months of goserelin and flutamide, 2 months before and 2 months during RT. A radiation dose of 65 to 70 Gy was given to the prostate and a dose of 44 to 50 Gy to the pelvic lymph nodes. Patients were randomly assigned to receive no additional therapy (short-term [ST]AD-RT) or 24 months of goserelin (LTAD-RT); 1,554 patients were entered onto the study. RESULTS: The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P =.73), compared with the STAD-RT arm. In a subset of patients not part of the original study design, with tumors assigned Gleason scores of 8 to 10 by the contributing institutions, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P =.044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P =.037), the cause of which is not clear. CONCLUSION: The RTOG 92-02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC. In the exploratory subset analysis of patients with Gleason scores 8 to 10, LT adjuvant AD resulted in a survival advantage.