I. Hodson

PURPOSE: The importance of the timing of thoracic irradiation (TI) in the combined modality therapy of limited-stage small-cell lung cancer (SCLC) was assessed in a randomized trial. METHODS: All 308 eligible patients received cyclophosphamide, doxorubicin, and vincristine (CAV) alternating with etoposide and cisplatin (EP) every 3 weeks for three cycles of each chemotherapy regimen. Patients randomized to early TI received 40 Gy in 15 fractions over 3 weeks to the primary site concurrent with the first cycle of EP (week 3), and late TI patients received the same radiation concurrent with the last cycle of EP (week 15). After completion of all chemotherapy and TI, patients without progressive disease received prophylactic cranial irradiation (25 Gy in 10 fractions over 2 weeks). RESULTS: Although complete remission rates were not significantly different between the two arms, progression-free survival (P = .036) and overall survival (P = .008) were superior in the early TI arm. Patients in the late TI arm had a higher risk of brain metastases (P = .006). CONCLUSION: The early administration of TI in the combined modality therapy of limited-stage SCLC is superior to late or consolidative TI.

BACKGROUND: Smoking is a risk factor for several cancers and may also limit the efficacy of treatment. In this study, we evaluated the influence of cigarette smoking during radiation therapy on the efficacy of treatment in patients with head and neck cancer. METHODS: Using a questionnaire, we obtained information on smoking behavior at base line and weekly during therapy in 115 patients with head and neck cancer who were treated with radiation therapy with or without fluorouracil. The side effects of therapy were evaluated weekly, and response was assessed 13 weeks after treatment was completed. The main outcomes measured were treatment response and survival. RESULTS: The prognostic variables were similar among the patients who smoked and those who did not smoke during treatment. The 53 patients who continued to smoke during radiation therapy had a lower rate of complete response (45 percent vs. 74 percent, P = 0.008) and poorer two-year survival (39 percent vs. 66 percent, P = 0.005) than the 62 patients who did not smoke or who had quit before treatment. Among the nonsmoking patients, mortality was influenced by the length of time between quitting and treatment, with a risk reduction (relative to that for patients who continued to smoke) of 40 percent for patients who had quit less than 12 weeks before diagnosis and of 70 percent for patients who had quit more than 1 year before diagnosis. After adjustment for other variables with proportional-hazards regression analysis, smoking remained an independent prognostic factor (P = 0.002), with a relative risk of 2.5 (95 percent confidence interval, 1.4 to 4.4) favoring the patients who abstained from smoking. The results could not be explained by the type of chemotherapy received, the presence of coexisting morbid conditions, differences in the side effects of radiation, or the number of interruptions of treatment. CONCLUSIONS: Patients with head and neck cancer who continue to smoke during radiation therapy have lower rates of response and survival than patients who do not smoke during radiation therapy.

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.

In order to assess the effect of scheduling of chemotherapy on the outcome of patients with limited small-cell lung cancer (SCLC), the Clinical Trials Group of the National Cancer Institute of Canada carried out a randomized trial comparing the alternation of cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH; doxorubicin) and vincristine (CAV) with etoposide (VP-16) and cisplatin for six cycles to the administration of these two combinations in a sequential fashion (three cycles of CAV followed by three of VP-16/cisplatin). Three hundred eligible patients were enrolled on the trial from September 1981 to October 1984. All responding patients were also treated after completion of chemotherapy with thoracic irradiation in randomly allocated doses of 2,000 and 3,750 cGy. The complete response (CR) rate to chemotherapy was slightly, but not significantly, higher on the alternating arm (52% v 44%, P = .20). However, there was no difference in disease-free or overall survival on the alternating and sequential arms, respectively (47.3 weeks v 45.1 weeks, P = .26; 61.7 weeks v 59.5 weeks, P = .56). Data on the effect of radiotherapy dose on survival are not yet mature, but it does not appear the results of this portion of the trial will alter the interpretation of the chemotherapy comparison. Patient characteristics favorably influencing survival were female sex, good performance status, younger age, and absence of supraclavicular node involvement. Two interpretations of these and other results in SCLC are suggested: (1) the difference between the schedules used is too small for the predictions of the Goldie-Coldman model to be realized in a trial of this size, or (2) VP-16/cisplatin is actually a superior regimen and any schedule that exposes patients to these drugs early in treatment will produce improved results.

BACKGROUND: The study objective was to confirm a previous finding that patients with stage III/IV squamous head and neck cancer (SHNC) who smoke during radiotherapy (RT) experience reduced survival. METHODS: An observational cohort study. Patients' smoking status was assessed weekly by questionnaire plus blood cotinine. Patients were assessed every 3 to 4 months for survival. Logistic regression and Cox proportional hazards analyses were used to detect the independent contribution of smoking on survival. RESULTS: Of 148 patients, 113 smoked during RT. Blood cotinine and smoking questionnaire responses were highly correlated (Spearman R = .69; p < .0005). Abstainers and very light smokers experienced better survival than light, moderate, and heavy smokers (median, 42 vs 29 months; p = .07). Tumor and nodal status and years smoked were the most important prognostic factors. Smoking during RT was not an independent predictor of survival, but baseline smoking status was (p = .016). CONCLUSION: Smoking status should be documented in all future trials of RT in SHNC to allow for pooled analyses with sufficient power to address this question.