Richard Wheeler

Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer

BACKGROUND Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown. METHODS We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer. RESULTS The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. CONCLUSIONS Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)

FINAL REPORT OF RTOG 9610, A MULTI-INSTITUTIONAL TRIAL OF REIRRADIATION AND CHEMOTHERAPY FOR UNRESECTABLE RECURRENT SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Our objectives were to determine the incidence of acute and late toxicities and to estimate the 2‐year overall survival for patients treated with reirradiation and chemotherapy for unresectable squamous cell carcinoma of the head and neck (SCCHN).

RTOG 96-10: Reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck

PURPOSE Patients with recurrent squamous cell cancer of the head and neck (SCH&N) are generally treated with systemic chemotherapy. Improvement in survival has not occurred, despite an increased objective response rate. This study was undertaken to explore the feasibility and toxicity, and estimate the therapeutic impact of, reirradiation (RRT) with concurrent hydroxyurea and 5-fluorouracil. METHODS AND MATERIALS The eligibility requirements included SCH&N presenting as a second primary or recurrence > or =6 months after definitive RT to > or =45 Gy, with > or =75% of the tumor volume within the previous field. The cumulative spinal cord dose was limited to 50 Gy, and measurable disease was required. Four weekly cycles were given, each separated by 1 week of rest. A cycle consisted of 5 days, Monday through Friday, of 1.5-Gy twice-daily repeated RT, with the fractions separated by > or =6 h, with 1.5 g of hydroxyurea given 2 h and 300 mg/m2 of a 5-fluorouracil IV bolus given 30 min before each second daily fraction. RESULTS Eighty-six patients were entered; 81 patients were assessable. The median prior radiation dose was 61.2 Gy. The 4 planned cycles were delivered in 79% of patients. Grade 3 mucositis occurred in 14% of patients, and Grade 4 in 5%. Grade 3 acute pharyngeal toxicity was seen in 17%. Grade 3 neutropenia occurred in 9%, Grade 4 in 10%, and Grade 5 in 7%. Six patients died of treatment-related toxicity. Two died of hemorrhage from the tumor site without thrombocytopenia. With a median follow-up of 16.3 months for living patients, the estimated median overall survival was 8.2 months and the estimated 1-year survival rate 41.7%. Patients treated >3 years after the previous RT had a 1-year survival rate of 48% compared with 35% for patients treated within 3 years (p = 0.017). The 1-year survival rate for patients with a second primary was 54% compared with 38% for patients with recurrence (p = 0.083). CONCLUSION Repeated RT with concurrent chemotherapy as given in this study is a feasible approach for selected, previously irradiated patients with SCH&N and may produce increased median and 1-year survival rates compared with systemic chemotherapy trials reported in the literature. A randomized study should be conducted to compare these two different approaches.

Phase 1 trial of combined chemotherapy and reirradiation for recurrent unresectable head and neck cancer.

The management of recurrent unresectable head and neck cancer remains a challenging problem. Based on the circadian rhythm concept, we sought to determine the maximum tolerated dose (MTD) of infusional 5‐flourouracil (5‐FU), hydroxyurea (HU), and reirradiation (RT).

Concurrent chemoradiation therapy with cisplatin and paclitaxel for locally advanced non-small cell lung cancer: long-term follow-up of a phase I trial

The purpose of this trial was to evaluate the feasibility of concurrent paclitaxel/cisplatin and conventional thoracic irradiation in locally advanced non-small cell lung cancer (NSCLC). Ambulatory patients with medically inoperable or unresectable stage II-III NSCLC, and performance status 0-2 were eligible. Patients were not excluded from this trial if they had lost more than 5% of their body weight during the preceding 3 months, and/or if they had small ipsilateral pleural effusion. The initial dose of paclitaxel/cisplatin was 110 and 50 mg/m(2), and was escalated through five dose levels. Four cycles of chemotherapy were planned; the first two cycles were given concurrently with radiotherapy (4 weeks apart), followed by two additional cycles (every 3 weeks). Conventional chest radiotherapy to a total dose of 60 Gy (2 Gy per day) was delivered in 6 weeks. Forty-three patients were enrolled of which 38 were evaluable for response. Dose-limiting toxicities were grade 4 neutropenia (43% of patients) and grade 3 esophagitis (26% of patients) during the chemoradiotherapy phase. Grade > or = 2 acute and late pulmonary toxicity occurred in 10 and 68% of the patients, respectively. In most patients, prompt symptomatic and radiologic improvement was observed with early steroid administration. The volume of lung receiving 15-30 Gy was correlated with late pulmonary toxicity. The overall response was 84% with ten complete and 22 partial responses. The median survival was 16.5 months (95% confidence interval, 9.5 to 25) for those patients evaluable for response. After a median follow-up of 70 months, 5 (13%) patients are alive without evidence of disease. The maximum tolerated dose (MTD) of paclitaxel and cisplatin with concurrent radiotherapy is at dose level 3 paclitaxel (135 mg/m(2)) and cisplatin (75 mg/m(2)). Toxicity, although significant, was manageable in the great majority of the patients. The activity observed with this regimen is particularly noteworthy when considering the advanced nature of these patients, and the fact that patients (N=18) with poor risk factors were included in the study.