• 11/13/2004
  • Sue S Yom and David I Rosenthal
  • Nature Clinical Practice Oncology (2004) 1, 14-15

Background:
Patients with advanced high-risk squamous-cell carcinoma of the head and neck frequently have a recurrence in the original tumor bed. Following tumor resection, radiotherapy can be effective in improving cancer control. This study assessed whether the addition of cisplatin to postoperative radiotherapy could improve local and regional control rates in head and neck cancer patients.

Design:
This phase III, multicenter, randomized, stratified study enrolled men and women with squamous-cell carcinoma, who were at high risk of disease, had undergone tumor resection, and who could tolerate chemotherapy. Patients were included if they were aged 18 years or more with a minimum Karnofsky Performance Status score of 60, and on the basis of particular clinical laboratory results.

Intervention:
Radiotherapy began not later than 8 weeks after surgery; patients were stratified according to age (>70 years vs <70 years), surgical margin, and tumor status. Patients were randomly assigned to receive 60 Gy radiosurgery in 30 fractions over 6 weeks, with or without 6 Gy boosts in 3 fractions over a 3-day period. Patients in the combined therapy group also received intravenous cisplatin at 100 mg/m2 of body-surface area on days 1, 22, and 43. Patients were examined weekly during treatment, and post-treatment evaluations were carried out after 9 weeks, then every 3 months for the first year, twice in the second and third years, and annually thereafter.

Outcome Measures:
Local and regional tumor control was the primary endpoint. Treatment failure was defined as the reappearance of tumor in the original tumor bed or development of cervical-node metastases. Secondary endpoints were disease-free survival, overall survival, and adverse events.

Results:
Of the 416 randomized subjects, 206 were assigned to combination therapy and 210 to radiotherapy alone. Local and regional control was significantly improved in the combined-therapy group than with radiotherapy alone (19% vs 30%, respectively, hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41 to 0.91, P = 0.01). Disease-free survival was significantly longer in the combined therapy group (HR 0.78, 95% CI 0.61 to 0.99, P = 0.04), but there was no significant difference in overall survival between treatment groups. Acute and late adverse events (combined) with grade 3 or greater were significantly more likely for patients receiving combined therapy than radiotherapy alone (78% vs 46%, P <0.001). In the combination group four patients died as a result of the treatment, whereas no patients died as a result of radiosurgery treatment.

Conclusion:
Combined radiotherapy and chemotherapy is effective in improving local and regional tumor control and disease-free survival following resection of high-risk squamous-cell carcinoma of the head and neck, but combined treatment is associated with increased rates of severe adverse effects.

Commentary:
(by David Bruce, Associate Editor, Nature Clinical Practice)

Locoregional recurrence remains a challenge in the management of locally advanced squamous-cell carcinoma of the head and neck. Locoregional control is the initial objective, as distant metastases develop later. Retrospective analyses demonstrate that postoperative radiotherapy increases locoregional control. One prospective trial showed no additional benefit for doses above 57.6 Gy except at high-risk sites where 63.0 Gy was required for equivalent control.(1) No improvement in locoregional control was achieved with further dose escalation. In contrast, prospective definitive chemoradiation trials have greatly improved locoregional control and survival compared with more intense radiotherapy alone.

The recent results of the simultaneously published RTOG and EORTC randomized phase III trials have confirmed the benefit of postoperative chemoradiation. In both studies, patients were randomized to receive radiotherapy with or without cisplatin. The RTOG trial by Cooper et al. was designed to detect a 15% benefit in locoregional control at 2 years but was not powered to detect a survival difference. At a median follow up of 45.9 months, postoperative chemoradiation produced a 10% advantage in locoregional control. No overall survival advantage was demonstrated. Interestingly, the EORTC trial by Bernier et al. showed a 13% estimated 5-year survival advantage favoring chemoradiation.(2) Patients in the RTOG trial had a much higher rate of advanced nodal disease (82% vs 57%), whereas patients in the EORTC trial had more positive margins (28% vs 18%). In both these trials, concurrent chemoradiation doubled the rate of high-grade acute toxicity and, in the case of the RTOG study, the regimen increased the number of treatment-related deaths. The RTOG trial had a higher treatment compliance rate. Chemotherapy exacerbates mucositis and aspiration, which may add to postoperative dysfunction. Given the importance of toxicity and functional assessment, future trials should provide well-designed documentation of swallowing and airway function.(3)

The primary objective of the chemoradiation RTOG and EORTC trials was an improvement in locoregional control, but the rate of distant metastases was not reduced. Accelerated radiotherapy alone, lower-dose weekly chemotherapy, or targeted therapies might also address locoregional control while reducing systemic toxicity. Sequential systemic therapy could also be investigated to decrease distant metastases that become more relevant as the rate of locoregional control improves.

A shorter overall treatment time may increase tumor control and survival.(4) The Medical Research Council in the UK is conducting a randomized phase III trial comparing an accelerated radiotherapy schedule of 3 weeks to a 7-week schedule, based on the hypothesis that accelerated radiotherapy may improve locoregional control without systemic toxicity. RTOG H-0024 has completed accrual and evaluates a sequential postoperative regimen of early low-dose weekly chemotherapy followed by concurrent weekly chemoradiation.(5) Targeted therapies combined with radiotherapy may improve locoregional control with less local and systemic toxicity.(6) One trial, RTOG H-0234, is evaluating postoperative radiotherapy and weekly cetuximab combined with either cisplatin or docetaxel.

The differing inclusion criteria and patient characteristics of the EORTC and RTOG trials will stimulate continued debate about specifics of patient selection. A forthcoming integrated analysis of patient data from both trials should provide further insight into appropriate patient selection and magnitude of expected benefit. In the meantime, additional strategies to improve outcome and reduce toxicity are being investigated.

References:
Peters LJ et al. (1993) Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. Int J Radiat Oncol Biol Phys 26: 3–11

Bernier J et al. (2004) Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350: 1945–1952

Trotti A and Bentzen SM (2004) The need for adverse effects reporting standards in oncology clinical trials. J Clin Oncol 22: 19–22

Rosenthal DI et al. (2002) Importance of the treatment package time in surgery and postoperative radiation therapy for squamous carcinoma of the head and neck. Head Neck 24: 115–126 | Article | PubMed | ISI |
Rosenthal DI et al. (2004) Early postoperative paclitaxel followed by paclitaxel and cisplatin concurrent with radiation therapy (RT) (Phase II Trial RTOG H-0024) is well tolerated for patients with resected, high-risk squamous carcinoma of the head and neck (HNSCC) [abstract]. Proc Am Soc Ther Rad Oncol, in press

Bonner JA et al. (2004) Cetuximab prolongs survival in patients with locoregionally advanced squamous cell carcinoma of head or neck: a phase III study of high dose radiation therapy with or without cetuximab [abstract]. Proc Am Soc Clin Oncol 22: 5507