Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck, RTOG 9501/Intergroup

Author: Reviewer: Courtney Lewis, MD, MPH
Content Contributor: The Abramson Cancer Center of the University of Pennsylvania
Last Reviewed: June 27, 2004

Source:N Engl J Med. 2004 May 6;350(19):1937-44


Combined chemotherapy and radiation has become a well-accepted treatment for unresectable or locally advanced head and neck cancer, due to the findings from several large clinical trials. Standard post-operative therapy for high risk disease (positive lymph nodes, microscopically positive margins, etc.) has consisted only of radiation therapy. No Phase III trial to date has demonstrated a survival advantage to using chemoradiation in the post-operative setting. With radiation alone, patients unfortunately still recur locally and/or distally 25-40% of the time, if they have high risk features at surgery. The RTOG trial presented here, along with the accompanying EORTC trial in this same issue of the New England Journal, present data to support using combined chemotherapy and radiation with a cisplatin-based regimen, in patients who have undergone a gross total resection but who have high risk disease.


  • Randomized Phase III trial of 549 patients, enrolled patients 1995-2000
  • All patients had squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx and had undergone a macroscopically complete resection
  • Patients had high risk features, defined as two or more regional lymph nodes, extracapsular spread of disease, or microscopically positive margins
  • Pre-operative workup included history and physical, labs, dental evaluation, chest x-ray, but CT or MRI of the head/neck was not required
  • Stratification:
    • Age, <70 vs > 70
    • Presence vs. absence of tumor at margin
  • Patients randomized to:
    • Radiation alone of 60 Gy in 30 fractions over 6 weeks +/- boost of 6 Gy in 3 fractions to high risk sites
    • Same radiation + Cisplatin, 100mg per square meter, days 1,22,43
  • XRT to begin at max 8 weeks (56 days) post-operatively, ideally 4-6 weeks post-operative initiation of treatment
  • Primary endpoints were local regional tumor control
  • Secondary endpoints were disease-free survival, overall survival, and adverse effects


  • Median follow-up was 45.9 months
  • Specified radiation was delivered to 80% of patients, and specified chemotherapy delivered to 83%
  • Hazard ratio for local or regional recurrence was 0.61 (0.41-0.91 98%CI), favored the combined group
    30% recurred in the RT alone group vs. 19% in the combined chemo/RT group
  • 2 year rate of local control was 72% in the RT alone group vs. 82% in the combined group
  • Disease-free survival hazard ratio was 0.78 (0.61-0.99 95%CI), again favoring the combined group
  • Overall survival was not significantly better in the combined group, with a hazard ratio 0.84 (0.65-1.09, p=0.19)
  • Incidence of acute adverse effects of grade 3 or greater 34% in RT alone group vs. 77% in combined group (p<0.001). Four patients died as a result of the combined treatment. The incidence of severe late effects did not differ.
  • Patterns of failure
    Local/regional recurrence as 1 st site of failure 29% in the RT alone group vs. 16% in the combined group (P=0.002)
    Distant metastases as 1 st site of failure 23% in the RT alone group vs. 20% in the combined group (p=0.46)


The authors present compelling data for the use of combined radiation and a cisplatin-based chemotherapy for post-operative findings for high risk disease. The patients in the combined therapy group had significantly lower local/regional failure and an improved disease-free survival. Unfortunately the overall survival was not improved in the combined therapy group, in contrast to the EORTC study also in this issue of the NEJM. There are several possible explanations for this. First, this study allowed inclusion of patients older than 70 and with a lower performance status. While these characteristics were equally distributed across the groups, the older patients may have done worse with combined therapy. Next, when compared to the EORTC trial, this study included more hypopharynx tumors, which historically have had a worse prognosis than other sites. Third, the high risk features of the studies differed, in that there were more patients with equal to/greater than two positive lymph nodes. Also, both studies failed to demonstrate an improvement in the distant metastatic rate with the addition of this chemotherapy regimen. Overall this study provides support for the use of combined chemotherapy and radiation to improve the local/regional control rate after surgery, for high risk disease. The improvement must be weighed against an increased incidence of severe side effects, so patients should be selected very carefully. The distant metastatic rate remains unchanged, thus in future studies the chemotherapy regimen should be modified in terms of dose, timing or type of drug.


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