Patterns of Failure for Resected Advanced Head & Neck Cancer Treated by Concurrent Chemotherapy and Radiation Therapy: An Analysis of RTOG 9501/Intergroup Phase III Trial

Reviewer: Roberto Santiago, MD
Last Modified: October 8, 2002

Presenter: Jay Cooper
Presenter's Affiliation: New York University Medical Center, New York, NY
Type of Session: Plenary


  • The most common failure after grossly or microscopically complete surgical resection and post-operative radiation therapy for advanced cancers of the head and neck is local-regional recurrence.
  • This study evaluates whether patients with completely resected advanced squamous carcinomas of the head and neck treated with adjuvant radiotherapy (RT) would have a local-regional control benefit from the addition of cisplatin (CDDP) chemotherapy.
  • Secondary endpoints addressed by the study include the anatomic pattern of first failure and the time course of local-regional relapse.

Materials and Methods

  • Between 9/95 and 4/00, 459 patients status post resection of squamous carcinomas of the head and neck deemed at high-risk for local-regional recurrence were enrolled in a randomized phase III clinical trial.
  • The following factors were used to define the patients as high risk: 2 or more involved lymph nodes, extra-capsular disease and/or microscopically involved mucosal margins of resection.
  • Forty three patients were ineligible.
  • Primary tumor sites included the oral cavity, oropharynx, larynx, and hypopharynx.
  • Eligible patients had KPS of at least 60.
  • Following gross total resection, 231 patients were randomly assigned to RT alone (60-66 Gy /30-33 fractions/ 6-6.6 weeks) and 228 patients were randomly assigned to identical RT plus CDDP (100 mg/m2 i.v. on days 1, 22 & 43).
  • The patients were stratified according to age (<70 vs >70) and the features mentioned above associated to high risk for local-regional recurrence.


  • Approximately 94% of patients in each arm were less than 70 years old.
  • Most had KPS between 80 and 90.
  • Oropharynx was the most common primary site.
  • Most patients had T4N2 tumors.
  • Central review confirmed good compliance with the protocol.
  • The mean RT dose was in excess of 60 Gy and 61% completed 3 cycles of chemotherapy.
  • With a median follow-up of 37 months, the 2-year L-R control rate is 71% for those assigned to RT and 76% for the RT plus CDDP group (p=0.16). The risk of local-regional recurrence began to favor combined therapy only after six months of follow-up had passed. No local-regional recurrences were observed after 36 months of follow-up.
  • Local-regional recurrence as the first site of treatment failure decreased from 25% in the group receiving RT only to 17% in the group receiving concurrent therapy (p=0.041, crude incidence).
  • Distant metastasis as the first site of failure occurred in 22% and 15% respectively (p=0.076, crude incidence).
  • Ninety-six patients were alive at 3 years. Neither the 2-year actuarial disease-free nor overall survival was significantly improved by the chemotherapy.
  • The chemotherapy arm experienced significantly more severe toxicity at any time of follow up that the RT alone arm.
  • Death from the index cancer was significantly reduced by the addition of chemotherapy when compared to adjuvant RT alone (76% vs. 62%, p<0.05). However, none of the patients treated by RT experienced protocol-related fatal toxicity, whereas 4% of the patients treated with concurrent chemoradiotherapy did.

Author's Conclusions

  • The concurrent addition of single agent cisplatin chemotherapy to post-operative radiation therapy (without any subsequent adjuvant chemotherapy) did not significantly reduce the overall incidence of local-regional recurrences.
  • It did reduce local-regional recurrences as the first evidence of treatment failure as well as distant recurrences.
  • The experimental arm was associated with more severe toxicity as well as treatment related mortality.
  • Unfortunately, neither the actuarial disease-free survival nor the overall survival was significantly improved by the chemotherapy.
  • The findings also suggest that three-year follow-up may be adequate to assess the ultimate rate of local-regional recurrence when concurrent chemotherapy and radiation therapy are used post-operatively.

Clinical/Scientific Implications

  • The poor outcome in this patient population and the contrast between the results of this negative trial and the results of a recent EORTC trial evaluating a similar therapeutic approach fuel the interest in adding chemotherapy to adjuvant radiotherapy.
  • Differences between the two trials that could have influenced the diverging results included: 1. more positive margins of resection in the EORTC trial 2. less oropharyngeal cancers in the EORTC trial 3. Longer time required to deliver the radiotherapy in the EORTC trial
  • Among the questions that remain unanswered are:
  • Is the benefit seen in the EORTC trial just the result of a compensation for poor surgery?
  • Is the RTOG study at a disadvantage because of higher proportion of relatively better prognosis patients (more oropharyngeal cancers)?
  • Was the adjuvant RT alone arm in the RTOG trial better that expected? If so, was it because RT was delivered over a shorter time?
  • Only 61% completed chemotherapy as planned in the RTOG trial. Also, there was a marked increase in severe toxicity and treatment related deaths in the chemotherapy arm of the RTOG trial. Is there a safer way to integrate these? modalities in the adjuvant setting?
  • At this time, the addition of chemotherapy to radiation therapy should still only be done as part of a clinical trial in the post-operative setting. The toxicity of this combined approach is significant while the results do not appear to be improved in patients treated in this trial.

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