• 4/1/2005
  • Durham, NC
  • Marshall R. Posner, M.D.
  • The Oncologist, Vol. 10, No. 3, 174-175, March 2005

In May of 2004, two articles appeared in the New England Journal of Medicine, reporting the final results of large Phase III trials comparing adjuvant post-operative chemoradiotherapy to standard post-operative radiotherapy in patients with resected, poor-prognosis Squamous Cell Cancer of the Head and Neck (SCCHN) [1, 2]. The trials were performed by the EORTC and the North American Intergroup; they gave identical chemotherapy, almost identical radiotherapy, treated somewhat different populations, and were started over a decade ago. In this issue of The Oncologist Jacques Bernier and Jay Cooper, the principal investigators of the trials, review the background, the results of the trials, and the evidence supporting a standard role for chemoradiotherapy for the post-operative adjuvant therapy of patients with resected SCCHN [3].

Graph of results available here

Both trials resulted in a substantial and significant increase in local regional control with post-operative adjuvant chemoradiotherapy in poor prognosis patients. There is no question that post-operative chemoradiotherapy with bolus cisplatinum improves local regional control and prevents the devastating consequences of locally or regionally recurrent disease in patients with SCCHN. Both trials and the historical data support the role of platinum based chemoradiotherapy for this purpose [4, 5]. Is this enough? Shouldn’t we expect a survival advantage for therapy? Both trials also demonstrated a substantial short-term increase in survival, although only the European trial proved to have significant and sustained increase in this important result. In absolute terms the gains in survival are small, 13% and 9% for the EORTC and the Intergroup, respectively. In relative terms this represents a 32% and 22% improvement, respectively. The relative changes are considerable for both trials but the bad news is that the 5-year estimated survival was 40% and 53% for the EORTC for radiotherapy and chemoradiotherapy, respectively, and 41% and 50% for the Intergroup. Clearly, these results leave quite a bit of room for improvement as noted by the authors. Where were the failures? Although bolus cisplatinum improved local regional control, there was no impact on the rate of distant metastases. Distant metastases represented greater the 40% of the failures in both studies. In fact, distant metastases have not been effectively treated by chemoradiotherapy in any setting with the exception of larynx preservation [6–8]. How else did patients die, if not from head and neck cancer? The EORTC monitored second primary tumors, but we don’t know the precise details of this group. In addition we don’t hear about long-term toxicity from swallowing and breathing problems associated with surgery and radiation-induced fibrosis and scarring, inanition, aspiration, stroke, and other therapy-associated late- and long-term complications. These are difficult data to acquire.

Finally, do these trials set the standard for post-operative adjuvant therapy in patients with operated head and neck cancer, and if so, who should be treated? I believe the answer to the former is yes. It is an unfortunate fact that many practitioners still do not use post-operative chemoradiotherapy for high-risk patients despite good evidence supporting control of local regional disease. Bolus cisplatinum-based chemoradiotherapy in the post operative setting was relatively well tolerated by many study patients and, in these studies, was associated with a small mortality and modest increase in short-term morbidity. I wonder whether a bolus treatment is better biologically than a weekly therapy, given the lack of impact on distant disease with bolus treatment and the potential for better radiosensitization with weekly therapy. In addition, weekly therapy is easier to adjust based on acute toxicities. These issues are being addressed in current RTOG trials. More important at this time is the latter question: Who should be treated? Aside from the obvious issues of co-morbidities, the primary decision rests on risk factors. The EORTC trial had better long-term survival outcomes then the Intergroup. Was it the inclusion of patients with low volume disease and bad features such as vascular or perineural invasion, or just a problem of population demographics between North America and Europe? I believe the inclusion of patients with low volume disease and bad prognostic features may well have had an important impact. It is unfortunate that in its new adjuvant trials, the RTOG has not adopted the more inclusive European standards.

In conclusion, we are now in an era when patients who have had primary ablative surgical therapy for SCCHN should receive adjuvant chemoradiotherapy as a standard of care when poor prognostic features are present and they can tolerate chemotherapy. Hopefully in the future we can use molecular markers and tumor profiling to more precisely decide who should get treated and with what agent. For the present we must rely on the pathologic features and the clinical condition of our patient to make this decision, but treat we must!

Author’s Affiliation:
Medical Director of the Head and Neck Oncology Program, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

REFERENCES
1. Cooper J, Pajak TF, Forastiere A, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. New England Journal of Medicine 2004;350:1937–1944
2. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. New England Journal of Medicine 2004;350:1945–1952
3. Bernier J, Cooper JS. Chemoradiation after Surgery for High-Risk Head and Neck Cancer Patients: How Strong Is the Evidence? The Oncologist 2005;10:215–224
4. Bachaud J, Cohen-Jonathan E, Alzieu C, et al. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: Final report of a randomized trial. International Journal of Radiation Oncology Biology and Physics 1996;36:999–1004
5. Laramore G, Scott C, Al-Sarraf M, et al. Adjuvant chemotherapy for resectable cell carcinomas of the head and neck: Report on intergroup study 0034. International Journal of Radiation Oncology Biology and Physics 1992;23:705–713
6. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced larynx cancer. The New England Journal of Medicine 2003;349:2091–2098
7. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French head and neck oncology and radiotherapy group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. Journal of Clinical Oncology 2004;22:69–76
8. Adelstein D, Li Y, Adams G, et al. An Intergroup Phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. Journal of Clinical Oncology 2003;21:92–98