EDITORIALS

Radiotherapy and Concurrent Chemotherapy: a Strategy That Improves Locoregional Control and Survival in Oropharyngeal Cancer

Arlene A. Forastiere, Andy Trotti

Affiliations of authors: A. A. Forastiere, Department of Oncology, The Johns Hopkins Oncology Center, Baltimore, MD; A. Trotti, Department of Radiation Oncology, H. Lee Moffitt Cancer Center at the University of South Florida, Tampa, FL.

Correspondence to: Arlene A. Forastiere, M.D., Department of Oncology, The Johns Hopkins Oncology Center, 600 N. Wolfe St., Rm. 128, Baltimore, MD 21287-8936.

In this issue of the Journal, Calais et al. (1), representing the French Groupe d'Oncologie Radiotherapie Tete et Cou (GORTEC), report a multicenter randomized comparison of radiotherapy and concurrent chemotherapy versus radiotherapy alone in patients with oropharyngeal cancer. Their results add to a growing list of trials that demonstrate superior survival and locoregional control with this combined-modality approach. A group of 222 eligible patients with stage III or IV locally advanced squamous cell carcinoma of the oropharynx were randomly assigned to receive standard daily fraction radiotherapy (2 Gy/day; total dose, 70 Gy), administered alone or with a 4-day regimen of carboplatin and 5-fluorouracil (5-FU), starting on days 1, 22, and 43. After a median follow-up of 35 months, 3-year overall survival (51% versus 31%; P = .02), 3-year disease-free survival (42% versus 20%; P = .04), and locoregional control (66% versus 42%; P = .03) exhibited a statistically significant improvement for combined treatment compared with radiotherapy alone. As observed in other comparative trials, the addition of platinum and 5-FU chemotherapy substantially increased mucocutaneous toxicity, consequent weight loss, and the requirement for feeding tubes. Treatment interruptions were longer for patients in the combined-modality group, but there was no difference in the overall treatment time or the frequency of treatment interruptions. Chemotherapy was discontinued after radiotherapy was completed, and thus 35% of the patients with delays in chemotherapy did not receive cycle three. Radiotherapy compliance was excellent, with 95% of the patients in both groups completing treatment.

This trial was limited to a specific anatomic site, with 74% of the patients having base of tongue or tonsillar cancer. The two treatment arms were well balanced for site, stage, and TN (tumor-node) status. The radiotherapy was standard and the mean total delivered dose was 69.2 Gy in one arm and 69.6 Gy in the other. The chemotherapy regimen was one used by other researchers, with carboplatin substituted for cisplatin. The study was adequately powered, and the data analysis was based on intention to treat.

Looking broadly at the published literature of radiotherapy versus radiotherapy and concurrent chemotherapy (termed radiochemotherapy), there are now multiple positive randomized trials, positive meta-analyses, trials containing both "resectable" and "unresectable" disease, and trials that tested standard-fractionation and altered-fractionation radiotherapy (2-6). Although some trials contained nonoropharyngeal sites, most contained cancers of the oropharynx predominately. The evidence is now clear: Radiochemotherapy provides a substantial and statistically significant improvement in survival and locoregional control compared with radiotherapy alone. Radiochemotherapy should be considered an accepted standard of care in cancers of the oropharynx, and the study by Calais et al. (1) adds further support to this conclusion. Cancers of the oral cavity continue to be managed primarily by a surgical approach at many institutions because resection produces less relative organ dysfunction, and anecdotal experience suggests that oral cavity cancer is somewhat less responsive to cytotoxic therapy.

That said, this article raises a number of important questions. When should radiochemotherapy be the treatment of choice? Certainly, it is indicated for patients with locally advanced, unresectable disease who have good performance status. Resectability status was not a defined eligibility criterion for patients enrolled in the GORTEC study. A universally accepted definition of an "unresectable" tumor has eluded the surgical community for decades. The experience of the surgeon, the available expertise in reconstruction techniques, and the expected rates of cure and morbidity more often influence treatment decisions than does the ability to remove all gross tumor (7). Calais et al. are not alone in performing a trial that does not specify resectability. For example, the last two nonsurgical Radiation Therapy Oncology Group (RTOG) trials enrolled any patient with stage III or IV (without metastases) cancer from multiple sites: R90-03 compared four radiation fractionation schedules (8), and R97-03 evaluated three variations of radiochemotherapy.

Given the current lack of a clear definition, attempts to define patient eligibility based on resectability are artificial and unlikely to yield a uniform population. Moreover, for cancers of the oropharynx in particular, there are two common but divergent approaches. Some treatment centers advocate a nonsurgical approach (e.g., primary radiotherapy) as definitive treatment for all stages of disease and limit the role of surgery to salvage therapy or to managing regional lymph node metastases. In contrast, other clinicians advocate immediate resection and postoperative radiotherapy as the "gold standard" (9). While this issue would be best addressed by a randomized trial, such a rigorous comparison is not likely to be feasible in the near future. In the absence of such data, when a nonsurgical approach is preferred in resectable disease, as a matter of local policy or desire for organ preservation, radiochemotherapy should be the treatment of choice—that is, provided the patient has sufficient performance status and psychosocial resources to weather the complexity and additional toxicity.

The natural history of head and neck cancer is one of locoregional disease progression, which still accounts for the majority of disease-related mortality. Surgery has evolved as the standard of care largely as a result of the antecedent availability of the specialty. Radiotherapy was added postsurgically without the benefit of comparative trials to document its relative impact or merit as a single modality. Altered fractionation regimens (hyperfractionation and accelerated fractionation) were developed to deliver a higher biologically effective dose to the tumor. Ten randomized trials comparing altered fractionation schedules with standard fractionation, recently reviewed by Ang (10), showed up to a 15% improvement in locoregional control, primarily in patients with intermediate-stage disease (tumor-node-metastasis [TNM] classification T2-3 N0-1). This translated into a statistically significant survival advantage in only one trial (11), and those results were criticized for poor outcomes in both study arms. Most recently, the RTOG reported better 2-year locoregional control by use of accelerated fractionation with concomitant boost or hyperfractionation compared with standard-fractionation radiotherapy, but a modest increase in locoregional control—from 45% to 54%—was not sufficient to improve overall survival (8).

In contrast, recent trials (1,3,4) comparing radiochemotherapy with radiotherapy alone, whether using standard or altered fractionation, report large differences in locoregional control and overall survival benefit (Table 1)Go. In a trial enrolling 298 unresectable patients, Wendt et al. (3) observed statistically significantly improved 3-year local control (17% versus 36%; P<.004) and overall survival (24% versus 48%; P<.0003) in those treated with cisplatin + 5-FU + leucovorin and twice daily radiotherapy. In a smaller study enrolling 116 patients with locally advanced disease, Brizel et al. (4) demonstrated statistically significant improvement in 3-year locoregional control (44% versus 70%; P = .01) and a trend that approached statistical significance for improved 3-year overall survival (37% versus 55%; P = .07) by use of split-course hyperfractionated radiotherapy and cisplatin + 5-FU. Thus, it appears that the gains in locoregional control achievable with radiochemotherapy are large enough to impact on survival, exceeding those achieved thus far by intensifying radiotherapy alone through variation in fractionation schemes. What has not been adequately addressed in these trials, however, is the prospective evaluation of late toxic effects and assessment of function.


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Table 1. Trials of radiotherapy versus radiochemotherapy

 
There is a natural propensity to intensify each modality to achieve better local control, survival, and preservation of the organ. However, preservation of the organ does not equate to preservation of function. Severe and chronic mucosal injury and tissue fibrosis as a late toxic effect of intensive radiochemotherapy regimens may leave patients with poor swallowing function and thus be dependent on a gastrostomy tube. In addition, intensive supportive care is required for successful completion of radiochemotherapy. Nonsurgical and surgical approaches to organ-function conservation need to be evaluated, with attention to objective assessments of speech and swallowing function in addition to local control and survival outcomes.

After more than 2 decades of combined-modality trials, we can now recommend radiochemotherapy as a standard of care for locally advanced oropharyngeal cancer. In recent years, we have witnessed the successful completion of numerous clinical trials that provide clinicians with evidence-based approaches in the management of head and neck cancer. It is our task to judiciously apply this knowledge to our patients on the basis of considerations of performance status, stage of disease, relative toxicity, available supportive care, and psychosocial resources.

REFERENCES

1 Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, et al. Randomized trial of radiation therapy versus concomitant chemoradiotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999;91:2081-6.[Abstract/Free Full Text]

2 Bourhis J, Pignon JP. Meta-analyses in head and neck squamous cell carcinoma. What is the role of chemotherapy? Hematol Oncol Clin North Am 1999;13:769-75.[Medline]

3 Wendt TG, Grabenbauer GG, Rodel CM, Thiel HJ, Aydin H, Rohloff R, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998;16:1318-24.[Abstract]

4 Brizel DM, Albers ME, Fisher SR, Scher RL, Richtsmeier WJ, Hars V, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998;338:1798-804.[Abstract/Free Full Text]

5 Merlano M, Vitale V, Rosso R, Benasso M, Corvo R, Cavallari M, et al. Treatment of advanced squamous cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med 1992;327:1115-21.[Abstract]

6 Adelstein DJ, Lavertu P, Saxton JP, Secic M, Wood BG, Wanamaker JR, et al. Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy (RT) alone in resectable stage III and IV squamous cell head and neck cancer (SCHNC) [abstract]. Head Neck 1998;20:444.

7 Forastiere A, Goepfert H, Goffinet D, Hong KW, Laramore G, Mittal B, et al. NCCN practice guidelines for head and neck cancer. National Comprehensive Cancer Network. Oncology 1998;12:39-147.

8 Fu KK, Pajak TF, Trotti A, Spencer SA, Jones CU, Phillips TL, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: preliminary results of RTOG 9003 [abstract]. Int J Radiat Oncol Biol Phys 1999;45(Suppl):145.[Medline]

9 Goepfert H, Ang K, Khuri F. Organ/function preservation treatment in cancer of the oropharynx. In: Perry MC, editor. American Society of Clinical Oncology Education Book. Alexandria (VA): American Society of Clinical Oncology; 1999. p. 551-6.

10 Ang KK. Altered fractionation trials in head and neck cancer. Semin Rad Oncol 1998;8:230-6.[Medline]

11 Pinto LH, Canary PC, Araujo CM, Bacelar SC, Souhami L. Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages III and IV oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1991;21:557-62.[Medline]


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