Concurrent Chemoradiotherapy in the Management of Squamous Cell Cancer of the Oropharynx: Current Standards and Future Directions

Abstract

The use of radiotherapy and concurrent chemotherapy has been explored in the management of squamous cell head and neck cancer for more than 3 decades. Even the earliest phase II and phase III studies, which used conventional radiotherapy and single-agent chemotherapy with drugs such as fluorouracil, bleomycin, and cisplatin, suggested a survival benefit from this approach. Validation of concurrent chemoradiotherapy as a community standard occurred in 1996, with the initial report from INT 0099, a randomized trial comparing radiotherapy alone with concurrent radiation and single-agent cisplatin, followed by adjuvant fluorouracil and cisplatin in patients with advanced nasopharyngeal cancer (1). This study, subsequently published in 1998, demonstrated a highly significant progression-free and overall survival advantage for patients treated with the combinedmodality regimen, and this regimen was rapidly accepted as a standard of care for advanced nasopharyngeal cancer. Also in 1998 came a report from a large meta-analysis of updated, individual data assessing the role of chemotherapy in squamous cell head and neck cancer (2). Patients from randomized trials conducted between 1965 and 1993 were included. This analysis, subsequently published in 2000, reviewed results from 63 separate trials involving 10,741 patients, comparing locoregional treatment with or without chemotherapy. Although no overall survival benefit was seen for treatment schedules using either induction or adjuvant chemotherapy,ahighlysignificantsurvivalbenefitwasidentified for concomitant chemotherapy and radiation. A hazard ratio of 0.81 (95% Confidence Interval (CI), 0.76‐0.88) with a p value of <0.0001 and an 8% 5-year survival benefit was observed, even from these older studies. Although oropharynx cancer often predominated in these clinical trials, they were, in general, not site specific. Nonetheless, this meta-analysis further justified the use of concurrent chemoradiotherapy as a standard nonoperative treatment for this disease. Results from a North American Intergroup trial of chemoradiotherapy in patients with unresectable head-and-neck tumors were first presented in 2000 and were published in 2003 (3). This study compared radiotherapy alone with radiotherapy and single-agent cisplatin and a third arm using a split course of radiotherapy and concurrent combination fluorouracil and cisplatin. As seen in nasopharynx cancer, the concurrent chemoradiotherapy arm using single-agent cisplatin proved superior to radiotherapy alone, with a projected 3-year survival improvement from 23% to 37% and a median survival improvement from 12.6 to 19.1 months (p = 0.014). The third treatment arm, which used a split course of radiotherapy, did not prove to be statistically different from the other two arms, an observation attributed to the scheduled break in radiotherapy delivery on this arm of the trial. This Intergroup study firmly established concurrent chemoradiotherapy with single-agent cisplatin as a treatment standard for unresectable head and neck cancer. Although it was not a site-specific study, primary tumors in the oropharynx predominated in the study population. During this same period, several other smaller single- and multi-institution trials were also published, comparing various combinations of concurrent chemotherapy and radiotherapy with radiotherapy alone as definitive treatment for this disease. In general, they were also not site-specific studies. The results, however, were very consistent. The addition of concurrent chemotherapy to radiotherapy reproducibly improved both survival and locoregional control.