January 28, 2008 — In the management of patients with head and neck cancer, "it is clear that the optimal approach for larynx preservation has not been identified," say a group of European researchers reporting a trial that compared 2 approaches and found no difference in outcomes.
The group, headed by Jean Lefebvre, MD, from the Centre Oscar Lambret, in Lille, France, compared sequential administration of chemotherapy and radiation with an approach that administered the 2 modalities in alternating cycles. The results, showing very similar outcomes for both approaches, were published online January 27 in the Journal of the National Cancer Institute.
In an accompanying editorial, experts from the United States agree with the group's conclusions that the optimal approach to larynx preservation has yet to be identified. Editorialists Arlene Forastiere, MD, from the Sidney Kimmel Cancer Center at John Hopkins University, in Baltimore, Maryland, and Andy Trotti, MD, from the H. Lee Moffitt Cancer Center at the University of South Florida, in Tampa, call for more studies, and say that "more effective and less toxic approaches are needed."
Success of Larynx Preservation
"Larynx preservation has been one of the most important achievements in head and neck oncology" over the past 2 decades, the researchers write. Before then, patients would undergo surgery, usually total laryngectomy, followed by radiation. But in the 1980s, several first-generation trials showed that chemotherapy with radiation — at the time considered to be an experimental approach — produced similar outcomes but preserved the larynx in 40% to 60% of patients.
Consequently, concurrent chemotherapy with radiation became a standard of care for advanced head and neck cancers, the researchers comment. But in an attempt to improve outcomes further, 2 second-generation trials comparing variations on this approach were carried out, and the current paper reports on 1 of these (the European Organization for Research and Treatment of Cancer EORTC 2495 trial).
The EORTC 2495 trial comprised 450 patients and had a median follow-up of 6.5 years. It compared sequential treatment with chemotherapy (up to 4 cycles of cisplatin and 5-fluorouracil) followed by radiotherapy (70 Gy total) with an approach that alternated the 2 modalities, in which each of the 4 cycles of chemotherapy was followed by radiotherapy (20 Gy) during the 2-week interval between cycles.
Dr. Lefebvre and colleagues report that overall survival, progression-free intervals, and larynx preservation were very similar in the 2 treatment groups, as were acute and late toxic effects.
There was no advantage for the regimen of alternating cycles of treatment over the traditional sequential approach, comment the editorialists. They also point out that 4 cycles of chemotherapy are not commonly used in practice because of toxicity, and that 3 cycles are more usual.
The other second-generation trial was conducted in the United States, and has already been published (N Engl J Med 2003;349:2091-2098). The Radiation Therapy Oncology Group 91-11 study was an intergroup trial comparing 3 therapies: induction chemotherapy followed by radiation; concurrent chemotherapy and radiation; and radiotherapy alone. This also showed similar outcomes (overall survival, disease-free survival, and laryngectomy-free interval) in the 3 different treatment groups, say Dr. Lefebvre and colleagues. The concurrent group did show better local control, they add, but it was associated with significantly more severe toxic effects than the other 2 groups.
More Recent Studies
Since those 2 second-generation trials, several more have been reported, note the editorialists. Three published trials (N Engl J Med. 2007;357:1695–1704; N Engl J Med. 2007;357:1705–1715; J Clin Oncol. 2005 23:8636–8645) have now shown that adding a third drug — a taxane — to the regimen of cisplatin plus 5-fluorouracil improves outcomes. Although the results from these 3 trials are not uniform, the editorialists comment that together the results "clearly support use of the 3-drug regimen when induction therapy is indicated," adding that hypopharynx cancer is such an indication.
The editorialists also emphasize the "strong need to standardize end point definitions" in future trials, because the studies conducted to date have differed in their definitions of larynx preservation and other outcomes. Towards this end, they note, the National Cancer Institute Head and Neck Steering Committee has appointed a Working Group on Endpoints, looking at definitions, the use of composite organ-preservation end points, and local–regional progression. This group intends to issue formal recommendations in 2009.
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