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Is concurrent chemotherapy/IMRT too toxic and dangerous for use in H&N cancer?

Is concurrent chemotherapy/IMRT too toxic and dangerous for use in H&N cancer?

ABSTRACT: Some state that concurrent chemotherapy/IMRT is not beneficial due to high toxicity, but others maintain that toxicity can be controlled when delivered by experts with use of prophylactic measures.

SAN FRANCISCO—In a recent debate, both speakers agreed that IMRT with concurrent chemotherapy is toxic in patients with head and neck cancer, but disagreed on whether the risk/benefit ratio justifies its use. The event was held at the 2008 International Conference on Head and Neck Cancer, sponsored by the American Head & Neck Society.

Asked to argue the pro side—that IMRT [intensity-modulated radiation therapy] plus concurrent chemotherapy is too toxic and dangerous—Avraham Eisbruch, MD, professor of radiation oncology, University of Michigan, focused on the hazards of IMRT, compared with conventional radiation therapy, and concluded that IMRT is too toxic to combine with chemotherapy and has not been proved to be more effective than conventional RT.

Taking the con side, Vincent Gregoire, MD, PhD, professor of radiation oncology, Universite Catholique de Louvain, Brussels, Belgium, argued that the toxicity of concurrent chemotherapy/IMRT is manageable and such therapy offers patients the best outcome when performed by experienced physicians at high-volume centers. He expects further improvements in technology to lower the risks of toxicity.

ProSelection bias

Dr. Eisbruch acknowledged that IMRT is effective in controlling oropharyngeal cancer. “All series have very good numbers [90% to 98% 2-year locoregional control], better than standard radiation,” he said. “However, there is obviously a selection bias in these IMRT series.”

He said that the studies offered no details on how many patients were treated at the same time period with conventional RT, and that patients with poor performance status, advanced tumors, and difficulties with prolonged treatment times were most likely excluded. “When IMRT is compared to conventional RT from the same era, there is no difference in outcome,” he said, citing Hodge et al (IJROBP 69:1032-1041, 2007).

Furthermore, Dr. Eisbruch said, the recent improvement in outcomes for oropharyngeal cancer may be due to a change in the disease rather than improved treatments. An increase in HPV (human papillomavirus)-related cases has driven a worldwide increase in the disease, but disease-specific survival is significantly better in HPV-positive than in HPV-negative patients.

In-field recurrences

Although IMRT clearly has a dosimetric advantage, Dr. Eisbruch suggested that this is “irrelevant,” since in IMRT-treated patients, the disease recurs more often at the center of the target rather than the periphery. The solution to this problem of in-field recurrences, he said, has been to escalate the dose per fraction and the total biologically effective dose to the gross target volume (GTV).

He cited two studies that used this approach—the SMART trial from Baylor College of Medicine (Butler et al: IJROBP 45:21-32, 1999) and the Medical College of Virginia dose-escalation study (Lauve et al: IJROBP 60:374-387, 2004). But in both of these studies, he pointed out, the combination of large fraction doses and high normalized total dose led to “hot spots” that, depending on their location, increased the risk of late complications.

In patients with advanced disease who require concurrent chemotherapy, such high-dose IMRT regimens may not be feasible, Dr. Eisbruch said. For example, the SMART regimen (60 Gy at 2.5 Gy/fraction) given with chemotherapy was not tolerable due to excessive mucositis. So, he said, “we need to choose between high fraction doses to the GTV or lower dose fractions with concurrent chemotherapy. We can’t do both.”

Given that concurrent chemotherapy has an established benefit in these patients, while the benefit/risk ratio for high-dose IMRT is unknown, Dr. Eisbruch said he would choose concurrent chemotherapy with conventional RT over high-dose IMRT alone.

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