November 16, 2009 — Cetuximab (Erbitux) plus radiotherapy should be considered a standard option in the treatment of locoregionally advanced squamous cell carcinoma of the head and neck, say researchers reporting long-term benefits from this combination.
The latest results, published online November 6 in the Lancet Oncology, show that the statistically significant improvement in overall survival for this combination is maintained after 5 years of follow-up.
The 5-year overall survival was 45.5% in patients who received the combination, compared with 36.4% in patients treated with radiotherapy alone, the researchers report. The updated median overall survival was 49 months for the combination and 29.3 months for radiotherapy alone (P = .018).
"The absolute benefit was 9% at 5 years, which is a pretty substantial finding," lead researcher James Bonner, MD, from the University of Alabama at Birmingham, said in an interview with Medscape Oncology.
Cetuximab plus radiation offers "an important treatment option for this group of patients," the authors conclude.
This view is in keeping with the guidelines issued by the National Comprehensive Cancer Network (NCCN) in 2007, which incorporated the option of cetuximab plus radiation after the 3-year significant survival advantage from this trial was reported (N Engl J Med. 2006:354;567-578).
Other options for such patients include the use of radiotherapy alone and the use of cytotoxic chemotherapy with radiation (chemoradiation), which often involves cisplatin. Compared with chemotherapy, the adverse effects with cetuximab are "much less," Dr. Bonner reported, but he emphasized that each patient should be evaluated individually for toxicity tolerance.
Another notable finding from this trial is the significantly better response to cetuximab in patients who developed a skin rash while taking the drug than in those who did not. This correlation between good response and skin rash with cetuximab has been reported previously (in patients with colon cancer), but this is the first time it has been seen in patients also undergoing radiotherapy, Dr. Bonner noted.
Chemoradiation a Popular Treatment Option
Chemoradiation has become a popular treatment option for locoregionally advanced head and neck cancer in recent years, the authors note; a large meta-analysis has shown a significant advantage over radiotherapy alone.
The meta-analysis was first published in 2000 with 63 trials, but was updated to include more recent trials; the update with 87 trials was published this year (Radiother Oncol. 2009:92:4-14). Both showed a statistically significant improvement in survival after chemoradiation, compared with radiotherapy alone, Dr. Bonner said, with a 5-year survival advantage of 4.5%.
The 9% benefit at 5 years that has been reported for cetuximab and radiation looks better, Dr. Bonner conceded, but he said the 2 results cannot be compared directly. This result for cetuximab and radiation comes from just 1 trial, whereas the benefit reported in the meta-analysis came from many different trials, some of which individually reported a greater benefit (e.g., 11%) and others of which showed no significant improvement. In addition, the cetuximab trial generally used radiotherapy delivered twice daily, which has been shown to produce better results than delivery once daily; once-daily delivery of radiation was used in many of the older trials in the meta-analysis. "That's another caveat to the whole field," he said.
Dr. Bonner also noted that at the time that this trial was being designed, in 1998, radiotherapy alone was the standard of care for these patients; the addition of cetuximab was the experimental group.
The trial was conducted in 424 patients with locoregionally advanced squamous cell carcinoma of the head and neck who were randomized to receive radiotherapy with or without cetuximab.
The overall survival benefit for the combination seen at 5 years (45.5% vs 36.6%) is "remarkably similar" to that seen in the 3-year analysis (55% vs 45%), the authors explain. This supports the validity of 3-year overall survival as a surrogate for long-term overall survival, they add.
These updated 5-year survival results provide further support for the combination of cetuximab plus radiotherapy as a standard treatment option, they conclude.
Further Trials Underway
Currently, the NCCN guidelines suggest that the intensity of treatment should be dictated by the severity of the disease or tumor burden. They describe the 3 cornerstones of treatment as radiotherapy alone, radiotherapy plus systemic therapy (such as cetuximab or cytotoxic chemotherapy), and sequential treatment of induction chemotherapy followed by concomitant chemoradiotherapy.
However, the authors note that more study is needed to determine if these severity-based recommendations are appropriate. An ongoing phase 3 trial is exploring the use of cetuximab with cisplatin chemoradiation and will "provide the rationale for further exploration in earlier stages of disease," they say.
Quite separately, cetuximab has shown good results in patients with advanced head and neck cancer when it was added to chemotherapy in the EXTREME trial, as previously reported by Medscape Oncology. These patients have metastatic disease that is considered incurable, and they are not treated with radiotherapy, Dr. Bonner explained. In contrast, the patients in the trial conducted by his team had locoregional disease that had not spread beyond the clavicles; these patients are considered curable, he added.
The study was funded by ImClone Systems, Bristol-Myers Squibb, and Merck KgaA, which manufacture and market cetuximab. Dr. Bonner reports serving as an occasional consultant, with honoraria for presentations, for Bristol-Myers Squibb, ImClone Systems, Merck KgaA, Oncolytics, and Sanofi Aventis. Several of his coauthors have disclosed relevant financial relationship; full details can be found in the paper.
Lancet Oncol. Published online November 6, 2009. Abstract
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