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Cetuximab in combination with standard chemotherapy offers a significant survival advantage, compared with standard chemotherapy alone, as a first-line treatment in patients with recurrent or metastatic squamous cell cancer of the head and neck, according to the results of the phase III European-based EXTREME trial.
Median overall survival was 10.1 months in the study's experimental arm versus 7.4 months with standard treatment (P = .036). Survival at 1 year was 39% with cetuximab (Erbitux) vs. 31% with standard therapy, Dr. Jan Baptist Vermorken reported.
"It is a unique observation to see the first systemic treatment in 25 years that shows a survival benefit over platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck," said Dr. Vermorken of the University of Antwerp, in Belgium.
"Head and neck cancer is a very difficult disease to treat," he said. Median survival is only 6 to 7 months for recurrent or metastatic patients receiving standard chemotherapy with carboplatin or cisplatin plus 5-fluorouracil (5-FU). This statistic has not changed much in the past 25 years, he noted.
Most squamous cell head and neck tumors express the epidermal growth factor receptor (EGFR). It is an independent and unfavorable prognostic factor. Cetuximab, an IgG1 monoclonal antibody, targets EGFR.
The EXTREME trial enrolled patients at 80 centers in 17 European countries, randomizing 442 patients with recurrent (54%) or metastatic (46%) squamous cell cancer of the head and neck and no prior chemotherapy in this setting. The primary tumor site was oral cavity/hypopharynx in approximately 35% of the population and other head and neck sites in 65%.
Patients were randomized to six cycles of standard treatment with carboplatin (AUC = 5) or cisplatin 100 mg/m² on day 1 plus 5-FU 1000 mg/m² on days 1-4, or to the same chemotherapy plus cetuximab 400 mg/m² loading dose on day 1 followed by 250 mg/m² weekly. After the end of chemotherapy, patients in the experimental arm could continue cetuximab.
Hematologic and nonhematologic toxicity was similar between the arms. Skin rash and a slight increase in vomiting and diarrhea were the only significant adverse effects attributed to cetuximab. Analysis of progression-free survival has not been completed.
Discussant Dr. Marshall R. Posner of the Dana-Farber Cancer Institute in Boston called the results extremely important, noting, "This is the first demonstration of a survival improvement in the palliative setting ever shown for any treatment in head and neck cancer."
Vermorken J. et al. Cetuximab extends survival of patients with recurrent or metastatic SCCHN when added to first line platinum based therapy - Results of a randomized phase III (Extreme) study. Abstract 6091.
Commentary |
Based on this study, it is reasonable to expect that all patients with head and neck cancer will at some point receive an anti-EGFR agent. Within this class, cetuximab is the most active and well studied. It remains unclear whether patients should receive cetuximab combined with standard cisplatin or carboplatin plus 5-fluorouracil (PF) chemotherapy—or as sequential treatment after PF. The study did not include a crossover protocol in which patients treated with PF got cetuximab upon progression. This trial has implications for curative therapy. The three-drug combination was more effective than the two-drug regimen. This suggests the three-drug combination may be more effective and reasonable in the induction setting. It will also be important to assess toxicity and dose reductions more fully. That being said, this study is the first demonstration of improved survival with combination chemotherapy in recurrent head and neck cancer. It will never be repeated because cetuximab should soon be approved in Europe, at least in the second-line setting for recurrent disease. — Marshall R. Posner, M.D.
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