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Most patients who stayed on a new regimen of cetuximab, standard chemotherapy, and radiation for advanced squamous cell carcinoma of the head and neck responded in an Eastern Cooperative Oncology Group study.
The phase II trial (ECOG E2303) has not yet yielded a report on its primary end point of 1-year event-free survival. About two-thirds of patients had a complete pathologic response at the primary site with induction therapy alone. The proportion rose to 98% after chemoradiotherapy.
"These results suggest a substantial biologic tumor effect by the combining of C225 [cetuximab (Erbitux)] with chemotherapy and chemoradiation," said lead investigator, Dr. Harold J. Wanebo.
The trial enrolled 74 patients with potentially operable stage III/IV squamous cell cancer of the head and neck. Patients with cancer of the nasopharynx, nodal metastases, and multisite invasion were excluded. Most participants were white (91%), and most were men (78%) with a history of smoking. The most common tumor site was the tonsils (33%), followed by the oropharynx (15%), the tongue (14%), the larynx (10%), the hypopharynx (4.6%), and the pyriform sinus (4.2%).
Dr. Wanebo of Landmark Medical Center in Woonsocket, R.I., presented data on 66 patients, who began induction therapy with 400 mg/m² of cetuximab over 2 hours the first week followed by weekly intravenous cetuximab doses of 250 mg/m² for the next 5 weeks. They also received weekly paclitaxel (90 mg/m²) and carboplatin (AUC=2) for 6 weeks.
At the end of induction therapy, clinical responders underwent a restaging biopsy of the primary site. If the biopsy was negative, they received 3 more weeks of chemotherapy and radiation for a total of 68-72 Gy of radiation.
Patients with positive restaging biopsies or not responsive to induction therapy resumed treatment with weekly cetuximab (250 mg/m² over 1 hour), paclitaxel (30 mg/m² over 1 hour) and carboplatin (AUC=1 over 15 minutes) for 5 weeks plus 50 Gy of radiation therapy in 25 fractions over 5 weeks.
After 14 weeks, another primary site biopsy was done. If it was positive, the patient had salvage surgery. Patients who had a negative biopsy at 14 weeks also were scheduled to receive 3 more weeks of chemotherapy and radiation for a total of 68-72 Gy of radiation.
Patients still in the study received maintenance therapy with cetuximab (250 mg/m²) weekly for 6 months.
Dr. Wanebo reported 40 patients were clinical responders and had a primary site repeat biopsy at week 8. Of these, 25 (63%) had no residual tumor. Some patients dropped out of the trial at this point, but 56 went on to chemoradiation. One of 31 patients with a restaging biopsy at week 14 had a positive biopsy. Overall, 55 of 56 patients had a negative biopsy during the study.
Adverse events forced 7 patients out of the trial. One patient died on study, and three progressed. Fourteen withdrew or ended treatment for other reasons. Only 23 patients completed 6 months of maintenance therapy.
Despite the strong pathologic responses, discussant Dr. Merrill S. Kies of the M.D. Anderson Cancer Center in Houston urged caution in interpreting the results. "We only have evidence that approximately 44% of patients completed the treatment sequence," he said, adding, "We can't really make any assessment of whether this treatment is something we should move to." n
Wanebo H.J. et al. Phase II evaluation of cetuximab (C225) combined with induction paclitaxel and carboplatin followed by C225, paclitaxel, carboplatin, and radiation for stage III/IV operable squamous cancer of the head and neck (ECOG, E2303). Abstract 6015.
Commentary |
This is a very interesting trial of an extremely aggressive sequential treatment plan using a triple-drug induction regimen of weekly chemotherapy followed by a three-drug chemoradiotherapy approach in operable cancer. The acute and long-term toxicity of this approach has not been fully addressed and may impact survival. More than one-third of patients withdrew, suggesting the regimen is acutely toxic and may need to be reconfigured for best results. One also has to question the utility of a highly aggressive approach in resectable tumors, when this might be more appropriate for patients with unresectable disease who lack a salvage therapy. Since no other induction regimens combine chemotherapy with cetuximab in a less toxic manner, the approach by Wanebo et al and ECOG may fall by the wayside in favor of user-friendly and potentially less damaging treatments. That being said, the overall negative biopsy results (55 of 56 patients) and short-term data suggest efficacy. We need to know how many patients will develop distant metastases and the long-term toxicities and ultimate survival rate. Until we see the full data, I would be hard pressed to recommend this therapy for my patients at this time. — Marshall R. Posner, M.D.
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