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An experimental strategy alternating radiotherapy and chemotherapy as a means of larynx preservation in advanced head and neck cancer failed to show a benefit over a more conventional induction approach in a phase III trial conducted by the European Organisation for Research and Treatment of Cancer's Head and Neck Group and Radiotherapy Group.
"Despite a 6.7% difference in larynx function preservation at 3 years favoring the alternating arm, this did not translate into a significant difference in survival with a functional larynx," said investigator Dr. Jean-Louis Lefebvre.
Dr. Lefebvre of the Centre Oscar Lambret in Lille, France, reported the results of EORTC 24954. At 5 years the difference still was not significant. Likewise, 5-year survival with a functional larynx, progression-free survival, and overall survival in the two arms were similar at a median follow-up of 6.5 years.
This study included 450 previously untreated patients with T2-T4 tumors of the larynx or hypopharynx requiring total laryngectomy. Men comprised about 90% of the population, which had a median age of 55 years.
Investigators randomized 226 patients to an experimental arm of cisplatin 20 mg/m² plus 5-fluorouracil 200 mg/m² on days 1-5, followed by radiation therapy 20 Gy, in alternating cycles; patients received chemotherapy in weeks 1, 4, 7, and 10, alternating with radiation therapy given in intervals lasting 2 weeks. The other 224 patients were randomized to a control arm that included a sequential induction regimen of two cycles of cisplatin 100 mg/m² plus 5-fluorouracil 1000 mg/m² (PF) on days 1-5, followed in patients who responded by two additional cycles of PF, followed by radiation therapy (70 Gy).
Responses were assessed at 6 weeks. Nonresponders in either arm received surgery and postoperative radiation.
Survival with a functional larynx (defined as not requiring laryngectomy, tracheostomy tube, or feeding tube), which was the primary end point, was not significantly different at 3 or 5 years. Also, the rates of local-regional failure were similar between the groups.
Patients in the control group reported slightly more grade 3/4 mucositis (32%) than those in the alternating group (21%), and more functional mucosal reactions (33% vs. 21%), but they received a higher radiation dose (70 Gy vs. 60 Gy total). There were few late effects of radiotherapy, with severe fibrosis/sclerosis limited to 10% with sequential and 7% with alternating treatment.
Discussant Dr. Merrill S. Kies of M.D. Anderson Cancer Center, Houston, said the data don't support a shift to alternating radiotherapy and chemotherapy. However, the investigators combined the data for tumors in the glottis, the superglottis, and the hypopharynx. These tumors can behave differently from each other and a reexamination of the data may shed more light on outcomes.
Lefebvre J. et al. Phase III study on larynx preservation comparing induction chemotherapy and radiotherapy versus alternating chemoradiotherapy in resectable hypopharynx and larynx cancers. EORTC protocol 24954-22950. Abstract LBA6016.
Commentary |
This trial is one of the few randomized phase III comparisons we have of induction chemotherapy and chemoradiotherapy. The cisplatin/5-fluorouracil (PF) regimen given with the radiotherapy was quite robust. The radiation dose in the alternating chemoradiotherapy group was somewhat lower than might be given compared to radiotherapy delivered in a nonalternating manner. It is doubtful that higher doses would have been deliverable, however; hence this is an adequate test of the treatment. The vigorous chemotherapy between radiation weeks produced overall results that were consistent with and better than those seen in similar trials involving the Merlano regimen (N. Engl. J. Med. 1992;327:1115-21) (J. Natl. Cancer Inst. 1996;88:583-9). It is important to recognize the induction chemotherapy was state of the art, but today PF would be replaced by the more effective docetaxel-PF (TPF) regimens reported by Calais et al. last year (Proc. Am. Soc. Clin. Oncol. 2006;24:281s. Abstract 5506). Nonetheless, the equivalence of PF induction and chemoradiotherapy makes this an important study supporting induction and chemoradiotherapy. — Marshall R. Posner, M.D.
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