Journal of the National Cancer Institute Advance Access published online on January 27, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn460
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© The Author 2009. Published by Oxford University Press.
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Phase 3 Randomized Trial on Larynx Preservation Comparing Sequential vs Alternating Chemotherapy and Radiotherapy
Affiliations of authors: Department of Head and Neck Cancer, Centre Oscar Lambret, Lille, France (JLL); Department of Oncology (FR) and Department of Radiotherapy (EB), Centre Rene Gauducheau, Nantes, France; Department of Radiotherapy, University Hospital, Leiden, the Netherlands (MT); Department of Head and Neck Surgery, VU University Hospital, Amsterdam, the Netherlands (CRL); Department of Radiotherapy, Centre Alexis Vautrin, Nancy, France (LG); Department of Radiotherapy, University Hospital, Maastricht, the Netherlands (PH); Department of Head and Neck Surgery, Azienda Ospedaliera Santa Maria Degli Angeli, Pordenone, Italy (LB); Department of Head and Neck Surgery, Centre François Baclesse, Caen, France (DdR); Department of Head and Neck Surgery, University Hospital, Lille, France (DC); Department of Oncology, Istituto dei Tumori, Milan, Italy (LL); Department of Head and Neck Surgery, Ospedale Civile, Monselice, Italy (FL); Department of Oncology, University Hospital, Lausanne, Switzerland (RS); EORTC Headquarters, Brussels, Belgium (DL, JBo); Department of Radiotherapy, Centre Georges Francois Leclerc, Dijon, France (JCH); Department of Radiotherapy, Clinique de Genolier, Genolier, Switzerland (JBe); Department of Oncology, Antwerp University Hospital, Edegem, Belgium (JBV)
Correspondence to: Jean L. Lefebvre, MD, Professor, Department of Head and Neck Cancer, Centre Oscar Lambret, 3 rue Frederic Combemale—BP 307, FR 59020 Lille Cedex, France (e-mail: jl-lefebvre{at}o-lambret.fr).
Background: Both induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy have been reported as valuable alternatives to total laryngectomy in patients with advanced larynx or hypopharynx cancer. We report results of the randomized phase 3 trial 24954 from the European Organization for Research and Treatment of Cancer.
Methods: Patients with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3–T4) or hypopharynx (T2–T4), with regional lymph nodes in the neck staged as N0–N2 and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arm. In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three 2-week intervals between chemotherapy cycles (60 Gy total). All nonresponders underwent salvage surgery and postoperative radiotherapy. The Kaplan–Meier method was used to obtain time-to-event data.
Results: The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68 to 1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm.
Conclusions: Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects.
| Context and Caveats Prior knowledge For patients with advanced larynx or hypopharynx cancer, induction chemotherapy followed by irradiation and concurrent chemotherapy and radiotherapy appear to be clinically valuable alternatives to total laryngectomy, so that the larynx can be retained. Study design Phase 3 randomized trial of patients with resectable advanced larynx or hypopharynx cancer. Patients (n = 450) who responded to two cycles of cisplatin and 5-fluorouracil were randomly assigned to another two cycles, followed by radiotherapy (the sequential arm, n = 224), or to a total of four cycles of cisplatin and 5-fluorouracil with radiotherapy being given between cycles of chemotherapy (the alternating arm, n = 226). Contribution Larynx preservation, progression-free interval, and overall survival were similar in both arms, as were acute and late toxic effects. Implications The optimal approach for larynx preservation has not been identified, and so additional research is warranted. Limitations A restrictive definition for larynx preservation was used (ie, a larynx without tumor, tracheotomy, or use of a feeding tube). Data on smoking habits were not collected. From the Editors
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Manuscript received April 1, 2008; revised November 3, 2008; accepted November 14, 2008.
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J Natl Cancer Inst 2009 101: 127.
J Natl Cancer Inst 2009 101: 127.
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  R. I. Haddad Re: Randomized Trial of Induction Chemotherapy With Cisplatin and 5-Fluorouracil With or Without Docetaxel for Larynx Preservation J Natl Cancer Inst, August 19, 2009; 101(16): 1157 - 1158. [Full Text] [PDF]
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