Phase 3 Randomized Trial on Larynx Preservation Comparing Sequential vs Alternating Chemotherapy and Radiotherapy

Authors

Lefebvre JL

Rolland F

Tesselaar M

Bardet E

Leemans CR

Geoffrois L

Hupperets P

Barzan L

de Raucourt D

Chevalier D

Licitra L

Lunghi F

Stupp R

Lacombe D

Bogaerts J

Horiot JC

Bernier J

Vermorken JB

Doi

10.1093/jnci/djn460

PMID: 19176454 · DOI: 10.1093/jnci/djn460 · Journal: Journal of the National Cancer Institute (2009)

TL;DR

EORTC trial 24954 randomized 450 patients with resectable advanced squamous cell carcinoma of the larynx (T3-T4) or hypopharynx (T2-T4) to sequential induction chemotherapy (cisplatin/5-fluorouracil x4 cycles then radiotherapy 70 Gy) versus an alternating schedule (cisplatin/5-FU alternated with split-course radiotherapy totaling 60 Gy). At a median follow-up of 6.5 years, survival with a functional larynx, overall survival, and progression-free interval were similar between arms, with the alternating arm showing lower acute mucosal toxicity but no efficacy advantage.

Cohort & data

  • 450 patients enrolled from 19 European institutions (July 1996 to April 2004)
  • Cancer types: LXSC (218 patients, 49%) and HPHSC (231 patients, 51%)
  • Staging: T2-T4, N0-N2, M0; 58% stage IV, 39% stage III
  • 89% male; median age 55 years in both arms
  • Median follow-up: 6.5 years
  • Clinical trial registry: NCT00002839

Key findings

  • Survival with a functional larynx (primary endpoint): median 1.6 years (sequential) vs 2.3 years (alternating); HR = 0.85, 95% CI 0.68-1.06, not significant (log-rank P = 0.155)
  • 3-year survival with functional larynx: 39.5% (sequential) vs 45.4% (alternating)
  • 5-year survival with functional larynx: 30.5% (sequential) vs 36.2% (alternating)
  • Median overall survival: 4.4 years (sequential) vs 5.1 years (alternating); HR = 0.91, 95% CI 0.71-1.16, P = 0.446
  • 5-year overall survival: 48.5% vs 51.9%
  • Median progression-free interval: 3.0 vs 3.1 years; HR = 0.96, 95% CI 0.76-1.22, P = 0.750
  • Grade 3-4 mucositis: 32% (sequential, n=200 receiving RT) vs 21% (alternating, n=220 receiving RT); acute toxicity significantly lower in alternating arm (P < 0.001)
  • Late severe edema/fibrosis: 16% (sequential) vs 11% (alternating); late connective tissue sequelae P = 0.029
  • Laryngectomy performed in 67/224 (30%) sequential vs 52/226 (23%) alternating patients
  • On multivariable analysis, stage IV disease (HR = 2.59 vs stage II) and older age (HR = 1.20 per 10 years) were adverse prognostic factors for overall survival

Genes & alterations

No gene-specific analyses were performed in this trial. The discussion mentions cetuximab (anti-EGFR monoclonal antibody) as a future direction for larynx preservation based on other trials, but no molecular profiling was conducted.

Clinical implications

  • Both sequential and alternating chemoradiotherapy with cisplatin/fluorouracil are viable organ-preservation strategies for advanced laryngeal and hypopharyngeal SCC, preserving the larynx in approximately one-third of patients at 5 years
  • The alternating schedule does not improve efficacy over the sequential approach but produces less acute mucosal toxicity (grade 3-4 mucositis 21% vs 32%)
  • Neither arm was compared to concurrent cisplatin-radiotherapy (the RTOG 91-11 comparator), leaving the optimal organ-preservation regimen unresolved
  • Approximately half of patients died of disease or other causes by 5 years, indicating that more effective systemic regimens are needed

Limitations & open questions

  • No concurrent chemoradiotherapy arm was included for direct comparison with the current standard of care
  • Restrictive definition of functional larynx preservation (no tumor, no tracheotomy, no feeding tube >3 months) may underestimate preservation rates compared to other trials
  • Smoking data were not collected, limiting ability to assess tobacco as a confounder
  • Cross-trial comparison with RTOG 91-11 is limited by differences in endpoint definitions and patient populations
  • The role of taxane-based triplet induction (TPF) and targeted therapy (cetuximab) in larynx preservation was not addressed

Citations from this paper used in the wiki

  • “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)”
  • “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”
  • “At 5 years, approximately one-half of all patients were alive, and one-third of all patients were alive with a functional larynx in place”

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