Background
Phase III, multicenter, randomized controlled trial (EORTC 24891). 194 eligible patients with previously untreated, operable squamous cell carcinoma of the pyriform sinus or aryepiglottic fold (hypopharynx), free of other cancers. Compared larynx-preserving induction chemotherapy approach with conventional radical surgery, in the context of hypopharyngeal cancer where standard treatment required laryngectomy.
Interventions and follow up
Arm A: Immediate surgery (total laryngectomy + partial pharyngectomy + radical neck dissection) + post-operative RT 50–70 Gy
Arm B: Induction chemotherapy (cisplatin 100 mg/m² + fluorouracil 1000 mg/m²/day × 5 days, q3wks × 2–3 cycles); complete responders → definitive RT 70 Gy; non-responders → conventional surgery + post-op RT
Primary endpoint: Equivalence in overall survival
mFollow up: Median survival 25 months (surgery) vs 44 months (induction arm)
Arm B: Induction chemotherapy (cisplatin 100 mg/m² + fluorouracil 1000 mg/m²/day × 5 days, q3wks × 2–3 cycles); complete responders → definitive RT 70 Gy; non-responders → conventional surgery + post-op RT
Primary endpoint: Equivalence in overall survival
mFollow up: Median survival 25 months (surgery) vs 44 months (induction arm)
Results
Overall survival (hazard ratio): HR 0.86 (logrank P=.006), significantly less than 1.43 threshold → treatments judged equivalent
Distant failures: 25% (surgery arm) vs 36% — wait, fewer distant failures in induction arm (25% induction vs 36% surgery, P=.041)
Larynx function preserved: 42% at 3 years and 35% at 5 years in the induction chemotherapy arm
Complete response to induction chemo: 54% (primary tumor), 51% (regional disease)
Distant failures: 25% (surgery arm) vs 36% — wait, fewer distant failures in induction arm (25% induction vs 36% surgery, P=.041)
Larynx function preserved: 42% at 3 years and 35% at 5 years in the induction chemotherapy arm
Complete response to induction chemo: 54% (primary tumor), 51% (regional disease)
Adverse events
Main adverse events: Chemotherapy toxicities (nausea, myelosuppression, mucositis) in induction arm. Surgical morbidity (pharyngocutaneous fistula, wound complications) in surgery arm. Late swallowing dysfunction in both arms.
Conclusions
Larynx preservation using induction cisplatin/5-FU followed by definitive radiotherapy for complete responders achieves equivalent survival to conventional surgery + RT in hypopharyngeal cancer, preserving the larynx in 35% of patients at 5 years. This is the EORTC counterpart to the VA Larynx Trial for the hypopharynx.
Key Limitations
Key Limitations: Equivalence design — only 202 patients enrolled, potentially underpowered for definitive conclusions. Larynx preservation at only 35% at 5 years — lower than expected. 5-FU/cisplatin induction is a less effective larynx preservation strategy than concurrent CRT. No assessment of swallowing quality in preserved-larynx patients. The induction approach has largely been superseded by concurrent CRT for eligible patients. Hypopharyngeal cancer generally has worse prognosis than laryngeal cancer, which may limit direct comparison.
Clinical Context
EORTC 24891 established that larynx preservation is feasible in hypopharyngeal cancer without compromising survival, analogous to the VA Larynx Trial for laryngeal cancer. Current standard favors concurrent cisplatin-RT (rather than induction) for larynx preservation in hypopharynx. However, hypopharyngeal T4 or large T3 tumors often require laryngopharyngectomy. TPF induction (docetaxel/cisplatin/5-FU; TAX 324/TAX 323) has shown improved larynx preservation rates over PF alone and is used when induction is preferred prior to RT.
References