M G Ghi1, A Paccagnella1, D Ferrari2, P Foa2, D Alterio3, C Codecà2, F Nolè4, E Verri4, R Orecchia3, F Morelli5, S Parisi6, C Mastromauro1, C A Mione7, C Rossetto8, M Polsinelli9, H Koussis10, L Loreggian11, A Bonetti12, F Campostrini13, G Azzarello14, C D'Ambrosio8, F Bertoni15, C Casanova8, E Emiliani16, M Guaraldi17, F Bunkheila18, P Bidoli19, R M Niespolo20, A Gava21, E Massa22, A Frattegiani23, F Valduga24, G Pieri25, T Cipani26, D Da Corte27, F Chiappa28, E Rulli28. 1. Medical Oncology Department, Ospedale dell'Angelo, Venezia. 2. Medical Oncology Unit, Ospedale San Paolo, Milano. 3. Advanced Radiotherapy Center. 4. Unit of Urogenital and Head and Neck Oncology, Istituto Europeo di Oncologia, Milano. 5. U.O.C. Medical Oncology. 6. U.O.C. Radiation Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni, Rotondo. 7. Radiotherapy Department, Ospedale SS Giovanni e Paolo, Venezia. 8. Medical Oncology Department. 9. S.O.C. Radiation Oncology, Azienda Ospedaliero-Universitaria S.Maria della Misericordia, Udine. 10. Medical Oncology Department 2, Istituto Oncologico Veneto- IRCCS, Padova. 11. Radiotherapy Department, Istituto Oncologico Veneto - IRCCS, Padova. 12. Medical Oncology Department, Ospedale Mater Salutis, Legnago. 13. Radiotherapy Department, Ospedale Mater Salutis, Legnago. 14. Oncology Unit, Department of Internal Medical Sciences, Mirano. 15. Radiotherapy Department, Azienda Ospedaliero Universitaria, Modena. 16. Radiotherapy Department, Azienda USL, Ravenna. 17. Medical Oncology Department, Policlinico Sant'Orsola-Malpighi, Bologna. 18. Radiotherapy Department, Policlinico Sant'Orsola-Malpighi, Bologna. 19. Medical Oncology Department, Ospedale San Gerardo, Monza. 20. Radiotherapy Department, Ospedale San Gerardo, Monza, Ospedale San Gerardo, Monza. 21. Radiotherapy Department, Ospedale Ca' Foncello, Treviso. 22. Department of Medical Science, Università degli Studi di Cagliari, Cagliari. 23. Radiation Oncology Department, Ospedale S. Maria della Misericordia, Perugia. 24. Medical Oncology Department, Ospedale S. Chiara, Trento. 25. Medical Oncology Department, AO Triestina, Trieste. 26. Niguarda Cancer Center, Ospedale Niguarda Cà Granda, Milano. 27. Oncology Department, Ospedale S. Martino, Belluno. 28. Laboratory of Clinical Research, Istituto di Ricerche Farmacologiche "Mario Negri," Milano, Italy.
Abstract
BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.
BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.
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