Phase III randomised trial Accelerated radiotherapy and concomitant high dose chemotherapy in non resectable stage IV locally advanced HNSCC: Results of a GORTEC randomized trial Jean Bourhis a,⇑ , Michel Lapeyre d,e , Jacques Tortochaux e , Antoine Lusinchi a , Atoussa Etessami a , Murielle Ducourtieux c , Lionel Geoffrois d , Christian Domenge b , Pierre Verrelle e , Pierre Wibault a , François Janot b , Stephane Temam b , Pierre Blanchard a , Yun G. Tao a , Anne Auperin c a Department of Radiation Oncology; b Department of Head and Neck; c Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, France; d Centre Alexis Vautrin, Nancy, France; e Centre Jean Perrin, Clermont-Ferrand, France article info Article history: Received 6 May 2011 Received in revised form 13 July 2011 Accepted 13 July 2011 Available online 8 August 2011 Keywords: Radiotherapy Chemotherapy Dose intensity Head and neck cancer abstract Background: The objective was to evaluate the efficacy of a strong increase of the dose-intensity of con- comitant radio-chemotherapy (RT-CT) in patients with far advanced non metastatic HNSCC. Methods: Eligible patients had N3 disease (UICC 1997) and the primary tumor and/or the node(s) had to be strictly unresectable. Patients with palpable N2B–C were also eligible if massive nodal involvement was present. 109 patients were included, with 53 randomized to RT-CT and 56 to accelerated RT. In the RT-CT arm, the RT regimen consisted of 64 Gy in 5 weeks and the CT regimen consisted of synchro- nous CDDP 100 mg/m 2 on days 2, 16, and 30 and 5FU 1000 mg/m 2 on days1–5 and 29–33 of the RT course. After RT-CT, two adjuvant cycles of CDDP-5FU were delivered in good responders. A control arm was using a very accelerated RT, delivering 64 Gy in 3 weeks. Results: The most common tumor sites were oropharynx and hypopharynx. Most of the patients had T4 disease (70%) and 100% had a massive nodal involvement (mainly N3 with a mean nodal size >7 cm in both arms). A significant difference was observed in favor of the RT-CT arm (p = 0.005) in terms of cumu- lative incidence of local regional failure or distant metastases. However, the overall survival and event free survival rates were not significantly different between the two arms (p = 0.70 and 0.16, respectively). The lack of survival benefit in favor of the RT-CT was partly due to an excess of initial early treatment related death in the RT-CT arm. Conclusion: The very intense RT-CT schedule was more efficient on disease control, but was also more toxic than accelerated RT alone, pointing out that there was no clear improvement of the therapeutic index. This study shows the limits of dose-intensification, with regard to concomitant RT-CT. Ó 2011 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 100 (2011) 56–61 In the recent decades, the role of chemotherapy (CT) in head and neck squamous cell carcinoma (HNSCC) has been extensively studied [1–4]. It has been used mainly in three ways in the treat- ment of locally advanced HNSCC: as induction treatment [5–7]; concomitantly with radiotherapy (RT) [1–4,8–11]; as adjuvant treatment after RT and/or surgery [1,2,5]. Based on evidence level 1A and in particular on the MACH-NC meta-analysis [1,2], which analyzed updated individual patients data from 87 randomized tri- als, concomitant RT-CT has become a standard of care in locally ad- vanced HNSCC. The magnitude of the survival benefit associated with the addition of CT, when given concomitantly with RT was found to be 6.5% at 5 years and higher with platinum based-CT [2]. Adding CT to RT is also associated with a substantial increased of acute and late toxicities [3,12,13], pointing out the need to opti- mize these therapeutic combinations. In the past decades, considerable interest has also been raised about non conventional fractionation schedules in RT for HNSCC, either with hyperfractionated and/or accelerated RT [14–19]. The aim of such altered fractionated RT was to increase the dose inten- sity of RT, either by increasing the total dose of RT (hyperfraction- ation) or by reducing the overall time of RT (acceleration). In both cases, an improved outcome has generally been observed, as com- pared to conventional RT and a meta-analysis based on the collec- tion of the individual patients data from more than 6500 patients randomized between conventional and altered fractionated RT concluded to a small but significant improvement, both in local control and survival, in favor of altered fractionated RT [20]. Taking into account the results of randomized studies, a new regimen was designed in an attempt to markedly increase the dose-intensity with the subsequent hypothesis to markedly in- crease the efficacy of RT-CT. This very intense regimen was tested 0167-8140/$ - see front matter Ó 2011 Published by Elsevier Ireland Ltd. doi:10.1016/j.radonc.2011.07.006 ⇑ Corresponding author at: Department of Radiation Oncology, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94805 Villejuif, France. E-mail address: bourhis@igr.fr (J. Bourhis). Radiotherapy and Oncology 100 (2011) 56–61 Contents lists available at ScienceDirect Radiotherapy and Oncology journal homepage: www.thegreenjournal.com