DeCIDE and PARADIGM: nails in the coffin of induction chemotherapy in head and neck squamous cell carcinoma?

Abstract

Induction chemotherapy was first used in squamous cell carcinoma of the head and neck (SCCHN) in the 1970s. High overall response rates were observed in previously untreated tumours [1] and a correlation between response to induction chemotherapy and favourable outcome following radiotherapy was noted [2]. Numerous subsequent randomised studies and meta-analyses nonetheless failed to demonstrate a significant survival advantage with the use of induction chemotherapy compared with locoregional treatment alone [3]. A marginally significant 5 % absolute improvement in 5 year survival was seen when analysis was restricted to studies using a platin and 5-fluorouracil (PF) as the induction regimen. This was however overshadowed by the larger survival benefit observed with concurrent chemoradiation (CRT). As a result, CRT became widely accepted as the standard of care in the nonsurgical management of patients with locoregionally advanced SCCHN. Recent years have witnessed a renewed interest in the use of induction chemotherapy in SCCHN. Increased locoregional tumour control and survival with CRT have resulted in a shift in the pattern of treatment failure, with a higher incidence of distant relapse compared with locoregional recurrence, especially in patients with advanced nodal disease at presentation [4]. Although induction chemotherapy has a limited impact on locoregional control, it is more effective than concurrent chemotherapy at reducing distant disease relapse [3]. By adding multi-agent induction chemotherapy to CRT, in a treatment paradigm known as sequential chemoradiotherapy (SCRT), survival of patients with advanced SCCHN can potentially be maximised with CRT providing optimal locoregional control and induction chemotherapy reducing distant disease relapse [5]. Such a paradigm also allows treatment selection based on the magnitude of response to induction chemotherapy. These potential roles of induction chemotherapy were tested against CRT in two key randomised controlled trials: DeCIDE and PARADIGM [6, 7]. Preliminary results from both studies were presented at the 2012 annual meeting of the American Society of Clinical Oncology and we await their full publication. DeCIDE is a multicentre randomised phase III study designed to assess whether the addition of 2 cycles of induction docetaxel, cisplatin and 5-fluorouracil (TPF) chemotherapy to CRT (docetaxel 25 mg/m day 1, continuous infusion 5-fluorouracil 600 mg/m days 0–4 and oral hydroxyurea 500 mg twice daily days 0–4 with hyperfractionated twice daily radiotherapy at 1.5 Gy per fraction days 1–5 every 14 days for 5 cycles) reduces the distant failure rate and improves overall survival in patients with previously untreated SCCHN and advanced nodal disease (N2/N3 M0) at presentation [6]. Target accrual was initially 400 patients, which would have provided 88 % power to detect an improvement in the 3 year survival rate of 50 % assumed with CRT to 65 % with SCRT. This was reduced to 280 patients as a result of slow accrual, with 80 % power to detect a hazard ratio of 0.5 for the primary endpoint of overall survival at 3 years. One hundred and forty-two patients were randomised to the induction chemotherapy arm of the study, while 138 were randomised to CRT. The majority presented with N2 disease and 55 % had primary tumours in the oropharynx. Of those randomised to induction chemotherapy, 91 % received 2 cycles of TPF with 9 % achieving a complete response and 55 % a partial response to treatment. Eighty-seven percent proceeded to CRT following induction chemotherapy. S. W. Loo (&) K. Geropantas T. W. Roques Department of Oncology, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK e-mail: suatloo@doctors.org.uk