ArticlesInduction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial
Introduction
The treatment of patients with locally advanced head and neck cancer continues to improve. There are in essence two different, non-surgical approaches available to treat these patients: concurrent chemoradiotherapy and induction chemotherapy followed by concurrent chemoradiotherapy.1 Concurrent chemoradiotherapy has emerged as a preferred treatment approach on the basis of various studies establishing the efficacy of cisplatin-based chemoradiotherapy.2, 3, 4 The standard approach has been to give cisplatin at 100 mg/m2 every 3 weeks during radiation therapy. The benefit of concurrent chemoradiotherapy was also shown in a meta-analysis of head and neck cancer.5, 6 No clear benefit exists in the addition of biological therapy to chemoradiotherapy, although the role of cetuximab and radiotherapy is being examined more closely in selected patient populations.7, 8 Induction chemotherapy has been added to chemoradiotherapy to try to decrease the likelihood of emergence of distant metastasis, improve local regional control, and support organ preservation. A regimen of docetaxel, cisplatin, and fluorouracil (TPF) has emerged as the standard induction chemotherapy regimen on the basis of phase 3 studies establishing its superiority over cisplatin and fluorouracil (PF) induction chemotherapy.9, 10 This benefit of TPF has been recorded in patients with both resectable and unresectable disease. It has also been observed in patients with laryngeal cancer treated for organ preservation.11 However, whether the addition of induction chemotherapy to chemoradiotherapy improves efficacy compared with chemoradiotherapy alone is unclear.
The PARADIGM study is an open-label, randomised, phase 3 study comparing two different treatments: induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in patients with locally advanced, previously untreated, head and neck cancer.
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Participants
In this open-label, randomised, phase 3 trial, patients with measurable, previously untreated, non-metastatic, histologically proven stage III or IV squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were eligible if the tumour was deemed to be either unresectable (because of tumour fixation, involvement of the nasopharynx, or fixed lymph nodes) or of low surgical curability on the basis of advanced tumour stage (3 or 4) or regional-node stage (2 or 3, except T1N2),
Results
From Aug 24, 2004, to Dec 29, 2008, we enrolled 145 patients across 16 sites. The study was halted because of slow accrual. 70 patients were assigned to receive induction chemotherapy followed by chemoradiotherapy (group A) and 75 patients assigned to receive chemoradiotherapy only (group B; figure 1). The primary analysis cutoff was March 30, 2012. Patient characteristics were well balanced between groups (table 1). Patients were relatively young with a median age of 54 years, mostly men, and
Discussion
Our findings show no overall survival advantage with induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy only. The trial closed prematurely in 2008 with insufficient accrual and power to see the predicted difference because survival was better than expected in both groups. A clinically important survival difference could have gone undetected at a significant level with this sample size.
The TAX 32310 and TAX 3249 studies, published in 2007, investigated the
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