Elsevier

The Lancet Oncology

Volume 14, Issue 3, March 2013, Pages 257-264
The Lancet Oncology

Articles
Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial

https://doi.org/10.1016/S1470-2045(13)70011-1Get rights and content

Summary

Background

The relative efficacy of the addition of induction chemotherapy to chemoradiotherapy compared with chemoradiotherapy alone for patients with head and neck cancer is unclear. The PARADIGM study is a multicentre open-label phase 3 study comparing the use of docetaxel, cisplatin, and fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin-based concurrent chemoradiotherapy alone in patients with locally advanced head and neck cancer.

Methods

Adult patients with previously untreated, non-metastatic, newly diagnosed head and neck cancer were eligible. Patients were eligible if their tumour was either unresectable or of low surgical curability on the basis of advanced tumour stage (3 or 4) or regional-node stage (2 or 3, except T1N2), or if they were a candidate for organ preservation. Patients were randomly assigned (in a 1:1 ratio) to receive either induction chemotherapy with three cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin. A computer-generated randomisation schedule using minimisation was prepared and the treatment assignment was done centrally at one of the study sites. Patients, study staff, and investigators were not masked to group assignment. Stratification factors were WHO performance status, primary disease site, and stage. The primary endpoint was overall survival. Analysis was by intention to treat. Patient accrual was terminated in December, 2008, because of slow enrolment. The trial is registered with ClinicalTrials.gov, number NCT00095875.

Findings

Between Aug 24, 2004, and Dec 29, 2008, we enrolled 145 patients across 16 sites. After a median follow-up of 49 months (IQR 39–63), 41 patients had died—20 in the induction chemotherapy followed by chemoradiotherapy group and 21 in the chemoradiotherapy alone group. 3-year overall survival was 73% (95% CI 60–82) in the induction therapy followed by chemoradiotherapy group and 78% (66–86) in the chemoradiotherapy alone group (hazard ratio 1·09, 95% CI 0·59–2·03; p=0·77). More patients had febrile neutropenia in the induction chemotherapy followed by chemoradiotherapy group (16 patients) than in the chemoradiotherapy alone group (one patient).

Interpretation

Although survival results were good in both groups there was no difference noted between those patients treated with induction chemotherapy followed by chemoradiotherapy and those who received chemoradiotherapy alone. We cannot rule out the possibility of a difference in survival going undetected due to early termination of the trial. Clinicians should still use their best judgment, based on the available data, in the decision of how to best treat patients. The addition of induction chemotherapy remains an appropriate approach for advanced disease with high risk for local or distant failure.

Funding

Sanofi-Aventis.

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.

Section snippets

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

References (23)

  • K Ang et al.

    A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinomas (HNC)

    Proc Am Soc Clin Oncol

    (2011)
  • Cited by (0)

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