Elsevier

The Lancet Oncology

Volume 17, Issue 11, November 2016, Pages 1509-1520
The Lancet Oncology

Articles
Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial

https://doi.org/10.1016/S1470-2045(16)30410-7Get rights and content

Summary

Background

The value of adding cisplatin, fluorouracil, and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma is unclear. We aimed to compare TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in a suitably powered trial.

Methods

We did an open-label, phase 3, multicentre, randomised controlled trial at ten institutions in China. Patients with previously untreated, stage III–IVB (except T3-4N0) nasopharyngeal carcinoma, aged 18–59 years without severe comorbidities were enrolled. Eligible patients were randomly assigned (1:1) to receive induction chemotherapy plus concurrent chemoradiotherapy or concurrent chemoradiotherapy alone (three cycles of 100 mg/m2 cisplatin every 3 weeks, concurrently with intensity-modulated radiotherapy). Induction chemotherapy was three cycles of intravenous docetaxel (60 mg/m2 on day 1), intravenous cisplatin (60 mg/m2 on day 1), and continuous intravenous fluorouracil (600 mg/m2 per day from day 1 to day 5) every 3 weeks before concurrent chemoradiotherapy. Randomisation was by a computer-generated random number code with a block size of four, stratified by treatment centre and disease stage (III or IV). Treatment allocation was not masked. The primary endpoint was failure-free survival calculated from randomisation to locoregional failure, distant failure, or death from any cause; required sample size was 476 patients (238 per group). We did efficacy analyses in our intention-to-treat population. The follow-up is ongoing; in this report, we present the 3-year survival results and acute toxic effects. This trial is registered with ClinicalTrials.gov, number NCT01245959.

Findings

Between March 1, 2011, and Aug 22, 2013, 241 patients were assigned to induction chemotherapy plus concurrent chemoradiotherapy and 239 to concurrent chemoradiotherapy alone. After a median follow-up of 45 months (IQR 38–49), 3-year failure-free survival was 80% (95% CI 75–85) in the induction chemotherapy plus concurrent chemoradiotherapy group and 72% (66–78) in the concurrent chemoradiotherapy alone group (hazard ratio 0·68, 95% CI 0·48–0·97; p=0·034). The most common grade 3 or 4 adverse events during treatment in the 239 patients in the induction chemotherapy plus concurrent chemoradiotherapy group versus the 238 patients in concurrent chemoradiotherapy alone group were neutropenia (101 [42%] vs 17 [7%]), leucopenia (98 [41%] vs 41 [17%]), and stomatitis (98 [41%] vs 84 [35%]).

Interpretation

Addition of TPF induction chemotherapy to concurrent chemoradiotherapy significantly improved failure-free survival in locoregionally advanced nasopharyngeal carcinoma with acceptable toxicity. Long-term follow-up is required to determine long-term efficacy and toxicities.

Funding

Shenzhen Main Luck Pharmaceuticals Inc, Sun Yat-sen University Clinical Research 5010 Program (2007037), National Science and Technology Pillar Program during the Twelfth Five-year Plan Period (2014BAI09B10), Health & Medical Collaborative Innovation Project of Guangzhou City (201400000001), Planned Science and Technology Project of Guangdong Province (2013B020400004), and The National Key Research and Development Program of China (2016YFC0902000).

Introduction

Nasopharyngeal carcinoma has a unique, unbalanced endemic distribution: 86 700 new cases of nasopharyngeal carcinoma were reported worldwide in 2012 with the highest incidences reported in southeast Asia, Micronesia and Polynesia, eastern Asia, and northern Africa.1 Unlike other head and neck cancers, radiotherapy is the primary treatment modality for non-disseminated nasopharyngeal carcinoma as a result of its anatomical location and sensitivity to irradiation. More than 70% of cases of newly diagnosed nasopharyngeal carcinoma are classified as locoregionally advanced disease.2 Concurrent chemoradiotherapy is now the standard treatment for locoregionally advanced nasopharyngeal carcinoma. With combined use of MRI, intensity-modulated radiotherapy, and concurrent chemoradiotherapy, locoregional control has substantially improved in nasopharyngeal carcinoma and distant metastasis is now the main source of treatment failure.3

Research in context

Evidence before this study

The aim of this study was to assess whether the addition of induction chemotherapy to standard concurrent chemoradiotherapy treatment provides further survival benefit in patients with locoregionally advanced nasopharyngeal carcinoma. We identified relevant studies through searches of PubMed and WHO’s International Clinical Trial Registry Platform for open or closed trials with a timeframe from database inception to June 8, 2016. Search terms included “nasopharyngeal carcinoma” or “cancer” or “neoplasm”, “neoadjuvant” or “induction chemotherapy”, and “chemoradiotherapy”. The search was limited to randomised clinical trials, with no language restrictions. So far, only three trials comparing concurrent chemoradiotherapy with induction chemotherapy followed by concurrent chemoradiotherapy have been published and the results are controversial. A phase 2 study comparing concurrent chemoradiotherapy alone with induction docetaxel and cisplatin followed by concurrent chemoradiotherapy reported improved overall survival in the induction chemotherapy plus concurrent chemoradiotherapy group. In another phase 2 trial, induction chemotherapy of cisplatin, epirubicin, and paclitaxel followed by concurrent chemoradiotherapy did not significantly improve overall survival or progression-free survival compared with concurrent chemoradiotherapy alone in stage IIB–IVB nasopharyngeal carcinoma. A randomised phase 2–3 trial comparing concurrent chemoradiotherapy alone with induction gemcitabine, carboplatin, and paclitaxel followed by concurrent chemoradiotherapy in stage III–IVB nasopharyngeal carcinoma did not record any significant improvements in survival. In three Bayesian network meta-analyses comparing concurrent chemoradiotherapy alone with induction chemotherapy plus concurrent chemoradiotherapy in nasopharyngeal carcinoma, the efficacies all seemed similar, except that induction chemotherapy plus concurrent chemoradiotherapy was associated with reduced distant metastasis. However, none of these trials used docetaxel, cisplatin, and fluorouracil (TPF), which has been shown to be an effective induction chemotherapy regimen for head and neck cancer. Besides this study (NCT01245959), several phase 3 randomised trials are also assessing the therapeutic benefits of adding different induction regimens to concurrent chemoradiotherapy (NCT00201396, NCT00705627, NCT01872962), and the results are awaited. From the aforementioned evidence, the efficacy of induction chemotherapy followed by concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma remains unclear and needs evidence from large-scale, randomised controlled trials.

Added value of this study

To the best of our knowledge, this is the first phase 3 study to assess the value of adding TPF induction chemotherapy to concurrent chemoradiotherapy in nasopharyngeal carcinoma. Our results show that compared with concurrent chemoradiotherapy alone, TPF induction chemotherapy followed by concurrent chemoradiotherapy significantly increases failure-free survival, overall survival, and distant failure-free survival with acceptable toxicity.

Implications of all the available evidence

This study suggests that adding TPF induction chemotherapy to concurrent chemoradiotherapy could improve survival and reduce distant failure in locoregionally advanced nasopharyngeal carcinoma. We recommend TPF induction chemotherapy followed by concurrent chemoradiotherapy to patients with advanced nasopharyngeal carcinoma; however, long-term follow-up is required to assess the eventual efficacy and toxicity of this strategy.

Additional cycles of chemotherapy, such as the addition of adjuvant or induction chemotherapy to concurrent chemoradiotherapy, might improve distant control in patients at high risk of distant failure. However, an important concern regarding the concurrent-adjuvant approach is the low compliance to three cycles of adjuvant chemotherapy (around 60%).4 Moreover, in our phase 3 trial,4 the addition of adjuvant cisplatin and fluorouracil (PF) chemotherapy to concurrent chemoradiotherapy did not significantly improve treatment outcomes.4 Compared with adjuvant chemotherapy, induction chemotherapy offers advantages of improved tolerability and early eradication of micrometastases; thus, an induction–concurrent approach might be a promising treatment strategy. However, in previous phase 3 studies that compared induction chemotherapy plus radiotherapy versus radiotherapy alone,5, 6, 7, 8 induction chemotherapy did not reduce distant metastasis or prolong survival; one explanation is that a truly effective induction chemotherapy regimen has not yet been identified.

Docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy is an effective induction chemotherapy regimen for locoregionally advanced head and neck cancer; several large-scale phase 3 trials have confirmed the statistically significant clinical benefits of adding docetaxel to the PF induction regimen.9, 10, 11 On the basis of encouraging results of TPF induction chemotherapy in head and neck cancer, two phase 1 studies of this induction chemotherapy in locally advanced nasopharyngeal carcinoma have been done at our institution (Sun Yat-sen University Cancer Centre, Guangzhou, China).12, 13 Several phase 2 trials also showed promising results with manageable toxicities for TPF induction chemotherapy in nasopharyngeal carcinoma.14, 15, 16 However, whether or not the addition of TPF induction chemotherapy to concurrent chemoradiotherapy provides any additional survival benefit in nasopharyngeal carcinoma remains unclear. Therefore, we did a multicentre, randomised controlled phase 3 trial to compare the efficacy of TPF induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma.

Section snippets

Study design and participants

This study was an open-label, multicentre, randomised controlled phase 3 trial that was done at ten hospitals in China (appendix p 3). Patients with previously untreated, non-distant metastatic, newly histologically confirmed non-keratinising stage III–IVB nasopharyngeal carcinoma (except T3–4N0; 7th Union for International Cancer Control and American Joint Committee on Cancer) were eligible. Patients had to be 18–59 years old with Karnofsky performance status scores of at least 70, and

Results

Between March 1, 2011, and Aug 22, 2013, 480 patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned to receive induction chemotherapy plus concurrent chemoradiotherapy (n=241) or concurrent chemoradiotherapy alone (n=239; figure 1). No patients were ineligible after randomisation. The baseline demographic and clinical characteristics of the treatment groups were well balanced (table 1). There was no significant difference in pretreatment imaging methods between

Discussion

The results of our trial show that compared with concurrent chemoradiotherapy alone, TPF induction chemotherapy followed by concurrent chemoradiotherapy could significantly increase failure-free survival, overall survival, and distant failure-free survival, but not locoregional failure-free survival, in locoregionally advanced nasopharyngeal carcinoma.

The efficacy of induction chemotherapy followed by concurrent chemoradiotherapy in nasopharyngeal carcinoma is controversial. Hui and colleagues23

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