Weekly cetuximab concurrent with IMRT aggravated radiation-induced oral mucositis in locally advanced nasopharyngeal carcinoma: Results of a randomized phase II study

doi:10.1016/j.oraloncology.2015.06.008

Oral Oncology

Volume 51, Issue 9, September 2015, Pages 875-879

https://doi.org/10.1016/j.oraloncology.2015.06.008 Get rights and content

Highlights

•
ERT was not more efficacious than CRT but was more likely to cause acute adverse events in LA NPC.
•
The recommended treatment modality was still concurrent cisplatin-IMRT.
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The combination of TP induction chemotherapy and concurrent cetuximab-radiotherapy should only be used in selected patients.

Summary

Background

To evaluate the clinical efficacies and toxicities of induction chemotherapy followed by concomitant cisplatin-chemoradiotherapy (CRT) or cetuximab-radiotherapy (ERT) in locally advanced nasopharyngeal carcinoma (NPC).

Methods

Previously untreated patients with stage III–IVb NPC were eligible. They were randomized to CRT arm: intensity modulated radiation therapy (IMRT) with weekly cisplatin (30 mg/m²/w) or ERT arm: IMRT with weekly cetuximab (loading dose of 400 mg/m² followed by weekly doses of 250 mg/m²). Two cycles of induction chemotherapy (docetaxel 75 mg/m² d1 and cisplatin 80 mg/m² d1) were administered to both arms. Endpoints were survivals, toxicities and quality of life (QoL).

Results

Because of the unexpectedly high rates of grade 3/4 mucositis observed in the ERT arm, the study was closed ahead of schedule. A total of 44 patients (23 in CRT arm and 21 in ERT arm) were enrolled. All patients completed the scheduled induction chemotherapy and radical radiotherapy. The results showed better compliance (P < 0.001) with more oral mucositis, acneiform rash and dysphagia (P < 0.05) of cetuximab. The 3-year disease-free survival (DFS) were achieved as 78.3% and 85.7% (P = 0.547) in CRT and ERT arm, respectively. In the analysis of QoL, the addition of cetuximab to radiotherapy temporarily increased the adverse symptoms but did not result in long-term dysfunction.

Conclusions

ERT was not more efficacious than CRT but was more likely to cause acute adverse events in LA NPC. The recommended treatment modality was still concurrent cisplatin-IMRT. The combination of TP induction chemotherapy and concurrent cetuximab-radiotherapy should only be used in selected patients.

Introduction

Locally advanced nasopharyngeal carcinoma (LA NPC) continues to be a source of morbidity and mortality worldwide [1] despite the improved radiotherapy techniques. The cisplatin-based concurrent chemoradiotherapy regimen was identified as the standard treatment, whereas in meta-analyses induction chemotherapy had shown to enhance treatment efficacy as a result of reduced distant metastases [2], [3], [4], [5].

The development of cetuximab, which targets an extracellular epitope in the EGFR ligand-binding domain [6], [7], [8], seemed to offer significant improvements when combined with radiotherapy and it by no means increased the radiation-related mucositis in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) [9].

The findings have stimulated attentions in integrating cetuximab into current treatment regimens in NPC patients [10], [11], [12]. The schedule of concurrent cetuximab–cisplatin-radiotherapy had certified to be more effective than their former outcomes without cetuximab in a Hong Kong study [11], but more adverse events were observed. And replacing chemotherapy with target agent may reduce the treatment toxicities without compromised therapeutic effect. It had been proved that combining cisplatin chemotherapy and RT concurrently significantly caused more grade 3/4 mucositis. The hypothesis that cetuximab/RT may deliver equivalent or improved results over standard DDP/RT with less toxicities (mainly grade 3/4 mucositis) remains untested. The TP regimen (docetaxel + cisplatin) had demonstrated its effectiveness and safety in a randomized phase II trail followed by concurrent cisplatin-chemoradiotherapy in NPC [13]. Therefore, we prospectively conducted the randomized trial that administered TP induction chemotherapy followed by concomitant cisplatin or cetuximab in combination with radical intensity modulated radiation therapy (IMRT) in LA NPC.

Section snippets

Patient selection

Between March 2010 and August 2011, patients with histologically confirmed non-keratinizing, stage III–IVb (7th AJCC/UICC staging system) NPC were randomly enrolled. Other inclusion criteria included an age of 18–70 years, Karnofsky performance status of at least 70% and no prior treatment. Adequate hematologic, hepatic and renal functions were also required.

All patients received pretreatment evaluations, including a complete history and physical examination, complete blood cell count,

Results

In the interim analysis, we evaluated both the survivals and toxicities. Because of the unexpectedly high rates of grade 3/4 mucositis in the ERT arm, the study was closed ahead of schedule. A total of 44 patients (23 in CRT arm and 21 in ERT arm) were enrolled when the trail ended. At the time of this analysis, all patients were under follow-up, eight with documented disease progression, and one who had died due to multiple distant metastases and regional recurrence.

Discussion

Although the combination of TP induction chemotherapy and concurrent cetuximab-radiotherapy was rather tolerable, there was no evidence to suggest that cetuximab significantly improved the 3-year survival rates compared to the CRT modality. The preliminary results showed a better compliance of the ERT arm than the CRT arm, however, the good tolerance to the treatment did not correlate to better efficacy. It might be due to the early closure of study and the limitation of the sample size.

Many

Funding sources for the study

None declared.

Conflict of interest statements

None declared.

Acknowledgments

Cetuximab was kindly provided by Merck Corporation.

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Citation Excerpt :
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^☆: Clinicaltrials.gov registration number: NCT01614938.

View full text

Weekly cetuximab concurrent with IMRT aggravated radiation-induced oral mucositis in locally advanced nasopharyngeal carcinoma: Results of a randomized phase II study☆

Highlights

Summary

Background

Methods

Results

Conclusions

Introduction

Section snippets

Patient selection

Results

Discussion

Funding sources for the study

Conflict of interest statements

Acknowledgments

Int J Radiat Oncol Biol Phys

Ann Oncol

Radiother Oncol

Ann Oncol

Eur J Cancer

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet Oncol

Radiother Oncol

Global cancer statistics

CA Cancer J Clin

The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature

J Clin Oncol

Induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy with or without adjuvant chemotherapy for locoregionally advanced nasopharyngeal carcinoma: meta-analysis of 1,096 patients from 11 randomized controlled trials

Asian Pac J Cancer Prev

Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck

Cancer Res