Chemotherapy in locally advanced nasopharyngeal carcinoma: An individual patient data meta-analysis of eight randomized trials and 1753 patients

doi:10.1016/j.ijrobp.2005.06.037

International Journal of Radiation OncologyBiologyPhysics

Volume 64, Issue 1, 1 January 2006, Pages 47-56

https://doi.org/10.1016/j.ijrobp.2005.06.037 Get rights and content

Objectives: To study the effect of adding chemotherapy to radiotherapy (RT) on overall survival and event-free survival for patients with nasopharyngeal carcinoma.

Methods and Materials: This meta-analysis used updated individual patient data from randomized trials comparing chemotherapy plus RT with RT alone in locally advanced nasopharyngeal carcinoma. The log–rank test, stratified by trial, was used for comparisons, and the hazard ratios of death and failure were calculated.

Results: Eight trials with 1753 patients were included. One trial with a 2 × 2 design was counted twice in the analysis. The analysis included 11 comparisons using the data from 1975 patients. The median follow-up was 6 years. The pooled hazard ratio of death was 0.82 (95% confidence interval, 0.71–0.94; p = 0.006), corresponding to an absolute survival benefit of 6% at 5 years from the addition of chemotherapy (from 56% to 62%). The pooled hazard ratio of tumor failure or death was 0.76 (95% confidence interval, 0.67–0.86; p < 0.0001), corresponding to an absolute event-free survival benefit of 10% at 5 years from the addition of chemotherapy (from 42% to 52%). A significant interaction was observed between the timing of chemotherapy and overall survival (p = 0.005), explaining the heterogeneity observed in the treatment effect (p = 0.03), with the highest benefit resulting from concomitant chemotherapy.

Conclusion: Chemotherapy led to a small, but significant, benefit for overall survival and event-free survival. This benefit was essentially observed when chemotherapy was administered concomitantly with RT.

Introduction

Nasopharyngeal carcinoma (NPC) is pathologically, epidemiologically, and clinically distinct from other head-and-neck cancers (1, 2). NPC is rare in the United States (except in Alaska) and Western Europe. Also, in these areas, the frequency of squamous cell carcinoma (World Health Organization [WHO] type 1) is about 25%, markedly greater than in the endemic areas. Areas of high incidence include Southern China, Southeast Asia, the Middle East, North Africa, Alaska, and Greenland. In these areas, the Epstein-Barr virus is strongly associated with NPC. Most patients have poorly or undifferentiated (WHO type 2 or 3) carcinoma and present with locally advanced disease. Nodal involvement and bilateral nodal disease are more frequently observed with NPC than with other head-and-neck cancers. NPC is commonly treated with radiotherapy (RT) and chemotherapy (2). RT at a dose of 65–75 Gy within 6–7 weeks is standard. The overall survival (OS) rate at 5 years ranges from 32% to 52% in large series of patients with locally advanced disease treated with RT alone (2). Chemotherapy has been proposed for locally advanced NPC to improve survival (1, 2). Despite 11 randomized trials comparing RT and RT plus chemotherapy in the English literature, the magnitude of the effect of chemotherapy on survival is not well-established. OS was the main endpoint in all these trials, except for one, but only two showed a beneficial effect on survival and four on relapse-free survival. Underpowered trials could account for the inconstancy of the benefit on survival, which was the case in the previously published Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) (3). The aim of the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) was to assess the impact of adding chemotherapy to RT on OS.

Section snippets

Methods and materials

The methods of the meta-analysis are specified in a protocol published in the Cochrane library (4). The meta-analysis was based on individual patient data (5) and used a method similar to that used in the MACH-NC study (3) and the Prophylactic Cranial Irradiation Overview (6).

Trial selection

Eleven trials, including 2,722 patients, were identified in the English literature. The data from one trial (229 patients) were lost at the institution (14). We received data from 10 trials. Two trials were excluded by the Steering Committee after blind review (740 patients) because they did not meet the eligibility criterion of unpredictable treatment assignment (15, 16).

We found 88 comparative trials in the Chinese literature (7) (list available on request). Twelve were selected according to

Discussion

Despite numerous trials investigating the effect of chemotherapy on NPC, to date, no consensus has been reached about the magnitude of its benefit and the optimal protocol. An individual patient data meta-analysis was therefore justified. The exhaustiveness principle of meta-analysis was impossible to reach because of the difficulties encountered when trying to include the Chinese trials. Thus, the term “pooled analysis” could also be applied to the present study. The quality of the missing

Conclusion

The addition of chemotherapy to standard RT provides a small, but significant, survival benefit in patients with NPC.This benefit is essentially observed when chemotherapy is administered concomitantly with RT. The role of induction chemotherapy and adjuvant chemotherapy given alone or added to concomitant chemotherapy is more questionable.

Acknowledgments

We are grateful to Denise Avenell for secretariat support, Francine Courtial for trial search, Catherine Hill for her comments on the manuscript, and Lorna Saint Ange for editing.

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Cited by (576)

Concurrent chemoradiotherapy versus radiotherapy alone in older patients with stage II nasopharyngeal carcinoma after intensity-modulated radiotherapy: A propensity score-matched cohort study
2024, Radiotherapy and Oncology
Whether concurrent chemoradiotherapy (CCRT) benefits the older (age ≥ 60 years) patients with stage II nasopharyngeal carcinoma (NPC) has not been determined. This study aimed to compare the outcomes and toxicities of CCRT with Intensity-Modulated Radiotherapy (IMRT) alone in older patients with stage II NPC.
Between January 2010 and December 2017, 220 older (age ≥ 60 years) patients with stage II NPC were analyzed. A pair of 53 patients were matched between the CCRT group and RT group by using propensity score matching (PSM) in terms of age, sex, pathological type, T and N stage, ACE-27 scores, CRP, LDH and Hb. Cancer-specific survival (CSS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS) were analysed by the Kaplan-Meier method and log-rank test. Multivariate analysis was performed to assess the prognostic risk factors by using a Cox’s proportional hazards regression model. Treatment toxicities were clarified and compared between the two groups by using the χ² test.
The median follow-up time of the whole cohort was 82.0 months (range, 11–151 months). PSM analysis indicated that compared with the RT group, significantly higher 5-year CSS (98.1 % vs. 83.0 %, P = 0.02), PFS (98.1 % vs. 79.2 %, P = 0.01) and DMFS (100.0 % vs. 92.4 %, P = 0.04) were observed in the CCRT group. Multivariate analysis showed that CCRT was an independent prognostic factor predicting CSS (HR, 0.34; 95 % CI, 0.15–0.79; P = 0.01), PFS (HR, 0.48; 95 % CI, 0.25–0.93; P = 0.03), and LRRFS (HR, 0.36; 95 % CI, 0.14–0.90; P = 0.03), and a higher ACE-27 score predicted a worse CSS. Patients in the CCRT group experienced higher frequencies of the acute toxicities than patients in the RT group. Late complications were comparable between the two groups.
CCRT significantly improved the survival benefits for the older patients with stage II NPC compared with IMRT alone without adding late complications, whereas increased some of the treatment-associated acute toxicities.
Nasopharyngeal carcinoma patient-derived xenograft mouse models reveal potential drugs targeting cell cycle, mTOR, and autophagy pathways
2023, Translational Oncology
Nasopharyngeal carcinoma (NPC) is associated with Epstein–Barr virus (EBV) infection. To test preclinical NPC drugs, we established two patient-derived xenograft (PDX) mouse models, EBV-positive PDX-B13 and EBV-negative PDX-Li41, for drug screening.
Based on next generation sequencing (NGS) studies, PDX-B13 had CCND1 copy number (CN) gain but CDKN2A CN loss, whereas PDX-Li41 had CDKN2A and RB1 CN loss, TSC1 (negative regulator of mTOR) frameshift deletion mutation, and increased activation of mTOR, a serine/threonine kinase that governs metabolism, autophagy, and apoptosis. Increased mTOR was also associated with poor NPC prognosis.
Everolimus, an mTOR inhibitor, suppressed tumor growth in the two PDX NPC models and had an additive antitumor effect with palbociclib, a CDK4/6 inhibitor. PDX tumors treated with various drugs or untreated were subjected to RNA sequencing, transcriptome profile analysis, and selective Western blotting to understand the interactions between these drugs and gene expression profiles. Palbociclib also suppressed EB viral nuclear antigen (EBNA1) expression in PDX-B13. Everolimus together with autophagy inhibitor, hydroxychloroquine, had additive anti-tumor effect on PDX-B13 tumor. Immunohistochemistry revealed that high mTOR levels were correlated with poor overall survival in patients with metastatic NPC (N = 90).
High mTOR levels are a poor prognostic factor in NPC, and cell cycle, mTOR and autophagy pathways may serve as therapeutic targets in NPC. In addition, PDX models can be used for efficiently testing potential NPC drugs.
Integrating pretreatment MRI-detected nodal features and Epstein-Barr virus DNA to identify optimal candidates for intensity-modulated radiotherapy alone in patients with stage II nasopharyngeal carcinoma
2023, Oral Oncology
To develop and validate a prognostic nomogram based on MRI-detected features of retropharyngeal and cervical lymph nodes and Epstein–Barr virus (EBV) DNA in patients with stage II nasopharyngeal carcinoma (NPC) to distinguish low-risk patients for whom intensity-modulated radiotherapy (IMRT) alone is sufficient.
This retrospective study enrolled 894 patients with stage II NPC (596 and 298 in the training and validation cohorts, respectively) with pretreatment MRI between August 2010 and May 2019. All patients received IMRT with or without additional chemotherapy. We identified independent risk factors using univariate and multivariate Cox regression analyses. Survival was compared using Kaplan–Meier curves with the log-rank test.
Independent factors derived from the multivariate analysis include cervical nodal necrosis (CNN), the extracapsular spread (ECS) of cervical and retropharyngeal lymph nodes, and gamma-glutamyl transferase (γ-GGT). Nomograms A, B, and C were established based on the clinical [tumor-node-metastasis (TNM) stage + Epstein–Barr virus (EBV) DNA], the clinical-radiological [all independent predictors] and the combined models [the clinical-radiological model + EBV DNA], respectively. Nomogram C (C-index 0.769 [0.718–0.820]) demonstrated better risk discrimination than nomogram B (0.762 [0.715–0.809]), nomogram A (0.619 [0.564–0.674]), and the TNM stage (0.560 [0.509–0.611]). In the low-risk group divided by nomogram C, no significant survival differences were observed between patients treated with radiotherapy (RT) alone and other regimens including additional chemotherapy.
The nomogram combining MRI-detected retropharyngeal and cervical lymph node features with pretreatment EBV-DNA improved the prognostic risk stratification for stage II NPC.
Role of chemotherapy in patients with nasopharynx carcinoma treated with radiotherapy (MAC-NPC): an updated individual patient data network meta-analysis
2023, The Lancet Oncology
The meta-analysis of chemotherapy for nasopharynx carcinoma (MAC-NPC) collaborative group previously showed that the addition of adjuvant chemotherapy to concomitant chemoradiotherapy had the highest survival benefit of the studied treatment regimens in nasopharyngeal carcinoma. Due to the publication of new trials on induction chemotherapy, we updated the network meta-analysis.
For this individual patient data network meta-analysis, trials of radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma that completed accrual before Dec 31, 2016, were identified and updated individual patient data were obtained. Both general databases (eg, PubMed and Web of Science) and Chinese medical literature databases were searched. Overall survival was the primary endpoint. A frequentist network meta-analysis approach with a two-step random effect stratified by trial based on hazard ratio Peto estimator was used. Global Cochran Q statistic was used to assess homogeneity and consistency, and p score to rank treatments, with higher scores indicating higher benefit therapies. Treatments were grouped into the following categories: radiotherapy alone, induction chemotherapy followed by radiotherapy, induction chemotherapy without taxanes followed by chemoradiotherapy, induction chemotherapy with taxanes followed by chemoradiotherapy, chemoradiotherapy, chemoradiotherapy followed by adjuvant chemotherapy, and radiotherapy followed by adjuvant chemotherapy. This study is registered with PROSPERO, CRD42016042524.
The network comprised 28 trials and included 8214 patients (6133 [74·7%] were men, 2073 [25·2%] were women, and eight [0·1%] had missing data) enrolled between Jan 1, 1988, and Dec 31, 2016. Median follow-up was 7·6 years (IQR 6·2–13·3). There was no evidence of heterogeneity (p=0·18), and inconsistency was borderline (p=0·10). The three treatments with the highest benefit for overall survival were induction chemotherapy with taxanes followed by chemoradiotherapy (hazard ratio 0·75; 95% CI 0·59–0·96; p score 92%), induction chemotherapy without taxanes followed by chemoradiotherapy (0·81; 0·69–0·95; p score 87%), and chemoradiotherapy followed by adjuvant chemotherapy (0·88; 0·75–1·04; p score 72%), compared with concomitant chemoradiotherapy (p score 46%).
The inclusion of new trials modified the conclusion of the previous network meta-analysis. In this updated network meta-analysis, the addition of either induction chemotherapy or adjuvant chemotherapy to chemoradiotherapy improved overall survival over chemoradiotherapy alone in nasopharyngeal carcinoma.
Institut National du Cancer and Ligue Nationale Contre le Cancer.
Long-term results of the phase II dose and volume de-escalation trial for locoregionally advanced nasopharyngeal carcinoma
2022, Oral Oncology
Patients with locoregionally advanced nasopharyngeal carcinoma (LANPC) were assigned to dose and volume de-escalated intensity-modulated radiation therapy (IMRT) based on response to induction chemotherapy (IC) to limit treatment related toxicity while preserving efficacy.
A single-arm de-escalated phase II trial was performed in this study. Patients with LANPC received two cycles of IC with docetaxel 60 mg/m² d1, cisplatin 25 mg/m²/day d1-3 and 5-fluorouracil 500 mg/m²/day d1-5 q21d, followed by IMRT. The gross tumor volume of the primary intracavity nasopharyngeal tumor and involved lymph nodes were delineated based on the post-IC tumor extension. Part of the prescribed doses were reduced from 70.4 Gy to 66 Gy for T3-4 diseases. The primary end point was 5-year progression-free survival (PFS) in stage III and IVA-B NPC compared with historical controls of 50% and 35%.
Between January 2010 and November 2013, 48 and 83 eligible patients with stage III and IVA-B NPC were accrued to this trial. With a median follow-up of 92 months, the 5-year and 8-year estimated PFS were 89.6% and 76.0%, 63.9% and 58.0% for patients with stage III and IVA-B disease, which were all improved in comparison with historical controls. Grade 3 acute mucositis were developed in 27.5% patients. Cranial neuropathy and asymptomatic temporal lobe necrosis were found in 2.3% and 1.5% patients.
Dose and volume de-escalated IMRT was associated with high PFS and mild late neurological toxicities for IC responders. Further exploration of de-escalation strategies in appropriate patients is needed.
Clinical trial registration: Clinical trials.gov identifier: NCT03389295.
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A complete list of the members of the MAC-NPC Collaborative Group is provided in the Appendix.

Supported by the Institut Gustave-Roussy, Aventis, Sanofi-Synthelabo, and Schering-Plough who had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The authors had full access to all the data and are fully responsible for the decision to submit the paper for publication.

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Clinical investigationHead and neckChemotherapy in locally advanced nasopharyngeal carcinoma: An individual patient data meta-analysis of eight randomized trials and 1753 patients

Introduction

Section snippets

Methods and materials

Trial selection

Discussion

Conclusion

Acknowledgments

Lancet

Lancet

Lancet Oncol

Controlled Clin Trials

Lancet

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Chemotherapy in advanced nasopharyngeal cancer

Oncology (Huntingt)

Chemotherapy for nasopharyngeal carcinoma (Protocol for a Cochrane Review)

The Cochrane Library, Issue 3

Prophylactic cranial irradiation for patients with small cell lung cancer in complete remissionA meta-analysis of individual data from 987 patients

N Engl J Med

Chemo-radiotherapy versus radiotherapy alone for nasopharyngeal carcinomaA meta-analysis of 78 randomized controlled trials (RCTs) from English and non-English databases

J Clin Oncol

Treatment of early breast cancer. Volume 1: Worldwide evidence, 1985–1990

Quantifying heterogeneity in a meta-analysis

Stat Med

Chemotherapy in non-small cell lung cancerA meta-analysis using updated individual patient data from 52 randomised clinical trials

BMJ

Clinical investigation
Head and neck
Chemotherapy in locally advanced nasopharyngeal carcinoma: An individual patient data meta-analysis of eight randomized trials and 1753 patients