Induction chemotherapy plus concurrent chemoradiotherapy ... · 2 . for Cancer Medicine, People’s Republic of China. 3 Division of Radiation Oncology, National Cancer Centre, Singapore

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Title page

Induction chemotherapy plus concurrent chemoradiotherapy in endemic

nasopharyngeal carcinoma: individual patient data pooled analysis of four

randomized trials

Running title: Pooled analysis of IC + CCRT for NPC

Authors list: Yu-Pei Chen, M.D.,1* Ling-Long Tang, M.D.,

1* Qi Yang, M.D.,

2,*

Sharon-Shuxian Poh, M.D.,3* Edwin P Hui, M.D.,

4* Anthony TC Chan, M.D.,

4

Whee-Sze Ong, MAppStats,5 Terence Tan, FRCR,

3 Joseph Wee, FRCR,

3 Wen-Fei Li,

M.D.,1 Lei Chen, M.D.,

1 Brigette BY Ma, M.D.,

4 Macy Tong, FRCR,

4 Sze-Huey Tan,

Ph.D.,5 Shie-Lee Cheah, FRCR,

3 Kam-Weng Fong, FRCR,

3 Kiattisa Sommat,

FRCR,3 Yoke Lim Soong, FRCR,

3 Ying Guo, M.D.,

6 Ai-Hua Lin, M.D.,

7 Ying Sun,

M.D., Ph.D.,1 Ming-Huang Hong, M.D.,

2 Su- Mei Cao, M.D.,

2† Ming-Yuan Chen,

M.D.,2†

AND Jun Ma, M.D.1†

Affiliations list:

1 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State

Key Laboratory of Oncology in South China, Collaborative Innovation Center for

Cancer Medicine, People’s Republic of China

2 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center,

State Key Laboratory of Oncology in South China, Collaborative Innovation Center

Research. on July 3, 2020. © 2018 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on February 5, 2018; DOI: 10.1158/1078-0432.CCR-17-2656

http://clincancerres.aacrjournals.org/

2

for Cancer Medicine, People’s Republic of China

3 Division of Radiation Oncology, National Cancer Centre, Singapore

4 Partner State Key Laboratory of Oncology in South China, Sir Y K Pao Centre for

Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute and Prince of

Wales Hospital, The Chinese University of Hong Kong

5 Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre,

Singapore

6 Clinical Trials Centre, Sun Yat-sen University Cancer Centre, State Key Laboratory

of Oncology in South China, Collaborative Innovation Centre of Cancer Medicine,

Guangzhou, People’s Republic of China

7 Department of Medical Statistics and Epidemiology, School of Public Health, Sun

Yat-sen University, Guangzhou, People’s Republic of China

* These authors contributed equally to this work.

†Corresponding authors:

Jun Ma, Department of Radiation Oncology, Sun Yat-sen University Cancer Center,

State Key Laboratory of Oncology in South China, Collaborative Innovation Center

of Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, People’s

Republic of China.

Tel.:+86-20-87343469; Fax:+86-20-87343295

E-mail: [email protected]



mailto:[email protected]


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Ming-Yuan Chen, Department of Nasopharyngeal Carcinoma, Sun Yat-sen

University Cancer Center, State Key Laboratory of Oncology in South China,

Collaborative Innovation Center of Cancer Medicine, 651 Dongfeng Road East,

Guangzhou 510060, People’s Republic of China.

Tel.:+86-20-87343469; Fax:+86-20-87343295


Su-Mei Cao, Department of Nasopharyngeal Carcinoma, Sun Yat-sen University

Cancer Center, State Key Laboratory of Oncology in South China, Collaborative

Innovation Center of Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060,

People’s Republic of China.

Tel.:+86-20-87343469; Fax:+86-20-87343295


Key words: Induction chemotherapy; Concurrent chemoradiotherapy;

Nasopharyngeal carcinoma; Pooled analysis; Randomized controlled trial

Acknowledgements

We thank the anonymous reviewers and editors for their insightful comments and great

efforts to improve this manuscript. We thank the Clinical Trials Centre, Sun Yat-sen

University Cancer Centre, for assistance with data interpretation.






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Grant Support

This work was supported by grants from the National Science & Technology Pillar

Program during the Twelfth Five-year Plan Period (2014BAI09B10), the Natural

Science Foundation of Guang Dong Province (2017A030312003), the National Key

R&D Program of China (2016YFC0902000), the National Natural Science Foundation

of China (81572658), the Innovation Team Development Plan of the Ministry of

Education (No. IR_17R110), and the Overseas Expertise Introduction Project for

Discipline Innovation (111 Project, B14035).

Conflict of Interest Statement

We declare that we have no conflicts of interest.

Word count: 3680

The total number of tables: 1

The total number of figures: 5




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Translational Relevance

Due to uneven geographical distribution and small number of randomized trials

available, the value of additional induction chemotherapy (IC) to concurrent

chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains

controversial. We performed an individual patient data (IPD) pooled analysis of four

randomized trials from endemic regions to comprehensively evaluate the precise role

of IC+CCRT in locoregionally advanced NPC. Our results indicate the benefits

associated with IC+CCRT versus CCRT alone, including significant improvements in

progression-free survival (PFS) and overall survival (OS), and a reduction in distant

failure; the benefit of IC did not differ among specific patient subgroups. No

statistically significant differences in survival between different IC regimens were

detected. This IPD pooled analysis demonstrate the superiority of additional IC over

CCRT alone in locoregionally advanced NPC, with the survival benefit mainly

associated with improved distant control. IC+CCRT may represent a promising

strategy for NPC in the era of intensity-modulated radiotherapy.




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Abstract

Purpose: Due to uneven geographical distribution and small number of randomized

trials available, the value of additional induction chemotherapy (IC) to concurrent

chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) remains

controversial. This study performed an individual patient data (IPD) pooled analysis

to better assess the precise role of IC+CCRT in locoregionally advanced NPC.

Experimental Design: Four randomized trials in endemic areas were identified,

representing 1,193 patients; updated IPD were obtained. Progression-free survival

(PFS) and overall survival (OS) were the primary and secondary end-points,

respectively.

Results: Median follow-up was 5.0 years. The hazard ratio (HR) for PFS was 0.70 (95%

CI, 0.56-0.86; P = 0.0009; 9.3% absolute benefit at 5 years) in favor of IC+CCRT

versus CCRT alone. IC+CCRT also improved OS (HR 0.75, 95% CI 0.57-0.99, P =

0.04) and reduced distant failure (HR 0.68, 95% CI 0.51-0.90; P = 0.008). IC+CCRT

had a tendency to improve locoregional control compared with CCRT alone (HR,

0.70; 95% CI, 0.48-1.01; P = 0.06). There was no heterogeneity between trials in any

analysis. No interactions between patient characteristics and treatment effects on PFS

or OS were found. After adding two supplementary trials to provide a more

comprehensive overview, the conclusions remained valid and were strengthened. In a

supplementary Bayesian network analysis, no statistically significant differences in

survival between different IC regimens were detected.

Conclusion: This IPD pooled analysis demonstrate the superiority of additional IC




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over CCRT alone in locoregionally advanced NPC, with the survival benefit mainly

associated with improved distant control.




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Introduction

Nasopharyngeal carcinoma (NPC) is a squamous-cell carcinoma with a unique,

unbalanced endemic distribution, with an especially high prevalence in east and

southeast Asia (1). Non-keratinizing (World Health Organization [WHO] types 2 and

3) constitutes most cases of NPC in endemic areas (>95%), whereas keratinizing

disease (type 1) is more common in other regions of the world (1, 2). Unlike other

head and neck cancers, radiotherapy (RT) is the primary treatment modality for

non-disseminated NPC due to its anatomic location and radiosensitivity. The

introduction of intensity-modulated radiotherapy (IMRT) substantially improved

locoregional control, and distant metastasis is now the major pattern of treatment

failure in locoregionally advanced NPC (3).

In recent decades, numerous trials have investigated the value of adding

chemotherapy to RT in NPC. Concurrent chemoradiotherapy (CCRT) is now the

standard treatment for locoregionally advanced disease (1, 4); the updated

Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC)

demonstrated CCRT with or without adjuvant chemotherapy (AC) was related to a 5

year survival benefit of 5-12% (5). However, the efficacy of AC after CCRT remains

uncertain, and our latest phase 3 trial observed no significant benefit for CCRT + AC

compared to CCRT alone (6). Moreover, the toxic effects and the low rate of

compliance to AC also need to be taken into account (4). Compared to AC, induction

chemotherapy (IC) offers the advantages of better tolerability and early eradication of

micrometastases (7), thus sequential IC followed by CCRT may represent a promising




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strategy for NPC in the IMRT era.

Though four reported randomized controlled trials (RCTs) have compared IC +

CCRT versus CCRT alone in the endemic area, their conclusions remain controversial.

A trial at the Prince of Wales Hospital (PWH), Hong Kong, compared induction

docetaxel and cisplatin (TP) followed by CCRT with CCRT alone in stage III-IVB

NPC, and found IC significantly improved 3-year overall survival (OS) and had a

non-significant effect on progression-free survival (PFS) (8). The National Cancer

Centre Singapore (NCCS) trial adopted gemcitabine, carboplatin and paclitaxel (GCP)

IC, and no significant differences in survival or distant control were observed between

the IC + CCRT and CCRT alone arms (9). Recently, two multicenter phase 3 trials

from Guangzhou (GZ) have been reported: the GZ2008 trial found cisplatin and

fluorouracil (PF) IC significantly improved disease-free survival, with a marginally

significant effect on distant control (10), while the GZ2011 trial found TPF IC

improved failure-free survival, OS and distant control in locoregionally advanced

NPC (11). Recent meta-analyses by the MAC-NPC Collaborative Group did not show

IC + CCRT had obvious superiority over CCRT alone (5, 12). However, these studies

included trials reported before 2013; thus they could not confirm the value of IC +

CCRT considering new RCTs reported in recent years.

Therefore, these controversial results highlight the need to determine whether the

addition of IC to CCRT provides any additional benefit in NPC. Given the paucity of

studies and potentially insufficient power to detect small improvements in the specific

end-points of each trial, the investigators of the four endemic trials launched an




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individual patient data (IPD) pooled analysis. We aimed to better determine the

efficacy, compliance rates and toxicity, as well as treatment interactions within

specific patient subgroups, of adding IC to CCRT in locoregionally advanced NPC. To

our knowledge, this is the first IPD analysis to provide a comprehensive overview of

the precise role of additional IC in NPC.

Materials and Methods

Study selection

We searched PubMed and EMBASE for RCTs in NPC using “nasopharyngeal

neoplasms,” “nasopharyngeal tumors” and “nasopharyngeal cancers” as keywords

and “clinical trials” or “randomized controlled trial” as limits; the search was

supplemented by searching the bibliographies of the retrieved articles. The final

search date was June 24, 2017. To be eligible, trials had to be from endemic regions as

indicated by Chua and colleagues (e.g., east and southeast Asia, etc.) (13), have a

randomized design, include patients with non-metastatic NPC treated with definitive

conventional fractionated radiotherapy, and had to compare IC followed by CCRT

with CCRT alone.

The selection process is shown in Supplementary Figure S1. Eventually, four

RCTs were found to be eligible for this study: the PWH, NCCS, GZ2008 and GZ2011

trials (8-11). During the search process, we identified two other trials that assessed IC

followed by CCRT: one was conducted in an non-endemic area (the Hellenic

Cooperative Oncology Group [HeCOG] trial) (14), and the other compared IC +




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CCRT with CCRT + AC (the NPC0501 trial) (15). These two RCTs were included in

supplementary analysis to provide a more comprehensive overview of the role of

additional IC.

Data collection

For the eligible RCTs, an updated IPD was established for patient and tumor

characteristics, treatment details, date of randomization, failure and death, pattern of

failure, cause of death, and adverse events during treatment. The studies were

conducted in compliance with the Declaration of Helsinki and local regulatory

requirements. Written informed consent was obtained from all patients; this study was

approved by the ethics committee or institutional review boards at each institution.

We examined the randomization process and intention-to-treat basis for each trial.

Randomization was assessed by checking the methods used and balance between

baseline characteristics. Patient follow-up was also compared between treatment

groups in each trial (16). The analyses were sent to the investigators for review and

validation, and all discrepancies were discussed by the investigators to reach

consensus.

For the two RCTs included in the supplementary analysis, we reviewed the

associated articles and previous IPD meta-analysis on NPC (5, 14, 15), then

summarized the trial characteristics and extracted survival data (obtained directly or

using the methods detailed by Parmar et al. (17)). We also assessed the quality of

these trials with respect to randomization and the intention-to-treat principle.




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Outcomes

The primary end-point was PFS, calculated from date of randomization to

locoregional failure, distant failure or death from any cause, whichever occurred first.

The secondary end-points were OS, distant control (DC), locoregional control (LRC),

and cancer and non-cancer deaths. OS was calculated from date of randomization to

date of death from any cause. DC and LRC were defined as the time from

randomization to the occurrence of distant or locoregional failure, respectively.

Patients with locoregional failure as a first event were censored for distant failure, and

vice versa. If both distant failure and locoregional failure occurred at the same time,

patients were considered to have a distant failure event only. Patients without distant

and locoregional failure were censored at the date of death or last follow-up if still

alive. Persistent primary/nodal disease was classified as locoregional failure.

Surviving patients without any event for all end-points were censored at date of last

follow-up. Deaths attributed to known causes other than NPC for patients with no

reported progression were defined as non-cancer deaths. All other deaths were defined

as cancer deaths, including deaths from NPC, deaths from any cause in patients with

previous progression and deaths from unknown causes. This definition has been

adopted by the MAC-NPC Collaborative Group (5), as it prevents underestimation of

deaths related to cancer and is less biased than other methods (18).

Statistical analysis

We performed analysis based on the intention-to-treat principle. Survival analyses




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were stratified by trial; the observed minus the expected number of deaths (O-E) and

its variance was used to calculate individual and overall pooled hazard ratios (HRs)

using a fixed effect model (17). Heterogeneity across trials was examined using the χ2

test and I2 statistic (19). Statistically significant heterogeneity was defined as a χ

2

P-value < 0.1 or an I2 statistic > 50%. If obvious heterogeneity existed, the

Dersimonian and Laird random effects model was adopted (20).

Median follow-up was calculated via the reverse Kaplan-Meier method (21). The

estimated Kaplan-Meier survival curves for the two treatment groups were plotted

(22), and the absolute benefits at 3 and 5 years and 95% confidence intervals (CIs)

were calculated (18). The interactions between treatment effect and patient subgroups

(i.e., sex, age, tumor category, nodal category, clinical stage, and radiotherapy

technique) were estimated with an interaction test, by adopting a single Cox model

stratified by trial and containing treatment effect, covariate (e.g., sex) effect, and

treatment–covariate interaction (one-stage model method) (23). An insignificant P

value in the interaction test indicates the effect in the experimental arm versus control

arm did not differ among that specific covariate group.

A supplementary analysis of PFS and OS between the experimental and control

groups was performed, including both the eligible and supplementary RCTs.

Moreover, to compare the potential differences in efficacy between different IC

regimens, we performed a supplementary Bayesian network analysis including all six

trials. The network analysis within a Bayesian framework using Markov chain Monte

Carlo methods were built using the model proposed by Woods and colleagues (24);




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treatment effects were estimated by posterior means with corresponding 95% credible

intervals (CrIs) (25). The fixed effects model was adopted as it resulted in lower

deviance information criterion (DIC) statistics (DIC provides a measure of model fit

that penalizes model complexity, with lower values suggesting a simpler model) (26).

We did not assess the probability of treatment ranking as it could be produced even

without clear statistical meaning, which is misleading; detailed methods have been

described in our previous study (4). All tests were two-sided. Statistical analyses were

performed using STATA version 12.0 (Stata Corporation, College Station, TX, USA)

and WinBUGS 1.4.3 (MRC Biostatistics Unit, Cambridge, UK).

Results

Trial and patient characteristics

Table 1 summarizes the key features of the PWH, NCCS, GZ2008, and GZ2011 trials.

With respect to the intention-to-treat principle, all randomized patients in all four

trials were analyzed; data was not available for only eight patients in the NCCS trial,

who were either found ineligible on retrospective review or withdrew before receiving

treatment. Overall, a total of 1,193 patients were included in the current analysis, with

599 and 594 patients allocated to the IC + CCRT and CCRT arms, respectively. None

of the four trials demonstrated unbalanced baseline characteristics between treatment

arms. The median follow-up was 5.0 years; no major bias appeared between treatment

arms in any trial as indicated by the reverse Kaplan-Meier curves. All trials recruited

patients with WHO histological type 2 or 3 NPC. The patient characteristics for the




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four eligible trials are summarized in Supplementary Table S1 and the two

supplementary trials are described in Supplementary Table S2.

Efficacy of IC + CCRT versus CCRT

The disease status and patterns of failure are summarized in Supplementary Table S3.

Overall, 208/1,193 (17%) patients died and 311/1,193 (26%) patients experienced

disease progression. IC + CCRT improved PFS compared to CCRT alone (HR, 0.70;

95% CI, 0.56-0.86; P = 0.0009; from 64.6% to 73.9% at 5 years] (Fig. 1A; Fig. 2A).

IC + CCRT also improved OS, with an HR of death of 0.75 (95% CI, 0.57 to 0.99; P

= 0.04) and 5.5% improvement at 5 years (Fig. 1B; Fig. 2B).

IC + CCRT was associated with a significantly lower rate of distant failure than

CCRT alone (HR, 0.68; 95% CI, 0.51-0.90; P = 0.008; absolute reduction from 84.8%

to 78.3% at 5 years) (Fig. 1C; Fig. 2C). No significant difference in locoregional

control was observed between IC + CCRT and CCRT alone, though IC + CCRT had a

tendency to improve LRC (HR, 0.70; 95% CI, 0.48-1.01; P = 0.06; Fig. 1D; Fig. 2D).

To confirm whether the results were sensitive to the choice of a fixed effects model as

opposed to a random effects model, we also calculated pooled HRs and corresponding

95% CIs using the random effects model. The results were the same as those

calculated with the fixed effects model. This is not surprising as the I2 statistic

(defined as variation in effect size attributable to heterogeneity) was equal to 0% for

all end-points (Fig. 1), which means no variation attributable to heterogeneity was

detected, and effect size was not affected by the model used.




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In total, 193 (16%) cancer deaths and 15 (1%) non-cancer deaths occurred. IC +

CCRT tended to reduce the risk of death, with an absolute difference of 4.8% (from

20.1% to 15.3%) at 5 years; there was no obvious difference in non-cancer deaths

between the two arms (Fig. 3).

Treatment compliance and toxicity

Of the 599 patients randomized to the IC + CCRT arm, 578 (96%) received at least

one cycle of IC, and 542 (90%) received IC as planned despite relatively lower

compliance to the TPF regimen (88%; Supplementary Table S4). In total, 566/599

(94%) patients in the IC + CCRT arm and 564/594 (95%) in the CCRT arm initiated

concurrent chemotherapy. Compliance to concurrent chemotherapy was significantly

different between arms: more patients completed at least five/two cycles (if

eight/three cycles were planned) of concurrent chemotherapy in the CCRT arm than

the IC + CCRT arm (92% vs. 87%). No obvious differences in the numbers of

patients starting and completing RT were observed between the IC + CCRT and

CCRT alone arms.

Supplementary Table S5 summarizes the major grade 3-4 adverse events. During

IC, the most common toxic effect was neutropenia (35%), followed by leukopenia

(20%). Other toxicities were not common, with incidences lower than 10%. During

CCRT, adverse events were similar between the two arms, though the IC + CCRT

arm experienced significantly higher rates of grade 3 or 4 leukopenia (26% vs. 21%;

P = 0.03) and neutropenia (15% vs. 9%; P = 0.003).




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Subgroup analyses for PFS and OS

No significant heterogeneity was observed between trials for any end-point. In order

to determine whether the treatment effect of IC + CCRT versus CCRT alone differs

among specific covariate groups, we performed subgroup analyses for PFS and OS in

patients stratified by the following characteristics (covariates): sex (male, female), age

(< 40, 40-59, ≥ 60), tumor category (T1-2, T3-4), nodal category (N0-1, N2-3),

clinical stage (III, IV), and RT technique (2D-RT, IMRT). No interactions between

these covariates and treatment were observed (all P > 0.1; Fig. 4), which means the

benefit of additional IC did not differ among specific populations. However,

considering the oldest subgroup had relatively few patients, large-scale studies are

warranted to assess the benefit of IC in older patients.

Supplementary analyses

When the two supplementary trials (14, 15) were added to the pooled analysis, the

conclusions remained valid: compared to CCRT ± AC, IC + CCRT improved both

PFS (HR, 0.72; 95% CI, 0.60-0.85; P = 0.0002) and OS (HR, 0.77; 95% CI, 0.62-0.97;

P = 0.02) in locoregionally advanced NPC (Supplementary Fig. S2). Supplementary

Bayesian network analysis was performed to help identify potential differences in the

efficacy of different IC regimens. Supplementary Figure S3 shows the network

established for PFS and OS. Figure 5 summarizes the results of multiple treatment

comparisons; probably due to the lack of relevant trials, no significant differences




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were detected between the different IC regimens. Still, it should be noted that

compared with no IC, only TPF regimen significantly improved both PFS [HR, 0. 70;

95% credible intervals (CrIs), 0.49-0.95] and OS (HR, 0.59; 95% CrI, 0.37-0.92),

suggesting TPF IC may be more effective.

Discussion

This IPD pooled analysis of patients from endemic regions shows the benefits

associated with the use of IC followed by CCRT in locoregionally advanced NPC,

including significant improvements in PFS and OS and a reduction in distant failure.

The absence of interactions between patient characteristics and treatment effects

indicates the benefit of additional IC does not differ among specific populations. The

efficacy of IC + CCRT remained valid and was even strengthened after adding the

supplementary trials, further supporting the conclusions.

Recently, the MAC-NPC Collaborative Group reported no significant differences

between IC + CCRT and CCRT alone with respect to treatment outcomes in NPC in a

network meta-analysis, though additional IC tended to improve distant control (12).

However, this study included trials reported before 2013 and did not include trials

using new IC regimens (e.g., GCP, TPF). Considering the publication of new trials in

recent years, we conducted this pooled analysis to confirm the role of IC followed by

CCRT. We primarily focused on trials conducted in endemic regions. In the original

trial reports, the PWH trial found additional IC significantly increased 3-year OS from

68% to 94%, but failed to detect a significant improvement in PFS (despite an




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obvious trend) (8). The NCCS trial observed a small but insignificant increase in

3-year OS, disease-free survival and distant metastasis-free survival (the absolute

differences were 2%, 8%, and 4%, respectively) (9). The multicenter GZ2008 trial

observed an 8% improvement in 3-year disease-free survival and a marginally

significant increase in distant metastasis-free survival (4% improvement), but no early

OS benefit (10). The GZ2011 trial detected 8% and 6% improvements in 3-year

failure-free survival and OS after IC (both P = 0.03), respectively (11). Combination

of IPD from these four trials enabled a more precise and comprehensive estimation of

the magnitude of the benefits provided by IC + CCRT compared with CCRT alone.

The results of this study demonstrate the superiority of additional IC over CCRT

alone in terms of PFS and OS, with the survival benefit mainly associated with

improved distant control. Considering the wide-spread use of IMRT, it is not

surprising that no significant improvement in locoregional control was observed. To

further validate the conclusions, we included two additional trials (HeCOG and

NPC0501 trials) in the supplementary analysis. The superior efficacy of IC + CCRT

versus CCRT alone remained unchanged, and no heterogeneity was observed.

Considering the varied regimens used for IC, these conclusions should be interpreted

with caution; to provide more information on the efficacy of different IC regimens,

we further conducted a supplementary Bayesian network analysis. Though no

statistically significant differences in PFS or OS between different IC regimens were

detected, the results may favor TPF over other regimens. The efficacy of adding

docetaxel to the PF induction regimen has been demonstrated in locally advanced




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head and neck cancers via large-scale phase 3 trials and IPD pooled analysis (27-29).

The unobvious superiority of one IC regimen over others may be result of a lack of

trials directly comparing different IC regimens. Though TPF has the potential to be a

better choice in IC for NPC, it is still of great significance to identify the optimal IC

regimen. The gemcitabine-based IC regimen may also be effective, as it provides a

significant advantage in advanced NPC (30). Several trials (NCT01872962 and

NCT02512315) are being undertaken to assess other IC regimens, such as

gemcitabine plus cisplatin, and this data should be publicly available in the near future.

Moreover, further trials are required to directly compare different IC regimens.

Compliance to IC was satisfactory, about 90% of patients completed their planned

cycles despite the relatively lower compliance to TPF (88%). During CCRT,

relatively fewer patients in the IC + CCRT arm completed more than half of their

planned cycles of concurrent cisplatin compared to the CCRT alone arm (87% vs.

92%), probably due to patient refusal and treatment toxicities (11). Overall,

compliance to IC and CCRT was satisfactory compared to that of locally advanced

head and neck cancers (about 80% of patients received IC as planned, with about 40%

being able to receive concomitant chemotherapy, and about 70% starting planned RT),

which could promote the clinical use of additional IC in NPC (29). The major grade 3

and 4 toxicities in the IC + CCRT arm were leukopenia (26%), mucositis (24%),

neutropenia (15%), vomiting (12%) and nausea (11%), which were manageable and

reversible; with the exception of leukopenia and neutropenia, adverse events were

similar between arms. Moreover, no obvious differences in deaths due to toxicities




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were observed between groups, further reflecting the acceptable toxicity of additional

IC.

The strengths of this pooled analysis are related to its size and its use of the IPD

that allowed re-analysis of each trial (e.g., standardized multiple end-points).

Nevertheless, we should state the limitations of this analysis. First, these trials

included different IC regimens. However, all regimens were platinum-based, and no

heterogeneity was observed for any end-points. Second, we should be cautious when

interpreting OS benefits. For some of the trials included, the failure to achieve a

significant increase in OS may be explained by a high salvage rate, which dilutes the

OS benefit, or relatively small sample sizes. With increased statistical power, our IPD

analysis could help to detect a significant improvement in OS. Still, whether

additional IC could provide a long-term OS benefit needs to be explored further when

more trials with long-term follow-up results are available. However, the MAC-NPC

Collaborative Group recently demonstrated that PFS and DC were valid surrogate

end-points for OS (31). Thus, considering the significant improvements in PFS and

DC observed for IC+CCRT, additional IC may also provide a long-term survival

benefit. Third, considering the uneven geographical distribution of NPC and the small

number of RCTs available, we also included the HeCOG trial (from a non-endemic

area) and NPC0501 trial (which also included adjuvant chemotherapy) in the

supplementary analyses, which may cause potential bias. Still, the conclusions

remained valid after including these supplementary trials, with no heterogeneity

detected. The supplementary analyses help to provide a more comprehensive




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overview of the value of IC+CCRT in NPC.

The National Comprehensive Cancer Network (NCCN) currently recommends

CCRT + AC for locoregionally advanced NPC (Category 2A); CCRT alone is also an

option (Category 2B) (32). IC + CCRT is recommended as a Category 3 option.

According to the European Society for Medical Oncology (ESMO), platinum-based

IC can be considered for locally advanced disease, but in no case should it negatively

affect the administration of CCRT (33). This updated IPD pooled analysis provides

important information to clarify the precise value of IC + CCRT in NPC. Our study

highlights the importance of identifying high risk patient groups that may benefit most

from IC + CCRT; certain biomarkers such as plasma Epstein-Barr virus (EBV) DNA

load may be helpful for participant selection (NCT02135042). In the future when data

from other trials is available, the MAC-NPC Collaborative Group could provide a

more comprehensive overview to help better understand the optimal treatment

modality for NPC.

In conclusion, this IPD pooled analysis indicates the benefits associated with the

addition of IC to CCRT in locoregionally advanced NPC; the precise value of IC in

specific patient subgroups and the optimal regimens still need further assessment.

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Figure legends

Figure 1. Forest plots for (A) progression-free survival, (B) overall survival, (C)

distant control and (D) locoregional control. The estimated hazard ratio (HR) for each

individual trial is indicated by the center of the squares and the horizontal line

indicates the 95% confidence interval (CI). The closed diamonds show the overall HR

and 95% CI. HR < 1 and 95% CI excluding 1 indicate improved survival/control for

the experimental versus control arm. A fixed effect model was used. CCRT,

concurrent chemoradiotherapy; GZ, Guangzhou; IC, induction chemotherapy; NCCS,

National Cancer Centre Singapore; O-E, observed minus expected deaths or events;

PWH, Prince of Wales Hospital.

Figure 2. Survival curves for (A) progression-free survival, (B) overall survival, (C)

distant control and (D) locoregional control. CCRT, concurrent chemoradiotherapy;

IC, induction chemotherapy.

Figure 3. Survival curves for cancer and non-cancer deaths. CCRT, concurrent

chemoradiotherapy; IC, induction chemotherapy.

Figure 4. Effect of IC + CCRT versus CCRT alone on (A) progression-free survival

and (B) overall survival, stratified by patient characteristics. 2D-RT, two-dimensional

radiation therapy; CCRT, concurrent chemoradiotherapy; IC, induction chemotherapy;




29

IMRT, intensity-modulated radiotherapy.

Figure 5. Bayesian network analysis of (A) progression-free survival and (B) overall

survival. Upper triangles denote pooled hazard ratios (HRs); treatments in rows were

compared with those in the columns. Numbers in parentheses indicate the

corresponding 95% CIs. Red numbers indicate the HRs with Bayesian P < 0.05. A

fixed effect model was used. CCRT, concurrent chemoradiotherapy; CEP, cisplatin,

epirubicin and paclitaxel; GCP, gemcitabine, carboplatin and paclitaxel; IC, induction

chemotherapy; PF, cisplatin and fluorouracil; PX, cisplatin and capecitabine; TP,

docetaxel and cisplatin; TPF, TP and fluorouracil.




30

Table 1. Summary of the Four Randomized Controlled Trials Included in the Pooled Analysis

Variable PWH Trial NCCS Trial GZ2008 Trial GZ2011 Trial

Region Hong Kong Singapore Mainland China Mainland China

No. of patients 65 172 476 480

IC + CCRT arm 34 86 238 241

CCRT arm 31 86 238 239

Inclusion period Nov 2002 to Nov 2004 Sep 2004 to Aug 2012 Jun 2008 to Feb 2015 Mar 2011 to Aug 2013

No. of centers 1 1 4 10

Randomization method Central randomization Central randomization Sealed envelopes Sealed envelopes

Stratification Stage (III vs. IV) N stage (N0-1 vs. N2-3) T and N stages (T4N0-1 vs. T1-3N2-3

vs. T4N2-3)

Center, and stage (III vs. IV)

Histology, WHO classification 2-3 2-3 2-3 2-3

Clinical stage III-IVB

(5th AJCC/UICC)

III-IVB

(5th AJCC/UICC)

III-IVB (except T3N0-1)

(6h AJCC/UICC)

III-IVB (except T3-4N0)

(7th AJCC/UICC)

Induction chemotherapy

Regimen TP (2 cycles) GCP (3 cycles) PF (2 cycles) TPF (3 cycles)

Dose Docetaxel 75 mg/m2 d1; cisplatin 75

mg/m2 d1; q3wks

Gemcitabine 1000 mg/m2 d1, d8; carboplatin AUC =

2.5 d1, d8; paclitaxel 70 mg/m2 d1, d8; q3wks

Cisplatin 80 mg/m2 d1; fluorouracil 800

mg/m2 d1-5; q3wks

Docetaxel 60 mg/m2 d1; cisplatin 60

mg/m2 d1; fluorouracil 600 mg/m2

d1-5; q3wks

Concurrent chemotherapy Cisplatin 40 mg/m2 d1, q1wk×8 Cisplatin 40 mg/m2 d1, q1wk×8 Cisplatin 80 mg/m2 d1, q3wks×3 Cisplatin 100 mg/m2 d1, q3wks×3

Radiotherapy*

Technique IMRT (26% of patients), 2D-RT

(74% of patients)

IMRT (98% of patients), 2D-RT (2% of patients) IMRT (43% of patients), 2D-RT (47%

of patients)

IMRT (100% of patients)

Dose 66 Gy (2 Gy/fr) for primary tumor,

residual boost of 7.5 Gy,

IMRT: 69.96 Gy (2.12Gy/fr) for primary tumor and

positive nodes, 60 Gy (1.82 Gy/fr) for negative nodes;

≥ 66 Gy (2–2.33 Gy/fr) for primary

tumor, ≥ 50 Gy for neck lymph nodes

≥ 66 Gy (2–2.27 Gy/fr) for primary

tumor, ≥ 50 Gy for neck lymph nodes




31

parapharyngeal boost of 20 Gy 2D-RT: 70 Gy (2 Gy/fr), for primary tumor and

positive nodes, 60 Gy (2 Gy/fr) for negative nodes

Median follow-up (months) 102 (IQR 97-113) 40 (IQR 25-60) 56 (IQR 40-71) 63 (IQR 56-67)

2D-RT = two-dimensional radiation therapy; AJCC = American Joint Committee on Cancer; AUC = area under the curve; CCRT = concurrent

chemoradiotherapy; fr = fraction; GCP = gemcitabine, carboplatin, and paclitaxel; GZ = Guangzhou; IC = induction chemotherapy; IMRT =

intensity-modulated radiotherapy; IQR = interquartile range; NCCS = National Cancer Centre Singapore; PF = cisplatin and fluorouracil; PWH = Prince of

Wales Hospital; q1wk = every 1 week; q3wks = every 3 weeks; TP = docetaxel and cisplatin; TPF = TP and fluorouracil; UICC = International Union Against

Cancer; WHO = World Health Organization.

* The guideline for radiotherapy is described in details in the primary publications of each trial (8-11).



















Published OnlineFirst February 5, 2018.Clin Cancer Res Yu-Pei Chen, Ling-Long Tang, Qi Yang, et al. pooled analysis of four randomized trials

datain endemic nasopharyngeal carcinoma: individual patient Induction chemotherapy plus concurrent chemoradiotherapy

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Induction chemotherapy plus concurrent chemoradiotherapy ... · 2 . for Cancer Medicine, People’s Republic of China. 3 Division of Radiation Oncology, National Cancer Centre, Singapore