A Bayesian network meta-analysis comparing concurrent chemoradiotherapy followed by adjuvant chemotherapy, concurrent chemoradiotherapy alone and radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma.

Annals of Oncology Advance Access published October 29, 2014 1

A Bayesian network meta-analysis comparing concurrent chemoradiotherapy followed by adjuvant chemotherapy, concurrent chemoradiotherapy alone and radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma

A.H. Lin3, Y. Sun1, J. Ma1 1

State Key Laboratory of Oncology in South China, Department of Radiation

Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China 2

Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People’s

Republic of China 3

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

Yat-sen University, Guangzhou, People’s Republic of China Correspondence to: Prof. Jun Ma, State Key Laboratory of Oncology in South China, Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China. Tel.:+86-20-87343469, Fax:+86-20-87343295, E-mail: [email protected] †

These authors contributed equally to this work.

© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Downloaded from http://annonc.oxfordjournals.org/ at University of California, San Francisco on December 14, 2014

Y.P. Chen1,†, Z.X. Wang2,†, L. Chen1,†, X. Liu1, L.L. Tang1, Y.P. Mao1, W.F. Li1,

2

ABSTRACT Background: Given the lack of studies, whether the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for locoregionally advanced nasopharyngeal carcinoma (NPC) remains unclear. The main objective of this Bayesian network meta-analysis was to determine

Patients and methods: We systematically searched databases and extracted data from randomized controlled trials involving NPC patients randomly assigned to receive CCRT+AC, CCRT, or radiotherapy (RT). Overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) with hazard ratios (HRs) were investigated. A Bayesian network for different outcomes was established to incorporate all evidence. Multiple treatment comparisons based on the network integrated the efficacy of CCRT+AC, CCRT, and RT. Results: Eight studies involving 2144 patients were analyzed. In the network meta-analysis, CCRT+AC and CCRT were both significantly better than RT alone for all outcomes, except that no significant difference was found between CCRT and RT for LRFS. Though ranking probabilities showed that CCRT+AC was ranked superior to CCRT for OS, LRFS and DMFS, no significant differences were found between CCRT+AC and CCRT for all outcomes (OS: HR = 0.86, 95% credible interval [CrI] 0.60–1.16; LRFS: HR = 0.72, 95%CrI 0.43–1.15; DMFS: HR = 0.86, 95%CrI 0.62–1.16).


the efficacy of CCRT+AC as compared with CCRT alone.

3

Conclusions: No significant improvement was found following CCRT+AC compared with CCRT alone. Whether the omission of additional AC can reduce toxic effects without adversely affecting survival in patients with locoregionally advanced NPC should be further explored, in addition to the precise patient status that would benefit from AC following CCRT.

nasopharyngeal carcinoma, network meta-analysis

Key Message: "It remains unclear whether the addition of adjuvant chemotherapy (AC) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). This Bayesian network meta‐analysis shows no significant improvement found following CCRT+AC compared with CCRT alone. Whether omitting additional AC can reduce toxic effects without adversely affecting survival should be further explored."


Key words: concurrent chemoradiotherapy, adjuvant chemotherapy, radiotherapy,

4

Nasopharyngeal carcinoma (NPC) has uneven worldwide distribution and high prevalence in Southeast Asia and North Africa [1]. Radiotherapy (RT) is the primary treatment modality for early-stage patients, but control of locoregionally advanced NPC with RT alone is usually unsatisfactory [2]. Combining chemotherapy and RT is a reasonable strategy for improving the prognosis of locoregionally advanced NPC. A recent meta-analysis [3] showed that concurrent chemoradiotherapy (CCRT) was more beneficial for NPC patients than RT alone, while another meta-analysis showed that neoadjuvant chemotherapy effectively enhanced overall survival (OS) and reduced the distant metastasis rate (DMR), and that adjuvant chemotherapy (AC) aided in improving control of the NPC locoregional recurrence rate (LRR) [4]. The Intergroup 0099 Study (IGS) was the first randomized controlled trial (RCT) to achieve a significant improvement in the 3-year OS for stage III–IVB NPC patients by adding concurrent-adjuvant chemotherapy to conventional RT [5]. Since then, the National Comprehensive Cancer Network (NCCN) has recommended RT with concurrent-adjuvant chemotherapy for locoregionally advanced NPC. However, there


INTRODUCTION

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have been serious concerns regarding the applicability of the IGS results, and the outcomes of several RCTs attempting to verify CCRT+AC efficacy were conflicting [6-13]. Moreover, despite the well-demonstrated efficacy of CCRT for locoregionally advanced NPC, whether adding AC to CCRT is better for locoregionally advanced NPC than CCRT alone has not been confirmed, as we lack trials for direct comparison.

trial comparing CCRT+AC with CCRT alone in endemic area, where short-term evaluation found no significant difference between failure-free survival and OS [14]. Therefore, this network meta-analysis is important because it would provide useful information on comparisons of CCRT+AC, CCRT, and RT by integrating direct and indirect methods to demonstrate the additional value of AC and to verify its efficacy in treating locoregionally advanced NPC. MATERIALS AND METHODS Supplementary material The study inclusion criteria, literature search strategy, quality control and data extraction methods, and associated references are described in the supplementary Methods, available at Annals of Oncology online. Statistical analysis The primary endpoint of our network meta-analysis was OS; the secondary endpoints were locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). The survival endpoint results are expressed as hazard ratios (HRs). Traditional pairwise meta-analyses were conducted first. Details


To the best of our knowledge, our previous reported study is the first head to head

6

on endpoints and direct meta-analysis are described in the supplementary Methods, available at Annals of Oncology online. Estimated survival curves for OS, LRFS and DMFS were plotted using the method detailed by Parmar et al. [15]. To address severe acute toxicities (≥Grade 3), we compared toxicity rates between CCRT and RT with the χ2 test.

random effects model proposed by Woods and colleagues. Treatment effects were estimated by posterior means with corresponding 95% credible intervals (CrIs), which can be interpreted similarly to conventional 95% confidence intervals (CIs). The main difference between the fixed and random effects model is that the latter considers between-study variance, thereby producing wider CrIs, and is preferred in the presence of heterogeneity. We used Bayesian deviance information criterion (DIC) statistics to compare the two models. The DIC provides a measure of model fit that penalizes model complexity, with lower values suggesting a simpler model and differences of 2–5 considered important. The probability of each treatment being the best, second best, and third best was estimated based on its posterior probabilities. The Bayesian network meta-analyses results were compared with pairwise meta-analyses results to evaluate inconsistency. Also, significant inconsistency was indicated if node-splitting analysis derived P < 0.05. Details on methods of Bayesian network meta-analysis and associated references are described in the supplementary Methods, available at Annals of Oncology online. RESULTS


The network meta-analyses were built in WinBUGS. We applied both the fixed and

7

Eligible studies During selection (supplementary Figure S1, available at Annals of Oncology online), we excluded the study by Chen et al. [16] as it involved stage II NPC patients, and excluded the study by Lin et al. [17] for not meeting the eligibility criterion of unpredictable treatment assignment [18]. As Kwong et al. [6] used uracil+tegafur

meta-analysis, but was included in an additional meta-analysis that did not restrict the agents used, and the results are described in the supplementary Results (available at Annals of Oncology online). Thus, 8 studies were considered eligible [5, 7-14, 19-22]. The study by Lee et al. was first published in 2005 [8] and updated in 2010 with the 5-year OS data [9]. The same updates were made to the studies of Lee et al. [10, 11], Chen et al. [12, 13], Chan et al. [19, 20], and Zhang et al. [21, 22]. In the study by Lee et al. [10, 11], patients were divided into four treatment groups: conventional fractionation (CF); CF with concurrent-adjuvant chemotherapy; accelerated fractionation (AF); and AF with concurrent-adjuvant chemotherapy. The benefit of AF has not yet been confirmed [11], and the two groups that were treated with AF were excluded as they did not meet our inclusion criterion for the use of CF. Table 1 lists the baseline characteristics of all included studies. These pooled 8 studies involved 2144 randomly assigned patients: 840 received CCRT+AC, 490 received CCRT, and 814 received RT alone. The OS was available for all trials (to include all 193 available patients in the study by Al-Sarraf et al. [5], we obtained the corresponding observed minus expected number of deaths [O-E] and variance from a


instead of platinum in concurrent chemotherapy, it was excluded from this network

8

previous meta-analysis based on individual patient data [18]). The LRFS and DMFS were available for only 7 studies [7-14, 19-22] (for the study by Chan et al. [19, 20], we could obtain corresponding O-E and variance from the individual patient data meta-analysis [18]). Al-Sarraf et al. reported only the absolute number of locoregional and distant failures of 147 patients [5]; information on the time to event was not

the assessment of the quality of all eligible RCTs. Direct meta-analysis Supplementary Figure S2, available at Annals of Oncology online presents all direct meta-analyses. Compared with RT alone, CCRT+AC (P < 0.0001, HR = 0.64, 95%CI = 0.53–0.76) and CCRT (P = 0.005, HR = 0.66, 95%CI = 0.49–0.88) benefited OS significantly; there was no significant difference between CCRT+AC and CCRT. CCRT+AC was associated with lower locoregional recurrence risk as compared with RT alone (P = 0.01, HR = 0.59, 95%CI = 0.40–0.89); there was no significant difference between CCRT+AC and CCRT, and CCRT and RT alone. There was significantly reduced distant failure in patients who received CCRT+AC (P = 0.002, HR = 0.67, 95%CI = 0.52–0.87) and CCRT (P = 0.02, HR = 0.68, 95%CI = 0.50–0.95) as compared with RT alone. No significant difference in DMFS was found between CCRT+AC and CCRT. There was no between-study effect size heterogeneity in all comparisons for all endpoints. To determine whether excluding the trial by Al-Sarraf et al. [5] would affect our conclusions on locoregional and distant failures, we performed direct meta-analyses of LRR and DMR for CCRT+AC versus RT that


available. Supplementary Table S1, available at Annals of Oncology online describes

9

included that study. The results are expressed as relative risk (RR) with 95%CIs using the Mantel–Haenszel method, and the conclusions remained valid (supplementary Figure S3, available at Annals of Oncology online). Network meta-analysis of efficacy We established a network to compare CCRT+AC, CCRT, and RT alone

summarizes the multiple treatment meta-analyses results for OS, LRFS, and DMFS. The respective sets of HRs and corresponding 95% CrIs from the fixed and random effects models had good consistency despite the relatively wider CrIs of the latter (Figure 1A, 1C, 1E). Moreover, we confirmed good coherence between direct and indirect comparisons for all endpoints; node-splitting analysis indicated no significant inconsistency (all P > 0.05). Based on the DIC (Figure 1A, 1C, 1E), the fixed effects model fit the data better than the random effects model, with relatively lower DIC values for all endpoints (though the differences were all between 1 and 2), indicating that heterogeneity might not be obvious. Furthermore, as both models yielded consistent conclusions, we applied the fixed effects model for the rest of the study. Except the CCRT and RT LRFS, CCRT+AC and CCRT outcomes were both significantly better than RT alone. However, CCRT+AC and CCRT shared equivalent efficacy, and there were no significant differences for all treatment outcomes (OS, LRFS, DMFS) (Figure 1A, 1C, 1E). Figure 1B, 1D, and 1F shows the probability of each treatment being ranked the


(Supplementary Figure S4, available at Annals of Oncology online). Figure 1

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best, second best, and third best, and the cumulative probabilities for the most efficacious treatments were as follows (OS, LRFS, DMFS): CCRT+AC (84%, 90%, 85%), CCRT (16%, 10%, 15%), RT (0%, 0%, 0%). Supplementary Figure S5, available at Annals of Oncology online depicts the estimated survival curves for all endpoints.

Supplementary Table S2, available at Annals of Oncology online summarizes the severe acute toxicities (≥Grade 3) of the studies included in this network meta-analysis. In the initial phase, severe adverse events occurred more often following CCRT compared to RT alone. No significant differences existed between the CCRT+AC and CCRT arms in the initial phase of the study by Chen et al. [14]. In the adjuvant phase, the commonly recorded severe acute toxicities were neutropenia (14.1%), nausea/vomiting (13.4%), leukopenia (13.3%), and mucositis (12.0%). Additional network meta-analysis The additional network meta-analysis results, which included the study by Kwong et al. [6], are described in the supplementary Results, supplementary table S3 and S4, and supplementary Figure S6, S7, and S8, available at Annals of Oncology online. The conclusions remained valid after including the abovementioned study, but there was effect size heterogeneity in the direct comparisons of CCRT+AC versus CCRT for DMFS. DISCUSSION Multiple treatment comparison is a powerful method for investigating RCT


Severe acute toxicities

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networks, and has been used for head and neck squamous cell carcinoma [23]. Our Bayesian network meta-analysis is the first study to compare CCRT+AC, CCRT, and RT efficacy for locoregionally advanced NPC through direct and indirect statistical comparisons based on all available information from the included RCTs. As HR was the only summary statistic allowing for both censoring and time to an event, we

consistency between direct and network meta-analyses of these endpoints. Compared with RT alone, CCRT+AC had a significant treatment effect on OS, LRFS, and DMFS; CCRT had a significant treatment effect on OS and DMFS, but did not improve locoregional control significantly. However, there was no significant difference between CCRT+AC and CCRT for all endpoints, indicating that AC following CCRT did not improve treatment outcome remarkably. All included studies involving AC used the IGS regimen for the adjuvant phase, adopting cisplatin and fluorouracil (PF regimen) as recommended [5]. A phase III study [24] showed that this combination improved the response rate but not the survival rate as compared with either agent individually, indicating that the adjuvant PF regimen may be insufficiently effective for eradicating micrometastases and improving OS in head and neck cancers and NPC. The well-recognized favorable results for CCRT may also have diluted any potential benefit of AC for controlling locoregional recurrence and distant metastases. Moreover, given the acute toxic effects during CCRT, adjuvant therapy compliance was similar (52–61%) and relatively poor in the CCRT+AC RCT [14], which may have affected the efficacy of AC. The actual magnitude of the AC


assessed OS, LRFS, and DMFS with HR and its 95%CI or CrI, confirming good

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survival benefit may also have been reduced due to the toxicities of chemotherapy, possibly successful salvage after relapse, and increased non-cancer deaths [8, 10, 12]. As expected, RT ranked worst for OS, LRFS, and DMFS. As for CCRT+AC and CCRT, the former ranked superior to the latter for all treatment outcomes. However, in network meta-analysis, even if the effect size differences among treatments were

produced without a clear statistical meaning. It would be misleading if clinical decisions regarding the therapeutic regimens selected were mainly dependent on it. In fact, CCRT+AC and CCRT did not differ significantly for all outcomes in our study. Also, it was noteworthy that the survival curves for CCRT+AC and CCRT were gradually separated by a slight difference in approximately the first 2–3 years, but later became relatively smoother and closer, with slightly smaller absolute differences at 5 years than at 3 years (Supplementary Figure S5, available at Annals of Oncology online). This trend may have been due to the more common occurrence of locoregional recurrence and distant metastasis in the early years after RT [12], and it has been hypothesized that AC may only prolong the latency of locoregional recurrence and distant metastasis occurrence instead of improving their long-term control effectively [13]. Overall, a dialectical and comprehensive view on the choice between CCRT+AC and CCRT in the clinic is required. Currently, the 2014 NCCN recommends CCRT followed by AC for locoregionally advanced NPC (Category 2A); CCRT alone is also an option (Category 2B) (http://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf). The


small and non-significant, a probability of treatment ranking would have been

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National Cancer Institute also recommends CCRT+AC for locoregionally advanced NPC((http://www.cancer.gov/cancertopics/pdq/treatment/nasopharyngeal/HealthProfe ssional). However, the European Society for Medical Oncology recommends CCRT alone for locoregionally advanced NPC, and indicates that the benefit of 3 cycles of adjuvant cisplatin–fluorouracil is uncertain and that it has a substantial toxic effect

relatively fewer toxic effects without additional adjuvant therapy; (2) more satisfactory compliance; (3) relatively lower expense. Although the CCRT and RT LRFS were not significantly different in our study, improved radiation techniques such as intensity-modulated RT may have compensated for it. Regardless, a trend towards a higher rate of efficacy for CCRT+AC compared with CCRT alone was observed. Certain patient statuses might therefore benefit most from additional AC following CCRT. The subgroup analysis by Lee et al. [9] showed that among NPC patients with T1–4N2–3M0 disease, CCRT+AC mainly benefited patients with T1–2N2–3 disease. A retrospective study [26] showed that CCRT+AC mainly benefited intermediate-risk patients (T2b–3N0–2M0), with significant benefit in 5-year OS as compared with RT or CCRT alone. Recently, it was reported that unfavorable Epstein–Barr virus DNA response midpoint of RT was an adverse prognosticator for treatment outcome in advanced-stage NPC [27], and may serve as an indicator for the addition of adjuvant therapy to initial treatment. Overall, CCRT+AC appears to benefit patients who meet certain selection criteria, and further studies are required to define this patient population.


[25]. Compared with CCRT+AC, CCRT alone has the following advantages: (1)

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The study limitations also should be acknowledged: extracted all information from published data other than individual patient data, which may have resulted in publication and reporting bias. Some of this unreported individual patient information may have aided better evaluation of the quality of an RCT. Moreover, without access to individual patient data, missing information on certain prognostic factors and

in the study by Al-Sarraf et al. [5]. To minimize the risk of bias, we restricted inclusion criteria, searched and reviewed the publications comprehensively, and two independent investigators extracted the data and assessed RCT quality. Excluding the study by Al-Sarraf et al. [5] from the LRFS and DMFS analysis might have affected the validity of our findings, although our conclusions remained valid following additional direct meta-analyses of LRR and DMR that included that trial. In conclusion, our network meta-analysis shows that there was no significant survival improvement following CCRT+AC as compared with CCRT alone. The long-term follow-up results of our trial [14], which would be instructive, is awaiting to be reported. Whether the omission of additional AC can reduce toxic effects without adversely affecting survival outcomes for patients with locoregionally advanced NPC should be further explored. In addition, the specific patient statuses that would benefit from AC following CCRT deserve further investigation. ACKNOWLEDGEMENTS We thank the anonymous reviewers for their insightful comments and great efforts to improve this manuscript.


endpoints could have affected our analysis, e.g., LRFS and DMFS were not available

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FUNDING The authors received no external funding for this meta-analysis. CONFLICT OF INTEREST The authors have declared no conflicts of interest.


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Figure legends Figure 1. Network meta-analysis results for (A, B) overall survival, (C, D)

C, E) Upper triangles denote pooled hazard ratios (HRs); treatments in the rows were compared with those in the columns. In each HR cell, the first and second lines contain the HRs from the fixed and random effects models, respectively. Numbers in parentheses indicate the corresponding 95% credible intervals. Red numbers, HRs with Bayesian P < 0.05. Lower triangles denote the Bayesian deviance information criterion (DIC) statistics from the fixed and random effects models. (B, D, F) Probabilities of each treatment ranking best, and second and third best based on the fixed effects model. CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; RT, radiotherapy.


locoregional recurrence-free survival, and (E, F) distant metastasis-free survival. (A,

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Median No. of

follow-up patients

Chemotherapy

Inclusion

Study

Stage

Radiotherapy

period (months)

Concurrent

Adjuvant

CCRT+AC vs. RT Al-Sarraf et al.

193

1989-1995 32.4

1998 Wee et al.

221

1997-2003 38.4

2005


Table 1. Summary of studies included in the network meta-analysis

AJCC

1.8-2.0Gy/fx/d, 5fx/wk, to

3* DDP 100 mg/m2

4* DDP 80 mg/m2(day 1) +FU

III-IV

66-70 Gy

(days 1,22, 43）

1,000mg/m2 (days 1-4 civ)

AJCC II-IV, 70Gy (2Gy/fx/d, 5fx/wk

DDP 25 mg/m2/d

DDP 20 mg/m2/d for 4days, +FU

any T, any for 7wks)

for 4days,

1000 mg/m2/d for 4 days

N

alternatively

30/30/40mg/m2/d for 3days Lee et al. 2005,2010

348

1999-2004 70.8

AJCC

≥66Gy (2Gy/fx/d,

III-IV, any

5fx/wk), +additional boosts (days 1,22,43)

3* DDP 100 mg/m2

q4wk DDP 80 mg/m2 +FU 1000 mg/m2/d (days 71,99 and

for parapharyngeal space,

N3, M0

primary or nodal sites when indicated not exceeding 20Gy

Lee et al.

93

1999-2004 75.6

2006,2011

2008,2013

2002-2005 70

q4wk DDP 80 mg/m2 +FU

≥66Gy (2Gy/fx/d, 5

III-IV,

fx/wk), +additional boosts (days 1,22,43)

1000 mg/m2/d (days 71, 99 and

T3-4, N0-1,

for parapharyngeal space,

127)

M0

primary or nodal sites when not

exceeding

20Gy 316

127)

AJCC

indicated

Chen et al.


T, N2 or

3* DDP 100 mg/m2

AJCC

≥68Gy (2Gy/fx/d,

7* DDP 40 mg/m2

3* q4wk DDP 80 mg/m2 (day 1)

III-IV,

5fx/wk for 7 weeks), +

(day 1) weekly

+FU 800 mg/m2/d (days 1-5 )

T1-4, N0-3,

additional boost in case of

M0

parapharyngeal extension,

residual nasopharyngeal disease CCRT vs. RT Chan et al.

350

1994-1997 66

2002,2005

AJCC II-IV, 66Gy,+additional boost

8* DDP 40 mg/m2

any T, any in case of parapharyngeal

(day 1) weekly

N, M0

extension, residual neck nodes, and/or residual nasopharyngeal disease (brachytherapy)

Zhang et al. 2005,2013

115

2001-2003 114


residual neck nodes and

AJCC

70-74Gy(2Gy/fx/d, 5fx/wk)

6* Oxaliplatin 70

III-IV, any

+additional boost in case

mg/ m2 weekly

T, N2 or

of parapharyngeal

N3, M0

extension, residual neck

None

None

nasopharyngeal disease CCRT+AC vs. CCRT Chen et al.

508

2012

2006-2010 38

AJCC


nodes and/or residual

2.0–2.27Gy/fx/day,5 fx/wk, 7* DDP 40 mg/m2

III-IV, any to 60–66 Gy, irradiation to (day 1) weekly T, any N, 50 Gy for potential sites a M0, except T3–4N0

3* q4wk DDP 80 mg/m2 (day 1) +FU 800 mg/m2/d (days 1-5 )

CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; RT, radiotherapy; AJCC, American Joint Committee on Cancer; fx, fraction; DDP, cisplatin; FU, fluorouracil; civ, continuous intravenous; q4wk, every 4 weeks. a

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Induction Chemotherapy Followed by Radiotherapy versus Concurrent Chemoradiotherapy in elderly patients with nasopharyngeal carcinoma: finding from a propensity-matched analysis.

IMRT combined with concurrent chemotherapy plus adjuvant chemotherapy versus IMRT combined with concurrent chemotherapy alone in patients with nasopharyngeal carcinoma.

Efficacy of the Additional Neoadjuvant Chemotherapy to Concurrent Chemoradiotherapy for Patients with Locoregionally Advanced Nasopharyngeal Carcinoma: a Bayesian Network Meta-analysis of Randomized Controlled Trials.

Neoadjuvant chemotherapy plus intensity-modulated radiotherapy versus concurrent chemoradiotherapy plus adjuvant chemotherapy for the treatment of locoregionally advanced nasopharyngeal carcinoma: a retrospective controlled study.

Concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: treatment outcomes of a prospective, multicentric clinical study.

Concurrent Chemoradiotherapy Versus Chemotherapy Alone for Unresectable Locally Advanced Pancreatic Cancer: A Retrospective Cohort Study.

Evaluation of the efficacy and safety of a neoadjuvant gemcitabine and nedaplatin regimen followed by radiotherapy or concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma.

Comparison of the efficacy between concurrent chemoradiotherapy with or without adjuvant chemotherapy and intensity-modulated radiotherapy alone for stage II nasopharyngeal carcinoma.

Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for advanced-stage unresectable intrahepatic cholangiocarcinoma.

Phase I trial of adoptively transferred tumor-infiltrating lymphocyte immunotherapy following concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

Phase II trial of concurrent chemoradiotherapy with S-1 versus weekly cisplatin for locoregionally advanced nasopharyngeal carcinoma.

Concurrent chemoradiotherapy was associated with a higher severe late toxicity rate in nasopharyngeal carcinoma patients compared with radiotherapy alone: a meta-analysis based on randomized controlled trials.

Immunomodulated anterior chemotherapy followed by concurrent chemoradiotherapy in locally advanced tongue cancer: An Institutional experience.

The effect of adjuvant chemotherapy on survival in patients with residual nasopharyngeal carcinoma after undergoing concurrent chemoradiotherapy.

The Effect of Adding Neoadjuvant Chemotherapy to Concurrent Chemoradiotherapy in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma and Undetectable Pretreatment Epstein-Barr Virus DNA.

Non-endemic locoregionally advanced nasopharyngeal carcinoma: long-term outcome after induction plus concurrent chemoradiotherapy in everyday clinical practice.

Induction chemotherapy followed by concurrent chemoradiotherapy for advanced stage oropharyngeal squamous cell carcinoma with HPV and P16 testing.

Tumor regression patterns by follow-up duration in patients with nasopharyngeal carcinoma treated with concurrent chemoradiotherapy.

A phase III randomized study comparing neoadjuvant chemotherapy with concurrent chemotherapy combined with radiotherapy for locoregionally advanced nasopharyngeal carcinoma: updated long-term survival outcomes.

Radiotherapy with neoadjuvant chemotherapy versus concurrent chemoradiotherapy for ascending-type nasopharyngeal carcinoma: a retrospective comparison of toxicity and prognosis.