IJC International Journal of Cancer

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1 IJC International Journal of Cancer Cetuximab or nimotuzumab plus intensity-modulated radiotherapy versus cisplatin plus intensity-modulated radiotherapy for stage II-IVb nasopharyngeal carcinoma Rui You 1,2, Rui Sun 1,2, Yi-Jun Hua 1,2, Chao-Feng Li 2,3, Ji-Bin Li 2,4, Xiong Zou 1,2, Qi Yang 1,2, You-Ping Liu 1,2, Yi-Nuan Zhang 1,2, Tao Yu 1,2, Jing-Yu Cao 1,2, Meng-Xia Zhang 1,2, Rou Jiang 1,2, Hao-Yuan Mo 1,2, Ling Guo 1,2, Ka-Jia Cao 1,2, Ai-Hua Lin 5, Chao-Nan Qian 1,2, Ying Sun 1,6, Jun Ma 1,6 and Ming-Yuan Chen 1,2 1 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, , People s Republic of China 2 Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, , People s Republic of China 3 Department of Information Technology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, , People s Republic of China 4 Department of Clinical Research, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, , People s Republic of China 5 Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, 74 Zhongshan Second Road, Guangzhou, , People s Republic of China 6 Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, , People s Republic of China To compare intensity-modulated radiotherapy (IMRT) with cisplatin (CDDP) versus cetuximab (CTX) and nimotuzumab (NTZ) for Stage II-IVb Nasopharyngeal Carcinoma (NPC). A total of 1,837 patients with stage II IV b NPC who received IMRT plus CTX or NTZ, or CDDP between January 2009 and December 2013 were included in the current analysis. Using propensity scores to adjust for potential prognostic factors, a well-balanced cohort of 715 patients was created by matching each patient who underwent IMRT plus concomitant NTZ/CTX with four patients who underwent IMRT plus concomitant CDDP (1:4). Efficacy and safety were compared between the CTX/NTZ and CDDP groups of this well-balanced cohort. Furthermore, we conducted multivariate analysis and subgroup analysis based on all the 1,837 eligible cases. There was no significant difference between CTX/NTZ group and CDDP group in terms of DFS (3-year, 86.7% vs. 86.2%, p > 0.05), LRRFS (96.2% vs. 96.3%, p > 0.05), DMFS (91.1% vs. 92.3%, p > 0.05) and OS (91.7% vs. 91.9%, p > 0.05). Subgroup analysis demonstrated a significant interaction effect between patients with IMRT plus CTX/NTZ and N3 node stage on LRRFS with the highest risk of loco-regional relapse (HR 8.85, p ). Significantly increased hematologic toxicities, gastrointestinal reactions were observed in the CDDP group (p < 0.05). Patients of % experienced severe hematologic toxicities during the treatment with concomitant CTX and NTZ. Increased rate of CTX related-skin reaction and mucositis was observed in the CTX group. CTX/NTZ used concurrently with IMRT may be comparable to those of the standard CDDP-IMRT combination for maximizing survival for patients with stage II-IVb NPC. Key words: nasopharyngeal carcinoma, intensity-modulated radiotherapy, cetuximab, nimotuzumab, survival outcome, adverse events Additional Supporting Information may be found in the online version of this article. R.Y., R.S., Y.-J.H. and C.-F.L. contributed equally to this study Conflict of interest statement: The authors declare that they have no conflicts of interest. Grant sponsor: Guangdong Provincial Natural Science Foundation in China; Grant number: S ; Grant sponsor: Program of Sun Yat-Sen University for Clinical Research 5010 Program; Grant number and ; Grant sponsor: Program for New Century Excellent Talents in University; Grant number: NCET ; Grant sponsors: Major Project of Sun Yat-Sen University for the New Cross Subject and Special Support Program for High-level Talents in Sun Yat-Sen University Cancer Center (to M.Y.C.); Grant sponsor: National Key Research and Development Program of China; Grant number: 2016YFC ; Grant sponsor: Guangdong Public Welfare Research and Capacity Building Projects; Grant number: 2014B ; Grant sponsor: National Natural Science Foundation of China; Grant number: DOI: /ijc History: Received 6 Feb 2017; Accepted 28 Apr 2017; Online 2 June 2017 Correspondence to: Prof. Ming-Yuan Chen, Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, Guangdong , P. R. China, Tel.: , Fax: , chmingy@mail.sysu.edu.cn

2 1266 The comparison of IMRT plus CTX/NTZ or CDDP What s new? Standard treatment for nasopharyngeal carcinoma (NPC) that has spread to lymph nodes in the head and neck entails concurrent cisplatin (CDDP) and intensity-modulated radiotherapy (IMRT). High toxicity rates, however, limit the utility of this approach. The present study examines an alternative strategy: cetuximab (CTX) and nimotuzumab (NTZ) plus IMRT. No differences in risk of disease progression, relapse, metastasis or death were observed in a direct comparison between CDDP plus IMRT and CTX/NTZ plus IMRT in NPC patients. Both regimens were associated with hematologic toxicities and with toxicities targeting different tissues, warranting further investigation of side effects specific to CTX/NTZ. Nasopharyngeal carcinoma (NPC) is most prevalent in eastern Asia, with the highest incidence reported among the Cantonese population from the province of Guangdong. There, the rates of NPC range from 22.2 to 27.2 per 100,000 in males and from 9.8 to 11.1 per 100,000 in females. 1 Most patients were classified as having stages II-IVb NPC at the time of diagnosis. According to the 2013 National Comprehensive Cancer Network (NCCN) guidelines for head and neck cancer, concurrent chemoradiotherapy (CCRT) is the standard treatment for patients classified with II-IVb stages of cancer. 2 Cisplatin (CDDP)-based chemotherapy combined with intensity-modulated radiotherapy (IMRT) has been the most commonly used treatment regimen for these patients in recent years. However, it is associated with toxicity rates higher than that of radiation alone, and it is frequently withheld from the therapeutic strategy in elderly people or in patients with poor performance status and comorbidities. 3,4 To reduce toxicity without affecting effectiveness, alternative schedules are urgently needed. Epidermal growth factor receptor (EGFR) represents a promising new therapeutic target in cancer. EGFR is highly expressed in most human epithelial carcinomas and has been correlated with a more aggressive phenotype, resistance to treatment and poor prognosis. 5,6 As previously reported, EGFR is expressed in >85% of NPC patients. Therefore, anti-egfr targeted treatment has been recommended as a potential combination treatment for NPC. Cetuximab (CTX) and Nimotuzumab (NTZ), both of which are anti-egfr monoclonal antibodies, are most frequently utilized in combination treatment of NPC in China. Bonner et al. published preliminary results of a randomized trial in which they compared radiotherapy (RT) alone with RT plus CTX for locoregionally advanced head and neck cancer (LASCCHN). They reported a 13% absolute improvement in loco-regional control and a 10% absolute improvement in 3-year survival, with minimal increase in toxicity. 7,8 Recently, Magrini et al. published the results of a randomized phase II trial in which they compared RT with concomitant CDDP versus concomitant CTX as first-line treatment of LASCCHN. Similar efficacy outcomes, lower compliance and increased acute toxicity rates were reported in the group treated with both CTX and RT compared with patients treated with both CDDP and RT. 9 However, a direct comparison between concomitant CDDP and RT and concomitant CTX/NTZ and RT treatment in NPC is lacking. Therefore, we conceived and initiated a non-profit, retrospective study to directly compare RT plus CTX/NTZ and RT plus CDDP in terms of efficacy and safety. Patients and Methods Patients and study design The 5,721 patients who were newly diagnosed with NPC were identified from an inpatient database at SYSUCC between January 2009 and December The disease was restaged according to the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM classification (7th edition, 2011) based on clinical and radiography data. 10 The pretreatment evaluation is presented in the Supporting Information. Our inclusion criteria included the following: (i) histologically confirmed NPC; (ii) disease classified as stages II-IVb; (iii) patient received RT plus concomitant NTZ or CTX or CDDP for at least one cycle; and (iv) the radiation technology used was IMRT. The exclusion criteria were as follows: (i) the patient was diagnosed with a previous malignancy or other concomitant malignant disease and (ii) the use of adjuvant chemotherapy or additional concurrent systemic therapy other than CDDP, CTX and NTZ. (iii) treatment with weekly cisplatin. Eventually, 1,837 patients were included in the current study (Supporting Information Appendix Table 1). The clinical research ethics committee of SYSUCC approved this study. We performed an analysis of variance, as well as a v 2 test, on the patients baseline demographics and clinical characteristics. Variable differences were identified between the two groups, including gender, age, the Karnofsky performance status score (KPS), tumor stage (T stage) and node stage (N stage), clinical stage and induction chemotherapy status, all of which were identified as prognostic factors for survival outcomes in previous studies. 11,12 Using propensity scores to adjust for these seven factors, we created a well-balanced cohort by attempting to match each patient who underwent IMRT plus concomitant NTZ or CTX with four patients who underwent IMRT plus CDDP year by year. Finally, we selected a total of 715 patients, including 143 patients in the IMRT plus NTZ/CTX group and 572 patients in the IMRT plus CDDP group (Table 1). We first conducted casematched comparison between the IMRT plus CTX/NTZ and IMRT plus CDDP arms in terms of efficacy and safety in

3 You et al Table 1. Baseline characteristics of patients in the 715 well-balanced cohort Characteristic this well-balanced cohort of 715. Then, we conducted multivariate and subgroup analyses based on all the 1,837 eligible cases (Fig. 1). Treatment at referral Treatment at referral is included in the Supporting Information. Follow-up and assessments During the course of irradiation, patients were examined weekly. The post-treatment clinical follow-up was generally performed at 3-month intervals for the first 2 years after treatment and every 6 months thereafter. The evaluation procedures were similar with those carried out at the pretreatment evaluation. Chemotherapy-related toxic effects were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0), and radiotherapy-related IMRT 1 CTX/NTZ N IMRT 1 CDDP N p 1 Gender no. (%) Female 23 (16.1%) 106 (18.5%) Male 120 (83.9%) 466 (81.5%) Age yr Median Range Karnofsky performance status score no. (%) (92.3%) 521 (91.1%) (7.7%) 51 (8.9%) T classification no. (%) T1 6 (4.2%) 31 (5.4%) T2 27 (18.9%) 73 (12.8%) T3 65 (45.5%) 306 (53.5%) T4 45 (31.5%) 162 (28.3%) N classification no. (%) No 20 (14.0%) 74 (12.9%) N1 66 (46.2%) 259 (45.3%) N2 47 (32.9%) 203 (35.5%) N3 10 (7.0%) 36 (6.3%) Clinical stage no. (%) II 18 (12.6%) 62 (10.8%) III 75 (52.4%) 323 (56.5%) IV 50 (35.0%) 187 (32.7%) Induction Chemotherapy no. (%) No 59 (41.3%) 243 (42.5%) Yes 84 (58.7%) 329 (57.5%) Data are the median or n (%), unless otherwise stated. IMRT 5 intensity-modulated radiotherapy; NTZ 5 Nimotuzumab; CTX 5 Cetuximab; CDDP 5 Cisplatin. 1 v 2 test or Fisher s exact test. 2 Mann Whitney U test. toxic effects were evaluated according to the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group. Acute toxicities were defined as those occurring either during the course of IMRT or within 90 days of its completion. Statistical analysis Statistical analysis was included in the Supporting Information. 6 Results The treatment characteristics and compliance There was no significant difference in pretreatment imaging methods between the two treatment groups (Supporting Information Appendix Table 2). The details were presented in the Supporting Information.

4 1268 The comparison of IMRT plus CTX/NTZ or CDDP Figure 1. CONSORT flow diagram.

5 You et al Table 2. Acute toxicities IMRT1CTX (N 5 58) Acute Toxicity IMRT1NTZ (N 5 85) IMRT1CDDP (N 5 572) P 1 P 2 P 3 Anemia ns <0.001 <0.001 G0-G1 54 (93.1%) 73 (85.9%) 438 (76.6%) G2 4 (6.9%) 12 (14.1%) 112 (19.6%) G3 0 (0.0%) 0 (0.0%) 16 (2.8%) G4 0 (0.0%) 0 (0.0%) 6 (1.0%) Thrombocytopenia ns G0-G1 53 (91.4%) 80 (94.1%) 486 (85.0%) G2 4 (6.9%) 3 (3.5%) 57 (9.9%) G3 0 (0.0%) 2 (2.4%) 22 (3.8%) G4 1 (1.7%) 0 (0.0%) 7 (1.2%) Neutropenia ns G0-G1 50 (86.2%) 72 (84.7%) 322 (56.3%) G2 6 (10.3%) 9 (10.6%) 114 (19.9%) G3 2 (3.4%) 4 (4.7%) 97 (16.9%) G4 0 (0.0%) 0 (0.0%) 39 (6.8%) Leukopenia ns <0.001 <0.001 G0-G1 42 (72.4%) 64 (75.2%) 212 (37.2%) G2 15 (25.9%) 17 (20.0%) 224 (39.1%) G3 1 (1.7%) 4 (4.7%) 123 (21.5%) G4 0 (0.0%) 0 (0.0%) 13 (2.3%) Hematologic toxicity G3 2 (3.4%) 4 (4.7%) 151 (26.3%) ns <0.001 <0.001 Skin reaction G0-G1 14 (24.1%) 58 (68.2%) 391 (68.4%) ns G2 21 (36.2%) 18 (21.2%) 160 (28.0%) G3 23 (39.6%) 9 (10.6%) 21 (3.7%) Mucositis ns G0-G1 13 (22.4%) 41 (48.2%) 147 (25.7%) G2 17 (29.3%) 21 (24.7%) 241 (42.1%) G3 20 (34.5%) 20 (23.5%) 161 (28.1%) G4 8 (13.8%) 3 (3.5%) 23 (4.0%) Nausea ns <0.001 <0.001 G0-G1 49 (84.5%) 65 (76.4%) 125 (22.1%) G2 19 (15.5%) 20 (23.6%) 360 (62.7%) G3 0 (0.0%) 0 (0.0%) 78 (13.6%) G4 0 (0.0%) 0 (0.0%) 9 (1.6%) Vomiting ns G0-G1 52 (89.7%%) 78 (91.8%) 434 (75.9%) G2 6 (10.3%) 7 (8.2%) 77 (13.5%) G3 0 (0.0%) 0 (0.0%) 58 (10.1%) G4 0 (0.0%) 0 (0.0%) 3 (0.5%) Diarrhea ns G0-G1 47 (81.0%) 76 (89.4%) 516 (90.2%) G2 11 (19.0%) 9 (10.6%) 43 (7.5%)

6 1270 The comparison of IMRT plus CTX/NTZ or CDDP Table 2. Acute toxicities (Continued) IMRT1CTX (N 5 58) Acute Toxicity IMRT1NTZ (N 5 85) IMRT1CDDP (N 5 572) P 1 P 2 P 3 G3 0 (0.0%) 0 (0.0%) 13 (2.3%) Hepatoxicity ns G0-G1 56 (96.6%) 80 (94.1%) 500 (87.4%) G2 2 (3.4%) 5 (5.8%) 55 (9.7%) G3 0 (0.0%) 0 (0.0%) 17 (3.0%) Nephrotoxicity G0-G1 57 (98.3%) 83 (97.6%) 491 (85.8%) ns G2 1 (1.7%) 2 (2.4%) 48 (8.4%) G3 0 (0.0%) 0 (0.0%) 33 (5.8%) Weight loss ns <0.001 <0.001 G0-G1 57 (98.3%) 81 (95.3%) 397 (69.4%) G2 1 (1.7%) 4 (4.7%) 165 (28.8%) G (1.7%) All data are presented as No.(%). P 1 value was calculated between CTX arm and NTZ arm; P 2 value was calculated between CTX arm and CDDP arm; P 3 value was calculated between NTZ arm and CDDP arm. ns 5 non-significant. Efficacy The median time of follow-up was 50.4 months (range, 0 95 months) and 55.1 months (range, 2 93 months) in the IMRT plus CTX/NTZ group and IMRT plus CDDP group, respectively. The risk of disease progression was similar among the patients treated with IMRT plus CTX/NTZ and those treated with IMRT plus CDDP (hazard ratio, HR, for DFS, 0.84, 95% confidence interval CI, ; p ). The one-, two- and three-year rates of DFS achieved with IMRT plus CTX/NTZ (95.0, 89.9 and 86.7%) were also similar to those achieved with CCRT (94.4, 89.7 and 86.2%). There was no significant difference in the risk of loco-regional relapse in the patients who received IMRT plus CTX/NTZ compared with those that received IMRT plus CDDP (HR 1.04, 95% CI , p ). The survival rates at one-, two-, threeyears achieved with IMRT plus CTX/NTZ (99.3, 97.0 and 96.2%) were also similar to those achieved with IMRT plus CDDP (98.6, 97.5 and 96.3%). The risk of distant metastasis was similar between the patients treated with IMRT plus CTX/NTZ and those treated with IMRT plus CDDP (HR 0.84, 95% CI, ; p ). The one-, two- and three-year rates of DMFS achieved with IMRT plus CTX/ NTZ (95.7, 92.7 and 91.1%) were similar to those achieved with IMRT plus CDDP (96.3, 93.4 and 92.3%). There was no significant difference in the risk of death between patients that received IMRT plus CTX/NTZ and those who received IMRT plus CDDP (HR 0.95, 95% CI , p ). The one-, two- and three-year rates of OS were 98.6, 95.6 and 91.7%, respectively, in the IMRT plus CTX/NTZ group, and 98.6, 94.5 and 91.9%, respectively, in the IMRT plus CDDP group (Fig. 2). Safety Table 2 displays the toxicity scores of each group. There was no significant difference in hematological toxicities between the CTX group and the NTZ group (p > 0.05). Severe hematological toxicities of G3-G4 were more common in the CDDP group compared with the CTX group and the NTZ group (CDDP group vs. CTX group, 26.3% vs. 3.4%, p < 0.001; CDDP group vs. NTZ group, 26.3% vs. 4.7%, p < 0.001). However, two and four episodes of G3-G4 hematologic toxicities also occurred in the CTX and NTZ group, respectively. Severe mucositis of Grades 3 4 were more common in the CTX group compared with the NTZ group and CDDP Group (48.3% vs. 27.0%, p ; 48.3% vs. 32.1%, p , respectively), whereas no significant differences in mucositis were observed between the NTZ group and CDDP group. There was no significant difference in the rate of skin reaction between the NTZ group and the CDDP group (p > 0.05). A higher frequency of G3 skin reactions was observed in the CTX group compared with the NTZ and CDDP groups (39.6, 10.6, 3.7%). More patients in the CDDP group had gastrointestinal reaction of any grade compared with those in the CTX group and the NTZ group (p < 0.05). Severe hepatoxicities and nephrotoxicities of any grade were more common in the CDDP group compared with the CTX group and the NTZ group. A higher frequency of weight loss was observed in the CDDP group, whereas no differences in weight loss were observed between the CTX group and the NTZ group (p > 0.05) (Table 2). Multivariate analysis Multivariate analyses of all 1,837 patients further demonstrated that there were no statistically significant differences

7 You et al Figure 2. Kaplan Meier curves of disease free survival (a), loco-regional recurrence-free survival (b), distant metastasis-free survival (c), and overall survival (d), according to IMRT plus concomitant CTX/NTZ or CDDP treatment in the 715 well-balanced cohort. Hazard ratios (HRs) were calculated with the Cox proportional-hazards model; p values were calculated with the log-rank test. IMRT 5 intensity-modulated radiotherapy; CTX 5 cetuximab; NTZ 5 nimotuzumab; CDDP 5 cisplatin. [Color figure can be viewed at wileyonlinelibrary.com] in the risk of disease progression, loco-regional relapse, distant metastasis and death among patients treated with IMRT plus CTX/NTZ and IMRT plus CDDP (p > 0.05), (Table 3). In addition, no significant differences were observed in the risk of disease progression, loco-regional relapse, distant metastasis and death among patients treated with IMRT plus NTZ, patients who received IMRT plus CTX, and those who received IMRT plus CDDP (p > 0.05) (Supporting Information Appendix Figure 1). Multivariate Cox regression analyses demonstrated that advanced N stage was a significant risk factor for DFS, LRRFS, DMFS and OS (N3 vs. N0 1, HR 3.40, 95% CI , p < 0.001; HR 3.31, 95% CI , p ; HR 3.76, 95% CI , p < 0.001; and HR 3.68, 95% CI , p < 0.001, respectively). In addition, male was validated as a significant risk factor for DMFS (HR 1.67, 95% CI , p ), and an age of >46 was also a significant risk factor for DFS and OS (HR 1.41, 95% CI , p ; HR 1.88, 95% CI , p < 0.001). However, the addition of induction chemotherapy was validated as a significant protective factor for DFS and DMFS (HR 0.78, 95% CI , p ; HR % CI , p , respectively) (Table 3).

8 1272 The comparison of IMRT plus CTX/NTZ or CDDP Table 3. Multivariate analysis of variables correlated with the treatment regimen status and other significant prognostic factors in eligible 1,837 cases HR Cl (95%) p values Disease free survival IMRT plus CDDP IMRT plus CTX/NTZ Induction chemotherapy No Yes Gender Female Male Age 46 > Karnofsky performance status score Tumor stage T1 T T T Node stage N0-N1 N <0.001 N <0.001 Clinical stage II-III IV Loco-regional relapse free survival IMRT plus CDDP IMRT plus CTX/NTZ Induction chemotherapy No Yes Gender Female Male Age 46 > Table 3. Multivariate analysis of variables correlated with the treatment regimen status and other significant prognostic factors in eligible 1,837 cases (Continued) HR Cl (95%) p values Karnofsky performance status score Tumor stage T1 T T T Node stage N0-N1 N N Clinical stage II-III IV Distant metastasis-free survival IMRT plus CDDP IMRT plus CTX/NTZ Induction chemotherapy No Yes Gender Female Male Age 46 > Karnofsky performance status score Tumor stage T1 T T T Node stage N0-N1 N <0.001 N <0.001

9 You et al Table 3. Multivariate analysis of variables correlated with the treatment regimen status and other significant prognostic factors in eligible 1,837 cases (Continued) HR Cl (95%) p values Clinical stage II-III IV Overall survival IMRT plus CDDP IMRT plus CTX/NTZ Induction chemotherapy No Yes Gender Female Male Age 46 > <0.001 Karnofsky performance status score Tumor stage T1 T T T Node stage N0-N1 N N <0.001 Clinical stage II-III IV Abbreviations: HR, hazard ratio; 95% CI, 95% confidence interval. Subgroup analysis When analyzing all 1,837 patients, after adjusting for gender, age, KPS, T stage, clinical stage and IC status, the interaction analysis showed a significant interaction effect between patients with IMRT plus CTX/NTZ and N3 of N stage on LRRFS (HR IMRT plus CTX/NTZ * N3 6.43, 95% CI ; p ) (Table 4). When these 1,837 NPC patients were stratified into six groups by treatment regimens and N stages, the adjusted HRs for LRRFS increased from N0 1 to N2 and N3 in both treatment regimens. Most importantly, the patients who underwent IMRT plus CTX/NTZ in N3 had the highest risk of loco-regional relapse (HR IMRT plus CTX/NTZ*N3 8.85, 95% CI , p ) (Supporting Information Appendix Figure 2). However, there were no interaction effects between IMRT plus CTX/NTZ therapy and N stage on other survival outcomes, such as DFS, DMFS and OS (p > 0.05). Regardless of treatment regimen status and induction chemotherapy status, treatment regimen status and age, treatment regimen status and gender, the interaction effects were all non-significant on all survival outcomes, including DFS, DMFS, LRRFS and OS (Table 4). In addition, we had further compared the survival outcome between IMRT plus CTX/NTZ arm and IMRT plus CDDP arm in all eligible 1,837 cases for different N stages. There was significant difference in the risk of loco-regional relapse between patients that received IMRT plus CTX/NTZ and those who received IMRT plus CDDP for N3 disease alone (HR 3.80, 95% CI , p ), not for N2 disease and N0 1 disease (HR 0.61, 95% CI , p ; HR 0.71, 95% CI , p , respectively). No significant differences were observed in the risk of distant metastasis, disease progression and death among patients treated with IMRT plus CTX/NTZ and those who received IMRT plus CDDP regardless of N stage (p > 0.05) (Supporting Information Appendix Figure 3 5). Discussion To the best of our knowledge, this study was the first to directly compare concomitant CDDP and RT and concomitant CTX/NTZ and RT treatment in NPC based on the largest number of patients reported and included 70 patients treated with RT plus CTX, 126 patients treated with RT plus NTZ and 1,641 patients treated with RT plus CDDP. Previous studies showed better survival and loco-regional disease control associated with CTX plus RT in patients with LASCCHN relative to RT alone. 7,8 As a consequence, CTX has increasingly been used in the treatment of patients with LASCCHN, particularly patients whose condition makes them clinically unfit for CDDP chemotherapy. Regarding the use of CTX in NPC, only two phase II prospective randomized studies from Hong Kong have demonstrated the feasibility of the addition of CTX to CCRT for the treatment of loco-regionally advanced NPC and recurrent/metastatic NPC. 13,14 In the current study, we observed that there was no statistically significant difference in the risk of disease progression, loco-regional relapse, distant metastasis and death among patients with IMRT plus CTX/NTZ and IMRT plus CDDP or among patients treated with IMRT plus NTZ, patients who received IMRT plus CTX, and those who received IMRT plus CDDP, which was similar to the results of a previous retrospective study comparing CTX and CDDP concomitant to IMRT in NPC. 15 The results of a prospective study by Lin Kong et al. were recently reported at an American Society of Clinical Oncology (ASCO) meeting ( meetinglibrary.asco.org/content/ ). The authors compared CDDP and NTZ concomitant to IMRT in patients

10 1274 The comparison of IMRT plus CTX/NTZ or CDDP Table 4. Interaction between treatment regimen status and other significant prognostic factors and its effect on disease free survival, distant metastasis-free survival, loco-regional relapse free survival and overall survival in all eligible 1,837 cases Disease free survival Loco-regional relapse free survival Distant metastasis-free survival Overall survival (95% CI) p value (95% CI) p value (95% CI) p value (95% CI) p value and Node Stage IMRT plus CDDP IMRT plus CTX/NTZ 0.73 ( ) Node Stage ( ) ( ) ( ) N0-N1 N ( ) N ( ) Interaction Effect IMRT plus CTX/NTZ * N ( ) IMRT plus CTX/NTZ * N ( ) < ( ) < ( ) ( ) ( ) ( ) ( ) ( ) ( ) < ( ) ( ) ( ) ( ) and Induction Chemotherapy IMRT plus CDDP IMRT plus CTX/NTZ 0.59 ( ) Induction Chemotherapy ( ) ( ) ( ) No Yes 0.75 ( ) Interaction Effect IMRT plus CTX/NTZ * Induction chemotherapy and Age 1.45 ( ) ( ) ( ) ( ) ( ) ( ) ( ) IMRT plus CDDP IMRT plus CTX/NTZ 0.75 ( ) Age ( ) ( ) ( ) 46 > ( ) Interaction Effect IMRT plus CTX/NTZ * Age > 46 yr 0.98 ( ) and Gender ( ) ( ) ( ) ( ) ( ) ( ) IMRT plus CDDP IMRT plus CTX/NTZ 0.80 ( ) ( ) ( ) ( ) <

11 You et al Table 4. Interaction between treatment regimen status and other significant prognostic factors and its effect on disease free survival, distant metastasis-free survival, loco-regional relapse free survival and overall survival in all eligible 1,837 cases (Continued) Loco-regional relapse free survival Distant metastasis-free survival Disease free survival Overall survival (95% CI) p value (95% CI) p value (95% CI) p value (95% CI) p value Gender Female Male 1.24 ( ) Interaction Effect IMRT plus CTX/NTZ * Male 0.95 ( ( ) ( ) ( ) ( ) ( ) ( ) 1 Multivariable cox regression model adjusted for age, gender, Karnofsky performance status score, tumor stage, node stage, clinical stage, induction chemotherapy. Abbreviations: HR 5 Hazard ratio; CI 5 confidence interval with loco-regionally advanced NPC and found less toxicity with NTZ but equivalent PFS and OS (CDDP vs. NTZ, 3- year PFS, 83.5% vs. 79.8%, p ; 3-year OS, 94.8% vs. 93.5%, p ). These findings further validate the results of the current study, despite the comparatively lower rate of 3- year PFS and higher rate of 3-year OS, which could be explained by differences in the inclusion criteria of patients and treatment. Even if there was no significant difference in terms of efficacy between IMRT plus CDDP and IMRT plus CTX/NTZ in our analysis, it should be noted that the highest risk of LRRFS was in patients with N3 stage treated with IMRT plus CTX/NTZ. This was indicted by the Kaplan Meier curve for LRRFS, which was in favour of the IMRT plus CDDP arm if patients were in N3 stage. Previous studies have demonstrated that RT combined with CDDP or CTX seemed to provide the most benefit for loco-regional control, and improved loco-regional control was achieved by CDDP compared with CTX, 7,16 19 which could partially explain the inferior loco-regional control achieved by IMRT plus CTX/ NTZ in N3 stage advanced stage patients with large lymph nodal diseases (median nodal volume, cubic centimeters) in current study. However, due to the relative limitations of a retrospective study, further work is necessary to validate these results especially for N3 disease. CCRT has been shown to significantly exacerbate radiotherapy-related and chemotherapy-related adverse events (AEs), such as mucositis, skin reaction and hematotoxicity. 20 Therefore, the newer combination treatment could be more relevant for patients who cannot tolerate the severe events caused by CCRT. CTX or NTZ may be an ideal alternative due to the limited AEs associated with these treatments. In the current analysis, fewer AEs were observed in patients treated with CTX or NTZ, especially with regards to hematologic toxicities, hepatoxicities, nephrotoxicities and gastrointestinal reactions. In addition, a lower frequency of weight loss was observed in the CTX and NTZ arms, and the general condition of these patients during treatment was better than those in the CDDP arm. However, several patients, %, experienced severe hepatoxicities during the treatment with concomitant CTX and NTZ. These results were similar to those published by Magrini et al. with a rate of 6% in the CTX arm in LASCCHN. 9 Biotherapeutics have been shown to have the potential for causing adverse drug reactions, including effects on peripheral blood cell counts, as a result of cellular activation, cytotoxicity, drug-dependent and independent immune responses. 21 Accordingly, increased risks of G3 leucopenia and/or neutropenia and anemia events have been reported in patients treated with CTX plus standard chemotherapeutic agents. 22 Notably, the occurrences of skin reactions and mucositis were the most frequent complaints by patients treated with CTX, with a higher frequency of G3 of 39.6%, G3-G4 of 48.3%, respectively. In addition, even though it was not documented in the current analysis, the incidence of CTX hypersensitivity infusion reactions could be high, as previously reported in literature. 23 Specifically, the overall rate of a G3 or G4 reaction can reach 22%, and fatal events related to infusion have also been documented. 24,25 Compared with the CTX arm, significantly lower frequencies of severe skin reactions, mucositis and hypersensitivity infusion reactions were observed in the NTZ arm, both in the current analysis and in previous studies This benefit could be attributed to the reduced affinity of NTZ, which results in binding with less avidity, compared to CTX, 29 thus sparing healthy tissues and avoiding severe toxicities. At our centre, approximately 40 50% of NPC patients in stages II-IVb received IC, whereas a few patients were treated with adjuvant chemotherapy. Our colleagues Ma et al. previously demonstrated adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve failure-free survival after concurrent chemoradiotherapy in locoregionally advanced NPC. 20 And recently, they further demonstrated addition of cisplatin, fluorouracil and docetaxel (TPF) induction chemotherapy to concurrent chemoradiotherapy could significantly improve failure-free survival in locoregionally

12 1276 The comparison of IMRT plus CTX/NTZ or CDDP advanced NPC. 12 Considering the quantity and quality of eligible cases, patients treated with IC were retained, whereas patients who underwent adjuvant chemotherapy were excluded. Although three IC regimens were allowed in the current study including TP, PF and TPF regimen, each of them was balanced in the IMRT plus CTX/NTZ and the IMRT plus CDDP groups. Using case-matched comparisons, multivariate analysis and subgroup analysis, the efficacy was more precisely compared among the CTX, NTZ and CDDP arms. This retrospective design has several limitations. First, although we eliminated some selection bias, such as gender, age, KPS, T and N stages, clinical stage and IC status, using propensity scores, it is unclear whether other confounding factors still exist. Second, this was a single-centre retrospective study of a high-prevalence area, and a well-designed, multi-centre, prospective, randomized study is needed to best evaluate the efficacy and safety of concomitant NTZ or CTX in NPC patients. In conclusion, CTX/NTZ used concurrently with IMRT showed results comparable to those of the standard CDDP- IMRT combination in terms of DFS, LRRFS, DMFS and OS. However, subgroup analysis showed inferior loco-regional control in N3 patients treated with CTX/NTZ. Additionally, significantly increased hematologic toxicities and more severe gastrointestinal reactions were observed in patients treated with CDDP. However, the severe episodes of G3-G4 hematologic toxicities observed in the CTX/NTZ arm and increased rate of CTX related-skin reaction and mucositis cannot be ignored. Therefore, multi-centre, prospective, randomized trials and further studies on the toxicity profiles of CTX and NTZ are strongly needed. s 1. Cao SM, Simons MJ, Qian CN. 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