Journal of Cancer 2018, Vol. 9 3352 Ivyspring International Publisher Journal of Cancer 2018; 9(18): 3352-3360. doi: 10.7150/jca.25530 Research Paper Surrogate endpoints shortening the therapeutic evaluation duration for different subgroups of patients with nasopharyngeal carcinoma receiving intensity-modulated radiotherapy: A retrospective analysis of 830 patients stratified by the 8th edition of the UICC/AJCC staging system and plasma Epstein-Barr viral Shu Zhou1,2*, Chen Chen 1,2*, Song-ran Liu 1,2, Ya-lan Tao 1,2, Hui Chang1,2, Xiao-hui Wang1,2, Xin Yang1,2, Wen-wen Zhang1,2, Shan Liu 1,2 , Shi-rong Ding1,2, Guan-nan Wang1,2, and Yun-fei Xia1,2 1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, P. R. China. 2. Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong, P. R. China. *These authors contributed equally to this work. Corresponding author: Yun-fei Xia, PhD, MD, State Key Laboratory of Oncology in South China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, P. R. China. Tel.: +86-20-87343373, Fax: +86-20-87343373, Email: [email protected] © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2018.02.13; Accepted: 2018.07.17; Published: 2018.09.08 Abstract Purpose: Investigating surrogate endpoints shortening the time of therapeutic evaluation in nasopharyngeal carcinoma (NPC) after radical treatment. Patients and Methods: We retrospectively analyzed 830 patients receiving intensity-modulated radiotherapy (IMRT) from 2008 to 2010 and being stratified by the 8th edition of UICC/AJCC staging system and the plasma Epstein-Barr virus DNA (EBV DNA). The annual rates of overall survival (OS), progression-free survival (PFS), loco-regional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were sequentially calculated using the life table and compared by the McNemar method. Results: The time of shortening therapeutic evaluation by surrogate endpoints: OS, PFS, LRFS and DMFS could be shortened to 1-year (100% vs 100%, P=1) in patients with stage I; OS, PFS, LRFS and DMFS could be shortened to 3-year (96.9% vs 96.1%, P = 1; 94.6% vs 92.2%, P = 0.125; 96.9% vs 95.3%, P = 0.5) and 4-year (92.2% vs 91.2%, P = 0.125) in stage II; In the high EBV DNA group , OS and DMFS could be shortened to 1-year (100% vs 100%, P = 1;100% vs 100%, P = 0.25) in stage II; OS and PFS could be shortened to 3-year (94.3% vs 91.4%, P = 1;82.9% vs 74.3%, P = 0.25) in stage III; OS could be shortened to 4-year (75% vs 72.7%, P = 1) in stage IVA. Conclusions: The time of therapeutic evaluation could be shortened to <5-year in stages I-II patients. The year of surrogate endpoints could be ahead in stages II-IVA with high EBV DNA. Key words: nasopharyngeal carcinoma; surrogate endpoints; intensity-modulated radiotherapy; the 8th edition of UICC/AJCC staging; Epstein-Barr Viral DNA; overall survival; progression-free survival; loco-regional recurrence-free survival; distant metastasis-free survival http://www.jcancer.org Journal of Cancer 2018, Vol. 9 3353 Introduction which interpreted these results as a strong indicator to apply the new edition in clinical practice and trials. Nasopharyngeal carcinoma (NPC) is a malignant Based on the new staging system and the tumor originating from nasopharyngeal epithelium, importance of EBV DNA, the aim of the present study with a unique geographical distribution pattern and is to investigate surrogate endpoints to shorten the high incidence in Southeast Asia and southern China, time of therapeutic evaluation for different subgroup especially in Guangdong [1-4]. Over the past 30 years, of patients with NPC receiving IMRT. the overall survival rate of nasopharyngeal carcinoma has been significantly improved due to the advances Materials and Methods in radiotherapy and the extensive use of chemotherapy [5, 6]. Presently, the 5-year survival 1. Patients rate of nasopharyngeal carcinoma is approximately We continuously reviewed the medical records 80-90%, with a local control rate of 90% or more. The of 3894 patients who were diagnosed with NPC in the distant metastasis free survival rate was 66% -84% Sun Yat-Sen University Cancer Center (Guangzhou, [7].Locoregional recurrence and distant metastasis at China) during the period between January 2008 and the time of 5 years after treatment accounted for December 2010. The inclusion criteria for this study nearly 100% [8]. Therefore, 5-year survival rate is used were: (1) Newly diagnosed M0 stage patients. (2) as the foremost endpoint in clinical trials [9, 10]. Receiving intensity modulated radiation therapy The 5-year survival endpoint was objective, (IMRT). (3) Epstein-Barr virus related test data was accurate and convenient to analyze and was the most complete. (4) No lost follow-up within 5 years. reliable clinical trial endpoint. However, there are According to the above criteria, our study excluded several disadvantages, including requirements for a 455 patients with non-M0 stage nasopharyngeal large sample size, high medical cost and prolonging carcinoma, 2080 patients who did not receive IMRT, the clinical trial proposal-validation-period. At the 481 patients without complete Epstein-Barr virus test same time, non-tumor-related death during data and 48 patients lost follow-up within 5 years. A follow-up, as well as some of the rescue treatment total of 830 patients met the criteria and were enrolled after the progression, will have a bias on the endpoint. in this retrospective clinical study. All patients were In the era of individualized treatment, utilizing the restaged according to the 8th edition of the 5-year survival endpoint has many limitations, and UICC/AJCC staging system and the patient data was more and more oncologists are beginning to study collected by two physicians specializing in surrogate endpoints instead of the "true clinical nasopharyngeal cancer. Any divergences were outcome" [11-14]. resolved by consensus. Previously, a study about surrogate endpoints shortening the time of therapeutic evaluation with 2. Treatment nasopharyngeal carcinoma conducted by our group Patients enrolled in this study underwent radical provided evidence supporting the use of overall IMRT. Prescribed radiation dose was 2.0 to 2.27 Gy survival (OS) and loco-regional control (LRC) per fraction with 5 daily fractions per week for 6 to 7 endpoints <5 years as surrogate endpoints [15]. The weeks. Cumulative doses were 66 Gy or greater to the research by the Meta-Analysis of Chemotherapy in primary tumor and ≥50 Gy to the bilateral cervical Nasopharynx Carcinoma (MAC-NPC) Collaborative lymph nodes and potential sites of local infiltration. Group demonstrated that two-year PFS and distant Chemotherapy included induction, concomitant metastasis-free survival (DMFS) are valid surrogate and adjuvant chemotherapy. The choice of end points for five-year OS to assess the treatment chemotherapy regimen and the number of courses effects of chemotherapy in loco-regionally advanced used were determined by the clinicians. The NPC [16].Nonetheless, none of the previous studies, chemotherapy regimen was mainly platinum based. including our previous study, have mentioned plasma Epstein-Barr virus DNA (EBV DNA). At 3. Follow-up and Endpoints present, pretreatment EBV load has been confirmed to The patients were followed up with by phone be greatly associated with patient outcome and can be and/or in the outpatient clinic. The follow-up items used as a strong prognostic biomarker [17-19]. included survival status, local failure and distant Recently, the 8th edition of TNM staging system metastasis. All the events were confirmed by was published to further help clinicians evaluate the pathological examination and/or imaging. The last prognosis and assign proper treatment [20, 21]. Tang date of follow-up was May 2017. Four common used LL et al [22] indicated a better segregation of survival survival endpoints were selected, overall survival curves in NPC patients using the 8th edition system (OS), progression-free survival (PFS), loco-regional compared with those using the 7th edition system, recurrence-free survival (LRFS), and distant http://www.jcancer.org Journal of Cancer 2018, Vol. 9 3354 metastasis-free survival (DMFS). OS was defined as than one standard deviation (the standard deviation is time from diagnosis to death from any cause. PFS was calculated from the 5 different year survival rates). defined as time from diagnosis to loco-regional failure, distant failure, or death from any cause, 5. Statistical Analysis whichever occurred first. LRFS was defined as time The survival rates were calculated by life table. from diagnosis to loco-regional failure. DMFS was Survival curves were drawn using the Kaplan-Meier defined as time from diagnosis to distant failure. method with the two-sided log-rank test. Survival rate comparisons were performed with the McNemar's 4. Study design test. All the tests were two-tailed and a P-value <0.05 The flowchart of our study design is presented in was considered to indicate a statistically significant Fig 1. All patients were divided into three groups difference. The statistical analyses were performed according to levels of EBV DNA measured: low EBV with Statistical Product and Service Solutions DNA (< 103 copies/ml), mid EBV DNA (≥103 software version 22.0 (SPSS Inc., Chicago, IL, USA). copies/ml and<105 copies/ml), high EBV DNA (≥105 copies/ml), plus all the patients as a group, for a total Results of four groups.