KEYWORDS: chemoradiotherapy, efficacy, late toxicity, nasopharyngeal carcinoma, radiotherapy, randomized controlled trial.

Transcription

1 A Multicenter, Phase 3, Randomized Trial of Concurrent Chemoradiotherapy Plus Adjuvant Chemotherapy Versus Radiotherapy Alone in Patients With Regionally Advanced Nasopharyngeal Carcinoma: 10-Year Outcomes for Efficacy and Toxicity Anne W. M. Lee, MD 1 ; Stewart Y. Tung, FRCR 2 ; Wai Tong Ng, MD 3 ; Victor Lee, MD 1 ; Roger K. C. Ngan, FRCR 4 ; Horace C. W. Choi, PhD 1 ; Lucy L. K. Chan, BSc 3 ; Lillian L. Siu, MD 5 ; Alice W. Y. Ng, FRCR 2 ; To Wai Leung, MD 6 ; Harry H. Y. Yiu, FRCR 4 ; Brian O Sullivan, MD 5 ; and Rick Chappell, PhD 7 BACKGROUND: Concurrent-adjuvant chemoradiotherapy (CRT) became a recommended treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) with the first report of a significant survival benefit from the Intergroup 0099 study. However, data on late toxicities are lacking. Previous reports from the current NPC-9901 trial have raised concerns about a failure to improve overall survival (OS) because of an inadequate impact on distant control and increases in toxicities/noncancer deaths. Validation of the longterm therapeutic ratio is needed. METHODS: In this phase 3, randomized trial, patients with nonkeratinizing NPC (stage T1-4/N2-3/ M0) were randomly assigned to radiotherapy alone (176 patients) or to CRT (172 patients) with concurrent cisplatin followed by adjuvant cisplatin plus fluorouracil. RESULTS: The early findings of significant improvements in tumor control were maintained: the CRT group achieved significantly higher 10-year overall failure-free (62% vs 50%; P 5.01) and progression-free survival rates (56% vs 42%; P 5.006) because of superior locoregional control (87% vs 74%; P 5.003), whereas the impact on distant control remained insignificant (68% vs 65%; P 5.24). The initial differences in toxicities diminished with longer follow-up: 52% versus 47% at 10 years for late toxicities (P 5.20), 4.1% versus 2.8% for deaths due to treatment toxicity, and 15.1% versus 13.1% for deaths due to incidental/unknown causes. The OS rate for the CRT group reached statistical superiority at 10 years (62% vs 49%; P 5.047). CONCLUSIONS: Long-term results have confirmed that CRT can significantly improve OS without excessive late toxicities for patients with regionally advanced NPC. However, more potent therapy is needed for improving distant control, especially for patients with stage IVA/B disease. Cancer 2017;123: VC 2017 American Cancer Society. KEYWORDS: chemoradiotherapy, efficacy, late toxicity, nasopharyngeal carcinoma, radiotherapy, randomized controlled trial. INTRODUCTION Radiotherapy (RT) has been the primary treatment modality for nasopharyngeal carcinoma (NPC) since the advent of megavoltage technology. The addition of chemotherapy to RT is an important strategy for improving the tumor control of locoregionally advanced NPC because this has the potential for both enhancing the local effect of RT and eradicating micrometastases. Although NPC is relatively chemosensitive, a survival benefit was not demonstrated until the Intergroup 0099 study using concurrent-adjuvant chemoradiotherapy (CRT). 1 Preliminary results for patients with stage II to IVB disease (based on the staging criteria of the TNM system, 5th edition) showed very impressive improvements in all endpoints, with overall survival (OS) of 78% versus 47% at 3 years. However, when the results were first reported in the late 1990s, there were concerns about the exact magnitude of the benefit because the outcomes for the RT group were substantially worse than those reported by other studies in the same period. Furthermore, there were no data on late toxicities. This led to confirmatory trials in Asia, where NPC is most prevalent. 2-8 Both Wee et al 2,3 and Chen et al 4,5 showed that concurrent-adjuvant CRT could significantly improve both event-free survival and OS for patients with stage III to IVB disease. The NPC-9901 trial, 6,7 initiated by the Hong Kong Nasopharyngeal Cancer Study Group, differed from the Corresponding author: Anne W. M. Lee, MD, Department of Clinical Oncology, University of Hong Kong Shenzhen Hospital, 1/F Professorial Block, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong, China; awmlee@hku.hk 1 Department of Clinical Oncology, University of Hong Kong and University of Hong Kong Shenzhen Hospital, Hong Kong, China; 2 Tuen Mun Hospital, Hong Kong, China; 3 Pamela Youde Nethersole Eastern Hospital, Hong Kong, China; 4 Queen Elizabeth Hospital, Hong Kong, China; 5 Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 6 Queen Mary Hospital, Hong Kong, China; 7 Department of Biostatistics, University of Wisconsin Medical School, Madison, Wisconsin. Additional supporting information may be found in the online version of this article. DOI: /cncr.30850, Received: April 25, 2017; Revised: May 24, 2017; Accepted: May 25, 2017, Published online June 29, 2017 in Wiley Online Library (wileyonlinelibrary.com) Cancer November 1,

2 other trials because it focused on patients with T1-4/N2-3 disease (the group with the highest risk of distant failure). Although this trial concurred that the Intergroup 0099 regimen could significantly improve event-free survival, the 3-year 6 and 5-year results 7 did not show significant gains in OS, partly because of insignificant improvements in distant control and partly because of increased deaths due to treatment toxicities and incidental causes. We continued to follow up the surviving patients to assess the late toxicities and pattern of failure. The current study provided a unique opportunity for evaluating the ultimate impact on the therapeutic ratio from the addition of concurrent-adjuvant CRT for NPC and for identifying learning points for future studies. MATERIALS AND METHODS Study Design and Patients This multicenter, phase 3, randomized controlled trial was performed by 4 centers from Hong Kong and 1 center from Canada. As shown in previous reports, 6,7 the key eligibility criteria included histologically confirmed nonkeratinizing (differentiated or undifferentiated) carcinoma of the nasopharynx, as classified by the World Health Organization system, and T1-4/N2-3/M0 disease, as classified by the TNM system (5th edition). All participants provided written informed consent. The protocol was approved by the institutional ethics committees of the individual participating centers. The trial was conducted in accordance with the Declaration of Helsinki and was monitored by an independent data monitoring committee. Eligible patients were stratified by the participating center, T category (T1-2 vs T3-4), and N category (N2 vs N3). They were randomly assigned with a blocked randomization scheme in a 1:1 ratio to receive either RT alone (the RT group) or RT in combination with concurrent-adjuvant chemotherapy (the CRT group). Randomization was generated by the consulting statistician in sealed envelopes labeled by the stratum; they were unsealed only after patient registration. Treatment allocation was not masked, but the statisticians were blinded. Assessment and Treatment Details of the assessment, treatment, and statistical methods have been described in previous reports. 6,7 Patients in both treatment groups were irradiated with megavoltage photons with the same RT technique and dose in line with the treatment policy of each individual center. Those assigned to the CRT group were given additional chemotherapy according to the Intergroup 0099 regimen: 1 cisplatin (100 mg/m 2 ) was given intravenously every 3 weeks for 3 cycles and was started with the commencement of RT, and this was followed by a combination of cisplatin (80 mg/m 2 ) and fluorouracil (1000 mg/m 2 /d by 96-hour infusion) every 4 weeks for 3 cycles. The first assessment of the tumor response was performed 6 to 16 weeks after the completion of RT. For statistical purposes, persistent primary or nodal disease 16 weeks after the completion of RT was defined as locoregional failure. The treatment of residual disease and tumor relapse (if detected) was provided in line with the policy of the individual center. RT-related late toxicities were graded according to the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group. Statistical Methods All events were measured from the date of the random assignment. The primary endpoints included the overall failure-free rate (FFR; time to first failure at any site) and progression-free survival (PFS; time to first failure or death from any cause). The secondary endpoints for treatment efficacy included the OS, locoregional failure-free rate (LR-FFR), and distant failure-free rate (D-FFR). The secondary endpoints for safety included major toxicities (except for xerostomia and dental caries) of grade 3 or higher; the current article is focused on late toxicities. For patients who had re-irradiation for the treatment of locoregional relapses, events were censored at the commencement of re-irradiation so that toxicities incurred solely by the primary treatment could be assessed. All analyses were performed on an intention-to-treat basis; statistical tests comparing treatment groups were 2- sided, and P values less than.05 were considered to indicate statistical significance. Furthermore, for the calculation of the hazard ratios (HRs) with the Cox regression model, the assumptions of proportional hazards were confirmed on the basis of Schoenfeld residuals. This trial was registered with the Hospital Authority Research Ethics Committee Clinical Trial Registry by the Hong Kong Hospital Authority (identification number HARECCTR ) in accordance with the World Health Organization s International Clinical Trial Registry Platform requirements. RESULTS From March 1999 to January 2004, in compliance with the targeted accrual size of 340, 348 eligible patients were randomly assigned (Fig. 1), and only 4% were lost to follow-up. All survivors had a minimum follow-up of Cancer November 1, 2017

3 10-Year Outcomes of CRT for Advanced NPC/Lee et al Figure 1. Consolidated Standards of Reporting Trials flow diagram showing the design, enrollment, and outcomes of this study (the NPC-9901 trial). Patients with T1-4/N2-3/M0 nasopharyngeal carcinoma were randomly assigned to radiotherapy either alone or with the addition of concurrent-adjuvant chemotherapy. years; the median duration for the whole series was 10.7 years (range, years). The 2 treatment groups were well balanced in all patient characteristics, tumor factors, and RT parameters (Supporting Table 1 [see online supporting information]). Four patients had major protocol violations (Fig. 1): 2 patients (1.2%) in the CRT group did not receive chemotherapy, and 2 patients (1.1%) in the RT group received chemotherapy. The compliance with chemotherapy in the CRT group has been described in a previous report. 6 Efficacy Details of the outcome comparisons are shown in Table 1 and Figure 2. Altogether, 150 patients experienced failure (at 1 or more sites), and 183 died (of any cause). In comparison with the RT-alone group, the CRT group achieved significantly higher overall FFR (62% vs 50%), PFS (56% vs 42%), and cancer-specific survival (72% vs 58%) at 10 years. The improvement was strongly significant for LR-FFR (87% vs 74%) but was insignificant for D-FFR (68% vs 65%). Among the patients suffering a relapse, the majority (44 of 63 [70%] in the CRT group and 66 of 87 [76%] in the RT group) were given further treatment. Besides aggressive locoregional treatment, chemotherapy was used in 33 patients in the CRT group and in 53 patients in the RT group. The successful salvage rate (ie, the patients were alive without disease at the last assessment) was 9% for both groups. The OS rate of the CRT group became superior to the OS rate of the RT group with longer follow-up (62% vs 49% at 10 years; P 5.010). Analyses of the incidence of deaths due to different causes (Supporting Table 2 [see online supporting information]) showed that the CRT group had a significant reduction in deaths due to disease progression (27.3% vs 42.6%; P 5.004) without a significant increase in deaths directly attributable to Cancer November 1,

4 TABLE 1. Comparison of Efficacy Outcomes: Chemoradiotherapy Group Versus Radiotherapy-Alone Group Subgroup Analysis Endpoint Whole Cohort: T1-4/N2-3 (n 5 348) III (n 5 206) IVA/B (n 5 142) Overall failure-free rate Actuarial rate at 10 y 62% vs 50% 75% vs 59% 44% vs 37% P HR of defining events (95% CI) 0.66 ( ) 0.51 ( ) 0.71 ( ) Progression-free survival Actuarial rate at 10 y 56% vs 42% 70% vs 50% 38% vs 29% P HR of defining events (95% CI) 0.68 ( ) 0.55 ( ) 0.74 ( ) Overall survival Actuarial rate at 10 y 62% vs 49% 74% vs 60% 45% vs 31% P HR of defining events (95% CI) 0.74 ( ) 0.62 ( ) 0.80 ( ) Cancer-specific survival Actuarial rate at 10 y 72% vs 58% 83% vs 68% 56% vs 42% P HR of defining events (95% CI) 0.61 ( ) 0.46 ( ) 0.68 ( ) Locoregional failure-free rate Actuarial rate at 10 y 87% vs 74% 90% vs 77% 83% vs 69% P HR of defining events (95% CI) 0.45 ( ) 0.39 ( ) 0.49 ( ) Distant failure-free rate Actuarial rate at 10 y 68% vs 65% 80% vs 74% 52% vs 49% P HR of defining events (95% CI) 0.80 ( ) 0.66 ( ) 0.82 ( ) Abbreviations: CI, confidence interval; HR, hazard ratio. P values were calculated with the log-rank test. chemotherapy/rt toxicity (4.1% vs 2.8%; P 5.74) or incidental/unknown causes (15.1% vs 13.1%; P 5.69). Further analyses of the pattern at a different period showed that the rate of excess noncancer deaths in the CRT group was 5.9% for patients with observation for 5 years, but there was no increase for those with longer follow-up. On the other hand, deaths due to treatment toxicity increased in the RT group from 0% to 1.8% to 3.6% for patients with observation for 5 years, for >5to 10 years, and for >10 years, respectively. Subgroup analyses (Table 1) showed a favorable trend for all endpoints (except for distant failure) with the addition of chemotherapy for both stage III (n 5 206) and stage IVA/B (n 5 142), but the magnitude of the hazard reduction was generally greater for stage III. The 10- year OS rate for the CRT group was 74% at stage III but only 45% at stage IVA/B (P 5.031; Fig. 3). Multivariate analyses (Table 2) based on the intention-to-treat principle showed that the addition of chemotherapy was an independent factor for improving all endpoints except for D-FFR. Further analyses of outcomes based on actual treatment showed that patients who had received 2 or more cycles in the concurrent phase (n 5 164) achieved significantly better LR-FFR (P 5.001), but the impact on D-FFR was insignificant (P 5.15). Patients who had received 2 or more cycles in both the concurrent phase and the adjuvant phase (n 5 140) achieved significant improvements in both 10-year LR-FFR (87.9% vs 75.0%; P 5.003) and D-FFR (73.0% vs 61.8%; P <.001). Safety Altogether, there were 132 occurrences of grade 3 or higher late toxicity (Table 3). The mean latency from the commencement of RT to the manifestation of late toxicity was 4.2 years in the CRT group and 4.7 years in the RTalone group (P 5.40). The overall actuarial rate of grade 3 late toxicity was higher in the CRT group during the first 3 years. However, the difference gradually diminished and became insignificant: 52.3% versus 46.8% at 10 years (absolute difference, 5.5%; P 5.20; HR, 1.25; 95% confidence interval [CI], ; Fig. 2). None of the damage to different normal structures was statistically significantly excessive in the CRT group (Table 3). The multivariate analysis (Table 2) showed that the addition of chemotherapy did not produce a significant increase in major late toxicity (HR, 1.22; 95% CI, ). Eleven patients developed a second malignancy within the irradiated areas; it was not possible to determine whether they were de novo or radiation-induced. However, 4150 Cancer November 1, 2017

5 10-Year Outcomes of CRT for Advanced NPC/Lee et al Figure 2. Comparisons of the CRT and RT-alone groups in terms of (A) overall failure-free rates, (B) progression-free survival, (C) overall survival, (D) disease specific survival, (E) locoregional failure-free rates, (F) distant failure-free rates, and (G) major late toxicity (grade 3 or higher) rates. The vertical, solid lines show the 95% confidence intervals of the Kaplan-Meier estimates at 5, 10, and 15 years. CRT indicates chemoradiotherapy; RT, radiotherapy. Cancer November 1,

6 Figure 3. Subgroup analyses: efficacy comparisons of the CRT and RT-alone groups at stages III and IVA/B in terms of (A,B) overall survival, (C,D) locoregional failure-free rates, and (E,F) distant failure-free rates. CRT indicates chemoradiotherapy; RT, radiotherapy. on the basis of their location and latency, we regarded them as RT toxicities to avoid underestimating the problem. There was no statistical difference in the mortality rate due to RT toxicity between the CRT and RT groups (3.5% vs 2.8%). Altogether, 11 patients died of RTinduced late toxicities: 8 because of a second malignancy 4152 Cancer November 1, 2017

7 10-Year Outcomes of CRT for Advanced NPC/Lee et al TABLE 2. Multivariate Analysis of the Significance of the Treatment Group (Based on the Intention-to-Treat Principle) and Other Potential Covariates Factor Locoregional Failure Distant Failure All Failures Failure or Death All Deaths Cancer-Specific Survival Late Toxicity Treatment group: CRT vs RT alone HR (95% CI) 0.41 ( ) 0.71 ( ) 0.58 ( ) 0.61 ( ) 0.68 ( ) 0.56 ( ) 1.22 ( ) P Stage group: IV vs III HR (95% CI) 1.55 ( ) 2.39 ( ) 2.18 ( ) 1.91 (1.43, 2.55) 1.77 ( ) 2.20 ( ) 1.52 ( ) P.11 <.001 <.001 <.001 <.001 < Lactate dehydrogenase per 10 IU/L increase HR (95% CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) P < Age per year increase HR (95% CI) 1.02 ( ) 1.01 ( ) 1.01 ( ) 1.02 ( ) 1.03 ( ) 1.03 ( ) 1.02 ( ) P < Sex: female vs male HR (95% CI) 0.40 ( ) 0.72 ( ) 0.59 ( ) 0.57 ( ) 0.56 ( ) 0.66 ( ) 1.70 ( ) P Radiotherapy technique: 3D vs 2D 6 boost HR (95% CI) 1.09 ( ) 1.01 ( ) 1.18 ( ) 1.29 ( ) 1.57 ( ) 1.25 ( ) 1.30 ( ) P Radiotherapy dose per gray increase HR (95% CI) 0.92 ( ) 0.94 ( ) 0.94 ( ) 0.94 ( ) 0.95 ( ) 0.96 ( ) 1.06 ( ) P <.001 <.001 <.001 <.001 < Abbreviations: 2D, 2-dimensional; 3D, 3-dimensional; CI, confidence interval; CRT, chemoradiotherapy; HR, hazard ratio; RT, radiotherapy. Factors that were statistically significant in the univariate analyses were as follows: age, sex, stage group, lactate dehydrogenase, radiotherapy technique, and total dose. Cancer November 1,

8 TABLE 3. Late Toxicities Chemoradiotherapy (n 5 172) Radiotherapy (n 5 176) Toxicity grade P a Neurological structures, No. (%) 11 (6.4) 1 (0.6) 2 (1.2) 15 (8.5) 0 (0) 0 (0).32 Temporal lobe necrosis 1 (0.6) 1 (0.6) 1 (0.6) 1 (0.6) 0 (0) 0 (0).75 Brainstem damage 0 (0) 0 (0) 0 (0) 1 (0.6) 0 (0) 0 (0) 1.00 Brachial plexopathy 0 (0) 0 (0) 0 (0) 1 (0.6) 0 (0) 0 (0) 1.00 Cranial neuropathy b 7 (4.1) 0 (0) 1 (0.6) 13 (7.4) 0 (0) 0 (0).25 Peripheral neuropathy 4 (2.3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0).06 Soft tissue and bone, No. (%) 13 (7.6) 6 (3.5) 4 (2.3) 18 (10.2) 5 (2.8) 5 (2.8).85 Bone necrosis 0 (0) 1 (0.6) 0 (0) 0 (0) 1 (0.6) 1 (0.6) 1.00 Soft-tissue damage c 12 (7.0) 4 (2.3) 0 (0) 17 (9.7) 1 (0.6) 0 (0).27 Dysphagia 2 (1.2) 0 (0) 0 (0) 4 (2.3) 0 (0) 0 (0).68 Vascular (bleeding) 2 (1.2) 2 (1.2) 0 (0) 1 (0.6) 1 (0.6) 0 (0).57 Radiation-induced malignancy d 0 (0) 1 (0.6) 4 (2.3) 0 (0) 2 (1.1) 4 (2.3) 1.00 Ear (hearing impairment/otitis), No. (%) 39 (22.7) 8 (4.7) 0 (0) 32 (18.2) 4 (2.3) 0 (0).26 Eye, No. (%) 1 (0.6) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0).49 Endocrine dysfunction, No. (%) 17 (9.9) 0 (0) 0 (0) 13 (7.4) 0 (0) 0 (0).45 Late toxicity at any structure (maximum grade), No. (%) 54 (31.4) 12 (7.0) 6 (3.5) 46 (26.1) 9 (5.1) 5 (2.8).52 a P values were calculated across toxicity grades (grades 0-2, 3, 4, and 5) with the chi-square test (or Fisher s exact test when appropriate). b Patients with toxicities in cranial neuropathies: XII (n 5 19), XII 1 VI (n 5 1), and VII (n 5 1). Optic nerve damage was not reported in this study. c Soft-tissue damage included head and neck tissue necrosis, fibrosis, and trismus. d Patients with radiation-induced malignancy: squamous cell carcinoma of the oral cavity / oropharynx (n 5 5), soft-tissue sarcoma over the irradiated area (n 5 5), and thyroid cancer (n 5 1). within the RT portal and 3 because of temporal lobe necrosis, skull base necrosis, or aspiration pneumonia related to the last 4 cranial nerve palsies. DISCUSSION Among the 4 randomized trials evaluating the addition of concurrent cisplatin plus adjuvant cisplatin-fluorouracil to conventional fractionated RT, 1-9 our NPC-9901 trial has the largest sample size and is the only trial focusing on patients with N2-3 disease (the group with the highest metastatic risk). The current update is the first report with detailed 10-year outcome data for both efficacy and late toxicities so that the ultimate therapeutic ratio can be evaluated. Similar to the trials by Wee et al 2,3 and Chen et al, 4,5 the current trial was confined to patients with nonkeratinizing carcinoma; the applicability to keratinizing carcinoma is uncertain. Another point to note is the RT technique used: only 51% of the patients in our series were irradiated with the 3-dimensional conformal technique throughout the study. The magnitude of the benefit in the modern era of intensity-modulated RT has yet to be studied. All 4 trials consistently confirmed that concurrentadjuvant CRT could significantly improve PFS. An evaluation at 5 years showed an absolute gain of 29% in the Intergroup 0099 study, 9 whereas the 3 confirmatory trials showed fairly consistent absolute gains of 9% to 13% 3,5,7 along with reductions in the hazard of failure or death of 28% to 35%. The current update confirmed that this significant improvement was maintained at 10 years (absolute gain, 14%; hazard reduction, 32%). The impact of concurrent-adjuvant CRT on the pattern of failures is less clear; the variation might be explained at least partly by the differences in the proportions of advanced T and N categories among the trials. Both the preliminary reports by the Intergroup 0099 study 1 and Chen et al 4 showed significant improvements in both LR- FFR and D-FFR. However, both endpoints became insignificant in the subsequent 5-year report by Chen et al. 5 In our NPC-9901 trial, assessments at all time points showed significant improvements in LR-FFR (42% with T3-4 disease and 100% with N2-3 disease); the current update confirmed a significant 13% absolute gain at 10 years with CRT (87% vs 74%). However, our trial raised the concern that the impact on D-FFR was statistically insignificant at all time points for this cohort of patients with an absolute gain of only 3% (68% vs 65% at 10 years). Although the other 3 trials showed significant improvements in OS, 1-5,9 previous reports from our NPC-9901 trial showed contrary results: OS in the CRT group was almost identical to OS in the RT-alone group at 3 years, 6 and it diverged only by a 4% gain at 5 years. 7 Interestingly, this divergence steadily widened to reach statistical significance with a hazard reduction of 26% and an absolute gain of 13% at 10 years (62% vs 49%; Fig. 2). This trend in OS was not due to the pattern of failures but rather was due to the pattern of deaths due to treatment toxicities and incidental/unknown causes 4154 Cancer November 1, 2017

9 10-Year Outcomes of CRT for Advanced NPC/Lee et al (Supporting Table 2 [see online supporting information]). Our early reports attributed the increase in deaths to incidental/unknown causes, 6,7 but these diminished with longer follow-up and became insignificant in the current analyses (19% vs 16%). At 3 years, CRT produced a significant 31% increase in acute toxicities and a 15% increase in late toxicities of grade 3 or higher in comparison with RT alone, but the difference in the actuarial late toxicity rate gradually narrowed to 6% at 5 and 10 years (Fig. 2). In this series, deaths due to treatment toxicity steadily increased in the RT group from 0% for survivors with 5 years of follow-up to 3.6% for those with >10 years. It appeared that the latency to RT-induced toxicities was shorter in the CRT group versus the RT group (4.7 vs 4.2 years), although the difference was not statistically significant (P 5.40). Our current study also suggests caution about the predicting power of short-term PFS for long-term survival endpoints. An NPC study by Rotolo et al 10 showed that 3-year PFS could predict 5-year OS. In our series, although there was no significant difference in PFS between the RT and CRT groups at 3 years, the difference became significant at 5 years and was maintained at 10 years. This occurred because, in the short term, the benefit of improved tumor control by CRT was offset by deaths from toxicities or incidental causes, and PFS combined both treatment failures and deaths due to any cause. It was only when we looked at just the treatment failure pattern that the overall FFR at 3 years could really predict the final tumor control rate as indicated by the FFR at 5 and 10 years. The pattern of failures at locoregional and distant sites at 3 years was also maintained at 5 and 10 years. Similarly, the difference in OS between the RT and CRT groups was statistically insignificant at both 3 6 and 5 years, 7 but this became significant at 10 years because of the slowly increasing rate of death due to late toxicities in the RT group. Hence, it is important to note that for a disease with a notoriously high risk of late toxicities, longterm follow-up is needed to fully assess the ultimate therapeutic ratio. On the other hand, it is reassuring that all 4 randomized trials consistently confirmed that concurrentadjuvant chemotherapy could significantly improve both PFS and OS. More importantly, the current update with a median observation period of 10.7 years showed that this treatment was safe: there was no significant increase in late toxicity or noncancer deaths. A study by the Meta- Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) Collaborative Group 11 with a median follow-up of 7.7 years similarly showed that the addition of concurrent-adjuvant chemotherapy (1267 patients in all) could significantly reduce the hazard of all deaths by 35% (HR, 0.65; 95% CI, ) without a significant increase in noncancer deaths (HR, 1.19; 95% CI, ). This favorable long-term therapeutic ratio for NPC is contrary to the results of the Radiation Therapy Oncology Group trial for laryngeal cancer, 12 which showed a loss of the survival gain with concurrent cisplatin (OS, 28% vs 32% at 10 years) due to a significant increase in noncancer deaths (31% vs 17%). One unresolved uncertainty is the exact magnitude of the contribution of the adjuvant phase. Results from the randomized trial by Chen et al 13 comparing concurrent-adjuvant chemotherapy and concurrent chemotherapy showed that the concurrent-adjuvant group did not achieve a significant increase in estimated 5-year FFR (HR, 0.88; 95% CI, ). However, it should be cautioned that the impact on NPC outcomes could take a prolonged period to manifest (as shown by our study); long-term follow-up is needed for definitive conclusions. The analyses by the MAC-NPC Collaborative Group favored additional chemotherapy. 11,14 The comparisons of concurrent chemotherapy were more heterogeneous: a review of individual trials showed that only the trial using concurrent cisplatin for patients largely with stage II disease treated by 2-dimensional RT achieved significant benefits for both PFS and OS. 15 The ranking of different treatment strategies by network analyses showed that the concurrent-adjuvant chemotherapy group achieved the highest benefits for OS and PFS in comparison with RT alone: the P scores were 96% and 94%, respectively, whereas the corresponding P scores for the concurrent chemotherapy group were 70% and 52%, respectively (the P score is a statistical score indicating the extent of the certainty that a treatment is better than other competing treatments; a higher P score means a greater probability of being the best). 14 The concurrent-adjuvant group achieved significantly better PFS than the concurrent group (HR, 0.81; 95% CI, ). Although the current concurrent-adjuvant chemotherapy is consistently superior to RT alone, our trial has shown that further improvements in efficacy for distant control are needed, especially for patients with stage IVA/ B disease. A major reason for its inadequate impact on distant control is the poor tolerance of the adjuvant phase. Analyses of outcomes based on actual treatment have shown that patients who receive 2 or more cycles in both the concurrent and adjuvant phases achieve significant improvements not only in LR-FFR but also in D-FFR. Cancer November 1,

10 One potential strategy for improvement is to change the time sequence to induction-concurrent chemotherapy because the early administration of this potent chemotherapy combination at the full dose could be more effective for the eradication of micrometastases. 16 Indeed, the network analyses by the MAC-NPC Collaborative Group 14 showed that the induction-concurrent group achieved the highest benefit for D-FFR in comparison with the concurrent-adjuvant chemotherapy group and the concurrent chemotherapy alone group: the P scores were 95%, 72%, and 48%, respectively. Early trials evaluating induction-concurrent chemotherapy and concurrent chemotherapy alone showed conflicting outcomes, but promising 3-year results were recently reported by Sun et al 17 with induction cisplatin, fluorouracil, and docetaxel followed by concurrent cisplatin (80% vs 72%; P 5.034) and by Cao et al 18 with induction cisplatin and fluorouracil followed by concurrent cisplatin (82% vs 74%; P 5.028). The NPC-0501 trial by the Hong Kong Nasopharyngeal Cancer Study Group was the only trial aiming to evaluate inductionconcurrent chemotherapy and concurrent-adjuvant chemotherapy: preliminary results showed that the group randomized to receive induction cisplatin-capecitabine followed by cisplatin in concurrence with conventional fractionated RT achieved better PFS than the concurrentadjuvant group (81% vs 75% at 3 years; P 5.045). 19 Longer follow-up of these trials is needed for confirmation, especially because there is a concern that induction chemotherapy may affect the tolerability of chemotherapy in the concurrent phase. Another key focus for future trials is personalized refinement of the treatment strategy. An ongoing NRG trial (NCT ) is attempting to use post-rt Epstein-Barr virus DNA levels for tailoring adjuvant chemotherapy. Furthermore, we should explore the possibility of identifying patients who could be safely treated with RT alone. Current guidelines recommend CRT for all stage II/IVB patients, but even for the current cohort treated with RT techniques that are suboptimal by modern standards, 50% of stage III patients and 29% of stage IVA/B patients treated with RT alone were progressionfree at 10 years. Further clinical and translational studies are needed to identify good-risk patients who can be spared unnecessary chemotherapy. In conclusion, the long-term results of the NPC trial confirm that adding concurrent cisplatin plus adjuvant cisplatin-fluorouracil to conventional fractionated RT could significantly improve both PFS and OS at 10 years without significant increases in late treatment toxicities and noncancer deaths. However, a more potent regimen for distant control is needed, especially for patients with stage IVA/B disease. Further clinical and translational studies are also needed to work toward personalized medicine and to spare good-risk patients overtreatment. FUNDING SUPPORT This trial was supported by grants from 3 nongovernmental organizations: the Hong Kong Cancer Fund, the Ho Hung Chiu Medical Foundation, Limited, and the Hong Kong Anti-Cancer Society. CONFLICT OF INTEREST DISCLOSURES The authors made no disclosures. AUTHOR CONTRIBUTIONS Anne W. M. Lee: Conceptualization, methodology, investigation, resources, writing original draft, writing review and editing, supervision, project administration, and funding acquisition. Stewart Y. Tung: Conceptualization, methodology, investigation, resources, writing review and editing, supervision, project administration, and funding acquisition. Wai Tong Ng: Conceptualization, methodology, investigation, resources, writing original draft, writing review and editing, supervision, and project administration. Victor Lee: Investigation, resources, and writing review and editing. Roger K. C. Ngan: Conceptualization, methodology, investigation, resources, writing review and editing, supervision, project administration, and funding acquisition. Horace C. W. Choi: Formal analysis, data curation, writing review and editing, and visualization. Lucy L. K. Chan: Formal analysis, data curation, writing review and editing, and visualization. Lillian L. Siu: Methodology and writing review and editing. Alice W. Y. Ng: Investigation, resources, and writing review and editing. To Wai Leung: Investigation, resources, and writing review and editing. Harry H. Y. Yiu: Investigation, resources, and writing review and editing. Brian O Sullivan: Methodology and writing review and editing. Rick Chappell: Methodology, formal analysis, and writing review and editing. REFERENCES 1. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemotherapy versus radiochemotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study J Clin Oncol. 1998;16: Wee J, Tan EH, Tai BC, et al. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union Against Cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol. 2005;23: Wee J. 4th FY Khoo Memorial Lecture 2008: Nasopharyngeal Cancer Workgroup the past, the present and the future. Ann Acad Med Singapore. 2008;37: Chen Y, Liu MZ, Liang SB, et al. Preliminary results of a prospective randomized trial comparing concurrent chemoradiotherapy plus adjuvant chemotherapy with radiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma in endemic regions of China. Int J Radiat Oncol Biol Phys. 2008;71: Chen Y, Sun Y, Liang SB, et al. Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy 4156 Cancer November 1, 2017

11 10-Year Outcomes of CRT for Advanced NPC/Lee et al alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China. Cancer. 2013;119: Lee AWM, Lau WH, Tung SY, et al. Preliminary results of a randomized study on therapeutic gain by concurrent chemotherapy for regionally-advanced nasopharyngeal carcinoma: NPC-9901 trial by the Hong Kong Nasopharyngeal Cancer Study Group. J Clin Oncol. 2005;23: Lee AWM, Tung SY, Chua DTT, et al. Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2010;102: Lee AWM, Tung SY, Chan ATC, et al. Preliminary results of a randomized study (NPC-9902 trial) on therapeutic gain by concurrent chemotherapy and/or accelerated fractionation for locally advanced nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2006;66: Al-Sarraf M, LeBlanc M, Giri PG, et al. Superiority of five year survival with chemoradiotherapy (CT-RT) vs radiotherapy in patients (pts) with locally advanced nasopharyngeal cancer (NPC). Intergroup (0099) SWOG 8892, RTOG 8817, ECOG 2388) phase III study: final report [abstract 905]. Proc Am Soc Clin Oncol. 2001;20:227a. 10. Rotolo F, Pignon JP, Bourhis J, et al. Surrogate end points for overall survival in loco-regionally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis. JNatlCancerInst.2017;109:djw Blanchard P, Lee A, Marguet S, et al. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol. 2015;16: Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31: Chen L, Hu CS, Chen XZ, et al. Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: long-term results of a phase 3 multicentre randomised controlled trial. Eur J Cancer. 2017;75: Ribassin-Majed L, Marguet S, Lee AWM, et al. What is the best treatment of locally advanced nasopharyngeal carcinoma? An individual patient data network meta-analysis J Clin Oncol. 2016;35: Chen QY, Wen YF, Guo L, et al. Concurrent chemoradiotherapy vs radiotherapy alone in stage II nasopharyngeal carcinoma: phase III randomized trial. J Natl Cancer Inst. 2011;203: Lee AWM, Yau TK, Wong DHM, et al. Treatment of stage IV(A-B) nasopharyngeal carcinoma by induction-concurrent chemoradiotherapy and accelerated fractionation. Int J Radiat Oncol Biol Phys. 2005; 63: Sun Y, Li WF, Chen NY, et al. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016;17: Cao SM, Yang Q, Guo L, et al. Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase III multicentre randomised controlled trial. Eur J Cancer. 2017;75: Lee AWM, Ngan RKC, Tung SY, et al. Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma. Cancer. 2015; 121: Cancer November 1,