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Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicentre randomised controlled trial
European Journal of Cancer 75 (2017) 150e158
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Original Research
Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicentre randomised controlled trial Lei Chen a,1, Chao-Su Hu b,1, Xiao-Zhong Chen c,1, Guo-Qing Hu d,1, Zhi-Bin Cheng e,1, Yan Sun f,1, Wei-Xiong Li g, Yuan-Yuan Chen c, Fang-Yun Xie a, Shao-Bo Liang h, Yong Chen a, Ting-Ting Xu b, Bin Li c, Guo-Xian Long d, Si-Yang Wang e, Bao-Min Zheng f, Ying Guo i, Ying Sun a, Yan-Ping Mao a, Ling-Long Tang a, Yu-Ming Chen j, Meng-Zhong Liu a, Jun Ma a,* a State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China b Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, 270 Dongan Road, Shanghai, 200032, People’s Republic of China c Department of Radiation Oncology, Zhejiang Cancer Hospital, 38 Guang Ji Road, Hangzhou, 310022, People’s Republic of China d Department of Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, 128 San Yang Road, Wuhan, 430030, People’s Republic of China e Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, 52 Mei Hua Road East, Zhuhai, 519000, People’s Republic of China f Department of Radiation Oncology, Beijing Cancer Hospital, 52 Bu Cheng Road, Beijing, 100142, People’s Republic of China g Department of Radiation Oncology, Guangdong General Hospital, 106 Zhong Shan Second Road, Guangzhou, 510080, People’s Republic of China h Department of Radiation Oncology, The First People’s Hospital of Foshan, 81 Lingnan Avenue North, Foshan, 528000, People’s Republic of China i Clinical Trials Centre, Sun Yat-sen University Cancer Centre, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China j Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, 74 Zhongshan Second Road, Guangzhou, 510080, People’s Republic of China
Received 7 November 2016; received in revised form 6 December 2016; accepted 1 January 2017
* Corresponding author: Fax: þ86 20 87343295. E-mail address: [email protected] (J. Ma). 1 These authors contributed equally to this study. http://dx.doi.org/10.1016/j.ejca.2017.01.002 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
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KEYWORDS Nasopharyngeal carcinoma; Adjuvant chemotherapy; Randomised clinical trial; Long-term results
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Abstract Aim of the study: Previous results from our trial showed that adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve survival after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term survival and late toxicities to further assess the ultimate therapeutic index of adjuvant chemotherapy (AC). Methods: Patients with stage IIIeIVB (except T3-4N0) NPC were randomly assigned to receive CCRT plus AC or CCRT only at seven institutions in China. Patients in both groups received cisplatin 40 mg/m2 weekly up to 7 weeks concurrently with radiotherapy. The CCRT plus AC group subsequently received adjuvant cisplatin 80 mg/m2 and fluorouracil 800 mg/m2/d for 120 h every 4 weeks for three cycles. The primary end-point was failurefree survival. Results: Two hundred and fifty-one patients were randomised to the CCRT plus AC group and 257 to the CCRT only group. After a median follow-up of 68.4 months, estimated 5-year failure-free survival rate was 75% in the CCRT plus AC group and 71% in the CCRT only group (hazard ratio 0.88, 95% confidence interval 0.64e1.22; p Z 0.45). 66 (27%) of 249 patients in the CCRT plus AC group and 53 (21%) of 254 patients in the CCRT only group developed one or more late grade 3e4 toxicities (p Z 0.14). Conclusion: Adjuvant cisplatin and fluorouracil chemotherapy still failed to demonstrate significant survival benefit after CCRT in locoregionally advanced NPC based on the longterm follow-up data, and addition of adjuvant cisplatin and fluorouracil did not significantly increase late toxicities. Registration number: NCT00677118. ª 2017 Elsevier Ltd. All rights reserved.
1. Introduction Radiotherapy is the primary treatment modality for non-disseminated nasopharyngeal carcinoma (NPC). The landmark Intergroup-0099 Study was the first randomised trial to achieve a 31% improvement in the 3year overall survival rate in the latter group by adding concurrent chemotherapy and adjuvant chemotherapy (AC) to radiotherapy, and, since 1998, this regimen has been deemed the standard of care for advanced NPC [1]. However, the Intergroup-0099 Study and subsequent three similar trials were unable to tease out the contribution of AC, as the control arm was radiotherapy alone [1e4]. In addition, there were three pure phase 3 ‘AC trials’ for NPC, in which AC was used alone, and all these trials failed to demonstrate a positive impact on survival [5e7]. Based on the results of above trials, the role of the addition of AC to concurrent chemoradiotherapy (CCRT) is questionable. We therefore performed a phase 3 trial to compare CCRT plus AC with CCRT alone, to appraise the contribution of AC in locoregionally advanced NPC. After a median follow-up period of 37.8 months, the 2year results had been published and demonstrated that adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve failure-free survival after CCRT in locoregionally advanced NPC [8]. However, it should be noted that the follow-up period is relatively short, especially for overall survival, and there were no data on detailed late toxicities at that time. Thereafter, meta-analyses which involved our trial and focused on
AC in advanced NPC, unanimously failed to demonstrate a significant advantage from using AC to treat advanced NPC [9e11]. Hence, the purpose of this progress report is to verify the long-term survival and late toxicities and to further assess the ultimate therapeutic index of AC in patients with locoregionally advanced NPC. 2. Patients and methods 2.1. Participants Between 1st June 2006 and 5th March 2010, we did an open-label phase 3 multicentre randomised controlled trial at seven institutions in China. Eligible patients were aged 18e70 years with non-metastatic, histologically proven non-keratinising stage III or IV NPC, except T3-4N0 (6th American Joint Commission on Cancer staging system) [8]. All participants provided written informed consent. Our protocol was approved by the ethics committee or institutional review board at each centre. 2.2. Randomisation and masking Random assignment was done (via sealed envelopes) by the Clinical Trials Centre, Sun Yat-sen University Cancer Centre, with a computer-generated random number code. Participants were stratified according to treatment centre and randomly assigned in blocks of four based on a one-to-one treatment allocation (the
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block size was known only by the statistician). Treatment allocation was not masked. Investigators of each centre enrolled participants and assigned them to interventions. 2.3. Procedures We compared CCRT plus three cycles of cisplatin and fluorouracil AC with CCRT alone. The chemotherapy component of the CCRT regimen consisted of 40 mg/m2 cisplatin given as a 2 h intravenous infusion every week for a maximum of seven cycles, beginning on the first day of radiotherapy [4,12]. Dose modifications were not permitted during concurrent chemotherapy. All patients were treated with 2.0e2.27 Gy per fraction with five daily fractions per week for 6e7 weeks, administered as megavoltage photons using either two-dimensional radiotherapy (2DRT), intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3DCRT), in accordance with the treatment policy adopted by each centre. The cumulative radiation doses were 66 Gy or greater to the primary tumour and 60e66 Gy to the involved neck area. All potential sites of local infiltration and bilateral cervical lymphatics were irradiated to 50 Gy or greater. Three cycles of AC were given to patients in the CCRT plus AC group on days 29e33, 57e61 and 85e89 after radiotherapy, by intravenous infusion of 80 mg/m2 cisplatin on day 1 and 800 mg/m2 per day fluorouracil on days 1e5 (120-h infusion) [4]. Dose modifications during AC were based on the preceding cycle nadir blood counts and interim toxic effects [8]. Participants were assessed every 3 months during the first 3 years, and every 6 months thereafter until death [8]. Our primary end-point was failure-free survival, and our secondary end-points were overall survival, distant failure-free survival, locoregional failure-free survival, initial response rates after treatment and toxic effects. We calculated failure-free survival from the date of randomisation to the date of treatment failure or death from any cause, whichever was first. We calculated overall survival from randomisation to death. For locoregional and distant failure-free survival analyses, we recorded the latencies (ie, time from randomisation) to the first locoregional or remote failure, respectively. We graded chemotherapy-related toxic effects in accordance with Common Terminology Criteria for Adverse Events (version 3.0). We graded radiotherapy-related toxic effects in accordance with both the Acute and the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group [13]. 2.4. Statistical analysis Our study had an 80% power to detect a treatment failure hazard ratio (HR) of 0.56 (two-sided log-rank test p Z 0.05), assuming a 2-year failure-free survival
rate of 85% in the CCRT plus AC group and 75% in the CCRT only group [4,12]. We anticipated that 96 events were needed from 480 patients (240 per treatment group), therefore we needed to recruit a maximum of 253 patients per group (total 506), assuming 5% early dropout or loss to follow-up [14]. Time-to-event data were described with the KaplaneMeier curves, time-to-event intervals compared with the log-rank test (primary analysis). We did multivariable analyses with the Cox proportional hazards model to test the independent significance of different factors. We compared toxicity rates and other categorical variables with the chi-squared test (or Fisher’s exact test, if indicated). All tests were two sided, we deemed p values of less than 0.05 to be significant. We reported the 2-year survival results after the prespecified number of events had occurred (98 patients experienced treatment failure; July 2011) [8]. The cutoff date for the analysis of long-term survival presented here was 30th April 2015, with the median follow-up of 68.4 months. We did all efficacy analyses in our intention-to-treat population, and only patients who received their randomly assigned treatments were included in adverse events analyses. All analyses were done with Stata (version 10).
3. Results Between 1st June 2006 and 5th March 2010, a total of 508 patients were randomly assigned, to receive CCRT plus AC (251) or CCRT alone (257). In total, 477 (94%) of the 508 patients received regular follow-up until death or the latest scheduled assessment (Fig. 1). The last follow-up was 30th April 2015, and the median followup for the entire cohort was 68.4 months (range, 1.3e104.7 months). The two treatment groups were well balanced according to baseline demographic, clinical characteristics and radiotherapy technique (Table 1). Two hundred fourty-seven (98%) of 251 participants in the CCRT plus AC group and 252 (98%) of 257 in the CCRT only group completed the scheduled total radiation dose. One hundred fourteen (45%) of 251 patients in the CCRT plus AC group and 105 (41%) of 257 in the CCRT only group completed all protocol-defined concurrent chemotherapy, with a median of six cycles (interquartile range [IQR] 5e7) for both groups. Reduced concurrent chemotherapy cycles were mostly because of leucopenia, accounting for 98 (74%) of 133 reduced doses in the CCRT plus AC group and 112 (76%) of 148 in the CCRT only group. All three cycles of AC were completed by 158 (63%) of 251 participants in the concurrent chemotherapy plus AC group, with a median three cycles (IQR 1e3). The median total cisplatin doses were 220 mg/m2 (IQR 80e240; 92% of total scheduled doses) and fluorouracil doses were 8000 mg/m2 (4000e12,000; 67% of total scheduled doses). Refusal by patients was the primary
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508 Patients underwent randomization
251 were assigned to receive CCRT plus AC (intention-to-treat population) 2 did not receive CCRT 249 started CCRT (acute safety analysis population during CCRT and late safety analysis population) 2 discontinued radiotherapy 135 discontinued concurrent chemotherapy
257 were assigned to receive CCRT (intention-to-treat population) 3 did not receive CCRT 254 started CCRT (acute safety analysis population during CCRT and late safety analysis population)* 2 discontinued radiotherapy 149 discontinued concurrent chemotherapy
44 did not receive AC 205 started AC (acute safety analysis population during AC) 47 discontinued AC
14 lost to follow-up 188 were alive 170 were disease free 18 were alive with disease 49 were dead 41 died from disease progression 1 died from treatment toxicities 6 died from incident cause 1 died from unknown cause
17 lost to follow-up 182 were alive 164 were disease free 18 were alive with disease 58 were dead 50 died from disease progression 2 died from treatment toxicities 3 died from incident cause 3 died from unknown cause
Fig. 1. Flow diagram. CCRT denotes concurrent chemoradiotherapy and AC adjuvant chemotherapy. * Three patients were subsequently given AC at their request.
reason for uncompleted AC, accounting for 69 (76%) of 91 patients who did not complete AC in the CCRT plus AC group. All dose reductions were because of haematological toxic effects or mucositis. After a median follow-up of 68.4 months, estimated 5-year failure-free survival rate was 75% in the CCRT plus AC group and 71% in the CCRT only group (HR 0.88, 95% confidence interval [CI] 0.64e1.22; p Z 0.45) (Table 2; Fig. 2A). Moreover, two groups did not differ significantly in overall survival, distant failure-free survival or locoregional failure-free survival (Table 2; Fig. 2BeD). On multivariable analyses, treatment group was not a significant predictive factor for failurefree survival (HR 0.90, 0.65e1.25; p Z 0.53), overall survival, distant failure-free survival or locoregional
failure-free survival (Table 3). We did exploratory subset analyses by radiotherapy techniques (IMRT versus 2DRT/3DCRT), stage groups (III versus IVA-B), N classification (N1 versus N2-3) and actual treatments (patients who received CCRT and three cycles of AC versus patients who only received CCRT). The results showed that the effect of AC on failure-free survival, overall survival, distant failure-free survival and locoregional failure-free survival was insignificant in all subgroups (Supplementary Table 1e4). The CCRT plus AC group did not have a significant reduction in the 5-year actuarial incidence of death from disease progression compared with the CCRT only group (14% versus 18%; HR 0.81, 95% CI 0.54e1.22; p Z 0.31); furthermore, the 5-year actuarial incidence of
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death from treatment-related toxicities, incidental causes or unknown reasons were similar in both groups (3% versus 3%, respectively; HR 0.99, 95% CI 0.37e2.63; p Z 0.98). Of the 508 patients in the present study, four patients (0.8%) died from secondary malignancies, two (0.4%) died from infection, two (0.4%) died from cerebral vascular incidents and one (0.2%) died from cardiovascular disease. During CCRT, 156 (63%) of 249 patients in the CCRT plus AC group and 156 (61%) of 254 in the CCRT only group experienced grade 3e4 toxic effects (p Z 0.78); there were no treatment-related deaths. During AC, 87 (42%) of 205 patients in the CCRT plus AC group experienced grade 3e4 toxic effects, and there were no treatment-related deaths (Table 4). Overall, 119 (24%) of 503 patients developed one or more late grade 3e4 toxicities, including 66 (27%) of 249 patients in the CCRT plus AC group and 53 (21%) of 254 patients in the CCRT only group (p Z 0.14). One (0.4%) of 249 patient in the CCRT plus AC group died from temporal lobe necrosis, and two (0.8%) of 254 patient in the CCRT only group died from temporal lobe necrosis and cranial neuropathy, respectively (p Z 0.57). The incidence of grade 3e4 peripheral neuropathy was higher in the CCRT plus AC group compared with the CCRT only group (2% versus 0.4%), and the difference was of borderline significance (p Z 0.05); other late toxicities were not significantly different between two groups (Table 4). Moreover, the incidence of late grade 3e4 toxicities according to
Table 1 Characteristics of the patients. Characteristic
CCRT plus AC CCRT only Total group (N Z 251) group (N Z 257) (N Z 508)
Male sexdno. (%) 192 (77) Agedyear Median 44 Range 19e68 Karnofsky scaledno. (%) 100 17 (7) 90 186 (74) 70e80 48 (19) T classificationdno. (%)a T1 15 (6) T2 57 (23) T3 111 (44) T4 68 (27) N classificationdno. (%)a N1 82 (33) N2 141 (56) N3 28 (11) Stagingdno. (%)a III 162 (65) IVA 61 (24) IVB 28 (11) RT techniquedno. (%) 2DRT 131 (52) IMRT 108 (43) 3DCRT 12 (5)
188 (73)
380 (75)
46 18e68
45 18e68
21 (8) 168 (65) 68 (26)
38 (8) 354 (70) 116 (23)
11 (4) 57 (22) 124 (48) 65 (25)
26 (5) 114 (22) 235 (46) 133 (26)
74 (29) 156 (61) 27 (11)
156 (31) 297 (59) 55 (11)
171 (67) 59 (23) 27 (11)
334 (66) 120 (24) 55 (11)
137 (53) 107 (42) 13 (5)
268 (53) 215 (42) 25 (5)
Abbreviations: CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; RT, radiotherapy; 2DRT, two-dimensional radiotherapy; IMRT, intensity-modulated radiotherapy; 3DCRT, threedimensional conformal radiotherapy. a The 6th American Joint Commission on Cancer staging system.
Table 2 Survival. Variable
CCRT plus AC group (N Z 251)
Failure-free survival Eventdno. (%) 69 Rated% At 3-year 82 At 5-year 75 Overall survival Eventdno. (%) 49 Rated% At 3 years 91 At 5 years 83 Distant failure-free survival Eventdno. (%) 41 Rated% At 3 years 86 At 5 years 85 Locoregional failure-free survival Eventdno. (%) 23 Rated% At 3 years 96 At 5 years 91
(27)
CCRT only group (N Z 257)
Hazard ratioa (95% CI)
p valueb
0.88 (0.64e1.22)
0.45
0.83 (0.57e1.22)
0.35
0.81 (0.53e1.22)
0.30
0.91 (0.51e1.60)
0.73
77 (30) 77 71
(20)
58 (23) 89 80
(16)
51 (20) 84 80
(9)
25 (10) 93 90
Abbreviations: CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; CI, confidence interval. a Hazard ratios were calculated by the unadjusted Cox proportional hazards model. b p values were calculated by the unadjusted log-rank test.
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Fig. 2. KaplaneMeier survival curves for the CCRT plus AC group and the CCRT only group. (A) Failure-free survival, (B) overall survival, (C) distant failure-free survival, (D) locoregional failure-free survival. CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; HR, hazard ratio and CI, confidence interval. HRs were calculated by the unadjusted Cox proportional hazards model. p values were calculated by the unadjusted log-rank test.
radiotherapy techniques (IMRT versus 2DRT/3DCRT) were presented in Supplementary Table 5. 4. Discussion In this trial, we focused on stage IIIeIVB NPC patients, except T3-4N0 patients and would like to include only the patients who had a relatively higher risk of distant metastasis. However, routine delivery of AC after CCRT for ‘all’ advanced-stage NPC patients should be reconsidered. In the present study, only 20% (51/257) patients in the CCRT alone group developed distant failure, which implied that unnecessary AC is frequently used. Thus, the key to effective AC should be the patients’ selection, which means individualising AC. These findings highlight the importance of improving patient selection beyond the TNM staging system. For example, AC guided by post-radiation detectable plasma EpsteineBarr virus (EBV) DNA is more reasonable [15]. In present, several ongoing trials are designed to investigate the utility of post-chemoradiotherapy plasma EBV DNA in individualising AC (NCT00370890, NCT02135042 and NCT02363400). Before our trial started, the quantitative plasma EBV DNA assay was not widely used at most cancer centres in China. Moreover, quantitative
polymerase chain reaction assays, even when performed in experienced clinical labs, can yield large variability in plasma EBV DNA copy numbers. Therefore, we did not incorporate this biomarker in our trial at that time. Delightedly, an international collaboration has harmonised the quantitative plasma EBV DNA assay for current biomarker-guided trials [16]. Adjuvant cisplatin and fluorouracil chemotherapy is the recommended regimen for advanced NPC [1]. However, this combination perhaps benefits only those with lower distant tumour burden. A subgroup analysis of the Taiwanese chemoradiotherapy trial showed that concurrent cisplatin and fluorouracil chemotherapy was only beneficial in patients without high-risk features such as N3 or T4N2 disease or bulky nodal metastases [17]. Therefore, it is possible that adjuvant cisplatin and fluorouracil is not a truly effective enough combination for the eradication of micrometastases in NPC. Intriguingly, newer drugs, such as taxanes and gemcitabine, have shown promising results in the settings of neoadjuvant and palliative chemotherapy in NPC [18,19]. An ongoing trial is designed to compare which AC regimen (cisplatin and fluorouracil or docetaxel and gemcitabine) is the best one in patients at high risk of disease recurrence (NCT02135042).
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Table 3 Summary of prognostic factors multivariable analyses. End-point
Variable
HR
95% CI for HR
p valuea
Failure-free survival
Sex, women versus men Age, 45 years versus <45 years Karnofsky scale, 100 versus 90 versus 70e80 T classification, T3-4 versus T1-2 N classification, N2 versus N1 N classification, N3 versus N1 RT technique, IMRT versus 2DRT/3DCRT Treatment group, CCRT plus AC versus CCRT Sex, women versus men Age, 45 years versus <45 years Karnofsky scale, 100 versus 90 versus 70e80 T classification, T3-4 versus T1-2 N classification, N2 versus N1 N classification, N3 versus N1 RT technique, IMRT versus 2DRT/3DCRT Treatment group, CCRT plus AC versus CCRT Sex, women versus men Age, 45 years versus <45 years Karnofsky scale, 100 versus 90 versus 70e80 T classification, T3-4 versus T1-2 N classification, N2 versus N1 N classification, N3 versus N1 RT technique, IMRT versus 2DRT/3DCRT Treatment group, CCRT plus AC versus CCRT Sex, women versus men Age, 45 years versus <45 years Karnofsky scale, 100 versus 90 versus 70e80 T classification, T3-4 versus T1-2 N classification, N2 versus N1 N classification, N3 versus N1 RT technique, IMRT versus 2DRT/3DCRT Treatment group, CCRT plus AC versus CCRT
0.84 1.34 0.99 1.19 1.25 2.20 0.87 0.90 0.77 1.45 0.98 1.26 1.26 2.75 0.93 0.84 0.68 1.22 0.99 1.21 1.28 2.39 0.89 0.82 0.99 1.13 1.05 1.12 0.97 1.81 0.68 0.88
0.56e1.26 0.96e1.87 0.96e1.02 0.97e1.47 0.83e1.88 1.26e3.85 0.62e1.23 0.65e1.25 0.47e1.26 0.98e2.15 0.95e1.02 0.98e1.62 0.78e2.04 1.48e5.14 0.63e1.38 0.57e1.23 0.40e1.17 0.80e1.85 0.95e1.03 0.93e1.58 0.76e2.15 1.21e4.74 0.58e1.36 0.54e1.23 0.51e1.94 0.64e2.02 0.99e1.11 0.78e1.62 0.49e1.92 0.64e5.08 0.37e1.24 0.50e1.57
0.39 0.08 0.55 0.10 0.28 0.01 0.43 0.53 0.30 0.06 0.31 0.07 0.35 <0.01 0.71 0.37 0.16 0.36 0.56 0.15 0.35 0.01 0.59 0.33 0.98 0.67 0.10 0.55 0.92 0.26 0.21 0.67
Overall survival
Distant failure-free survival
Locoregional failure-free survival
Abbreviations: HR, hazard ratio; CI, confidence interval; RT, radiotherapy; IMRT, intensity-modulated radiotherapy; 2DRT, two-dimensional radiotherapy; 3DCRT, three-dimensional conformal radiotherapy; CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy. a p values were calculated using an adjusted Cox proportional hazards model. The following parameters were included in the model as the covariates for each analysis: sex, age (<45 years versus 45 years), Karnofsky scale (70e80 versus 90 versus 100), T classification (T1-2 versus T3-4), N classification (N1, N2, N3), RT technique (2DRT/3DCRT versus IMRT) and treatment group (CCRT versus CCRT plus AC).
Moreover, compliance of AC was a problem; only 63% (158/251) of patients could complete the planned AC, which was similar to other studies (52e61%) [1e4]. It was obvious that acute toxicities during CCRT decreased patient tolerance to AC. Therefore, induction chemotherapy was thought to be a potentially more feasible and effective strategy of treatment intensification than adjuvant sequencing. In recent years, our team conducted two phase 3 trials to assess the contribution of induction chemotherapy to CCRT (NCT01245959 and NCT01536223). One of these trials has finished and the results indicated that addition of cisplatin, fluorouracil and docetaxel induction chemotherapy to CCRT significantly improved failure-free survival in locoregionally advanced NPC [18]. Another trial on gemcitabine and cisplatin induction chemotherapy is ongoing and the results are eagerly awaited. The incidence of peripheral neuropathy showed a trend to increase in the CCRT plus AC group (p Z 0.05). This trend may be attributed to the larger doses of cisplatin in the CCRT plus AC group, since the
accumulation of cisplatin in the nervous system, particularly the dorsal root ganglia, can result in neurotoxicity [20]. For most late toxicities, radiation parameters probably remain the key determinants of damage. However, it should be noted that 18% (46/251) of patients in the CCRT plus AC group did not receive any AC, and 49% (100/205) of patients receiving AC had dose reductions. Thus, underestimation of increased late toxicities caused by AC can not be excluded. To our knowledge, the progress report of this trial is the first study to confirm the ultimate therapeutic index of AC in addition to CCRT in locoregionally advanced NPC. However, it should be noted that this trial was not designed as a non-inferiority trial, so the negative results should be interpreted with caution. One could argue that the magnitude of any theoretic gain from AC would be small, and this implies that a much larger phase 3 study is needed. Moreover, the different radiotherapy techniques used in this trial might have confounded the findings. Nevertheless, two treatment groups were well balanced according to radiotherapy technique (Table 1),
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Table 4 Adverse events. CCRT plus AC group Grade 3e4 acute adverse events No. of safety analysis population Anaemia Thrombocytopaenia Neutropenia Leukopenia Dermatitis Stomatitis (mucositis) Oesophagitis, dysphagia or odynophagia Nausea Vomiting Dry mouth Ototoxicity Neurotoxicity Grade 3e4 acute adverse events No. of safety analysis population Anaemia Thrombocytopaenia Neutropenia Leukopenia Stomatitis (mucositis) Oesophagitis, dysphagia or odynophagia Nausea Vomiting Diarrhoea Ototoxicity Nephrotoxicity Neurotoxicity Grade 3e4 late adverse events No. of safety analysis population Symptomatic brain damage Temporal lobe necrosis Cranial neuropathy Peripheral neuropathy Eye damage Ear (deafness/otitis) Bone necrosis Neck tissue damage Trismus Dry mouth
CCRT only group
p valuea
during CCRT 249 254 3 (1%) 14 (6%) 25 (10%) 59 (24%) 25 (10%) 76 (31%) 8 (3%)
6 (2%) 16 (6%) 29 (11%) 65 (26%) 29 (11%) 82 (32%) 13 (5%)
0.33 0.75 0.62 0.62 0.62 0.67 0.29
32 (13%) 29 (12%) 13 (5%) 2 (1%) 1 (0.4%) during AC 205
37 (15%) 33 (13%) 21 (8%) 1 (0.4%) 1 (0.4%)
0.75 0.63 0.17 0.55 0.99
157
demonstrate significant survival benefit over CCRT alone in locoregionally advanced NPC based on the data of this long-term update. Although addition of adjuvant cisplatin and fluorouracil chemotherapy did not significantly increase late toxicities, a definitive recommendation regarding such regimen should not be allowed. Funding This work was supported by the Sun Yat-sen University Clinical Research 5010 Programme [2007037]; the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period [2014BAI09B10]; the Science and Technology Project of Guangzhou City, China [14570006]; the Planned Science and Technology Project of Guangdong Province [2013B020400004]; and the Health & Medical Collaborative Innovation Project of Guangzhou City, China [201400000001]. Role of the funding source
3 (2%) 8 (4%) 21 (10%) 29 (14%) 43 (21%) 9 (4%)
Our study was mainly funded by the Sun Yat-sen University Clinical Research 5010 Programme (No. 2007037), which was involved in trial management and audit.
23 (11%) 20 (10%) 6 (3%) 6 (3%) 1 (0.5%) 2 (1%)
Writing assistance None. Conflict of interest statement
249
254
3 (1%) 8 (3%) 5 (2%) 6 (2%) 2 (1%) 33 (13%) 1 (0.4%) 5 (2%) 3 (1%) 18 (7%)
5 (2%) 8 (3%) 6 (2%) 1 (0.4%) 2 (1%) 29 (11%) 0 3 (1%) 1 (0.4%) 16 (6%)
0.49 0.97 0.79 0.05 0.98 0.53 0.31 0.46 0.31 0.68
Abbreviations: CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy. a p values were calculated by the chi-squared test.
and subset analyses by radiotherapy techniques showed no differences in the effect of AC (Supplementary Table 1). Therefore, different radiotherapy techniques had a limited impact in our results, but these findings can not be directly extrapolated to IMRT-treated patients. Finally, the data of late toxicities were based largely on clinical observations, and regular audiometry and/or imaging were not specified in the protocol, thus, the underestimation can not be excluded. In conclusion, addition of three cycles of adjuvant cisplatin and fluorouracil chemotherapy still failed to
None declared.
Acknowledgements The authors thank Fei Han, Yong-Hong Hu, ZhenYu He, Qiao-Qiao Li, Yan Xu, Xiao-Fen Xiao, XiaoQing Hu and Hui-Xia Feng (Department of Radiation Oncology, Sun Yat-sen University Cancer Centre) for contributing their patients to the study, assistance with the data management and logistic support. They thank the Clinical Trials Centre, Sun Yat-sen University Cancer Centre, for trial monitoring, data management and statistical assistance. They also thank the patients and their families for their willingness to participate in this trial. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejca.2017.01.002.
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L. Chen et al. / European Journal of Cancer 75 (2017) 150e158 advanced nasopharyngeal cancer: phase III randomized Intergroup Study 0099. J Clin Oncol 1998;16:1310e7. Wee J, Tan EH, Tai BC, Wong HB, Leong SS, Tan T, 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;23:6730e8. Lee AW, Tung SY, Chua DT, Ngan RK, Chappell R, Tung R, et al. Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst 2010;102:1188e98. Chen Y, Sun Y, Liang SB, Zong JF, Li WF, Chen M, et al. Progress report of a randomized trial comparing long-term survival and late toxicity of concurrent chemoradiotherapy with adjuvant chemotherapy versus radiotherapy alone in patients with stage III to IVB nasopharyngeal carcinoma from endemic regions of China. Cancer 2013;119:2230e8. Rossi A, Molinari R, Boracchi P, Vecchio MD, Marubini E, Nava M, et al. Adjuvant chemotherapy with vincristine, cyclophosphamide and doxorubicin after radiotherapy in local-regional nasopharyngeal cancer: results of a 4 year multi-center randomized study. J Clin Oncol 1988;6:1401e10. Chi KH, Chang YC, Guo WY, Leung MJ, Shiau CY, Chen SY, et al. A phase III study of adjuvant chemotherapy in advanced nasopharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 2002;52:1238e44. Kwong DL, Sham JS, Au GK, Chua DT, Kwong PW, Cheng AC, et al. Concurrent and adjuvant chemotherapy for nasopharyngeal carcinoma: a factorial study. J Clin Oncol 2004;22:2643e53. Chen L, Hu CS, Chen XZ, Hu GQ, Cheng ZB, Sun Y, et al. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a multicentre randomised controlled phase 3 trial. Lancet Oncol 2012;13:163e71. Blanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, et al. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol 2015; 16:645e55. Ouyang PY, Xie C, Mao YP, Zhang Y, Liang XX, Su Z, et al. Significant efficacies of neoadjuvant and adjuvant chemotherapy for nasopharyngeal carcinoma by meta-analysis of published literature-based randomized, controlled trials. Ann Oncol 2013; 24:2136e46.
[11] Chen YP, Wang ZX, Chen L, Liu X, Tang LL, Mao YP, et al. 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. Ann Oncol 2015;26:205e11. [12] Chan AT, Teo PM, Ngan RK, Leung TW, Lau WH, Zee B, et al. Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: progression-free survival analysis of a phase III randomized trial. J Clin Oncol 2002;20:2038e44. [13] Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341e6. [14] Chow SC, Shao J, Wang H. Sample size calculations in clinical research. New York: Marcel Dekker; 2003. [15] Chan AT, Lo YM, Zee B, Chan LY, Ma BB, Leung SF, et al. Plasma Epstein-Barr virus DNA and residual disease after radiotherapy for undifferentiated nasopharyngeal carcinoma. J Natl Cancer Inst 2002;94:1614e9. [16] Le QT, Zhang Q, Cao H, Cheng AJ, Pinsky BA, Hong RL, et al. An international collaboration to harmonize the quantitative plasma Epstein-Barr virus DNA assay for future biomarkerguided trials in nasopharyngeal carcinoma. Clin Cancer Res 2013;19:2208e15. [17] Lin JC, Liang WM, Jan JS, Jiang RS, Lin AC. Another way to estimate outcome of advanced nasopharyngeal carcinomadis concurrent chemoradiotherapy adequate? Int J Radiat Oncol Biol Phys 2004;60:156e64. [18] Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, 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;17:1509e20. [19] Zhang L, Huang Y, Hong S, Yang Y, Yu G, Jia J, et al. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial. Lancet 2016;388:1883e92. [20] Gregg RW, Molepo JM, Monpetit VJ, Mikael NZ, Redmond D, Gadia M, et al. Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurological tissue and morphological evidence of toxicity. J Clin Oncol 1992;10: 795e803.
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Original Research
Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicentre randomised controlled trial Lei Chen a,1, Chao-Su Hu b,1, Xiao-Zhong Chen c,1, Guo-Qing Hu d,1, Zhi-Bin Cheng e,1, Yan Sun f,1, Wei-Xiong Li g, Yuan-Yuan Chen c, Fang-Yun Xie a, Shao-Bo Liang h, Yong Chen a, Ting-Ting Xu b, Bin Li c, Guo-Xian Long d, Si-Yang Wang e, Bao-Min Zheng f, Ying Guo i, Ying Sun a, Yan-Ping Mao a, Ling-Long Tang a, Yu-Ming Chen j, Meng-Zhong Liu a, Jun Ma a,* a State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China b Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, 270 Dongan Road, Shanghai, 200032, People’s Republic of China c Department of Radiation Oncology, Zhejiang Cancer Hospital, 38 Guang Ji Road, Hangzhou, 310022, People’s Republic of China d Department of Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, 128 San Yang Road, Wuhan, 430030, People’s Republic of China e Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-sen University, 52 Mei Hua Road East, Zhuhai, 519000, People’s Republic of China f Department of Radiation Oncology, Beijing Cancer Hospital, 52 Bu Cheng Road, Beijing, 100142, People’s Republic of China g Department of Radiation Oncology, Guangdong General Hospital, 106 Zhong Shan Second Road, Guangzhou, 510080, People’s Republic of China h Department of Radiation Oncology, The First People’s Hospital of Foshan, 81 Lingnan Avenue North, Foshan, 528000, People’s Republic of China i Clinical Trials Centre, Sun Yat-sen University Cancer Centre, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China j Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, 74 Zhongshan Second Road, Guangzhou, 510080, People’s Republic of China
Received 7 November 2016; received in revised form 6 December 2016; accepted 1 January 2017
* Corresponding author: Fax: þ86 20 87343295. E-mail address: [email protected] (J. Ma). 1 These authors contributed equally to this study. http://dx.doi.org/10.1016/j.ejca.2017.01.002 0959-8049/ª 2017 Elsevier Ltd. All rights reserved.
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KEYWORDS Nasopharyngeal carcinoma; Adjuvant chemotherapy; Randomised clinical trial; Long-term results
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Abstract Aim of the study: Previous results from our trial showed that adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve survival after concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term survival and late toxicities to further assess the ultimate therapeutic index of adjuvant chemotherapy (AC). Methods: Patients with stage IIIeIVB (except T3-4N0) NPC were randomly assigned to receive CCRT plus AC or CCRT only at seven institutions in China. Patients in both groups received cisplatin 40 mg/m2 weekly up to 7 weeks concurrently with radiotherapy. The CCRT plus AC group subsequently received adjuvant cisplatin 80 mg/m2 and fluorouracil 800 mg/m2/d for 120 h every 4 weeks for three cycles. The primary end-point was failurefree survival. Results: Two hundred and fifty-one patients were randomised to the CCRT plus AC group and 257 to the CCRT only group. After a median follow-up of 68.4 months, estimated 5-year failure-free survival rate was 75% in the CCRT plus AC group and 71% in the CCRT only group (hazard ratio 0.88, 95% confidence interval 0.64e1.22; p Z 0.45). 66 (27%) of 249 patients in the CCRT plus AC group and 53 (21%) of 254 patients in the CCRT only group developed one or more late grade 3e4 toxicities (p Z 0.14). Conclusion: Adjuvant cisplatin and fluorouracil chemotherapy still failed to demonstrate significant survival benefit after CCRT in locoregionally advanced NPC based on the longterm follow-up data, and addition of adjuvant cisplatin and fluorouracil did not significantly increase late toxicities. Registration number: NCT00677118. ª 2017 Elsevier Ltd. All rights reserved.
1. Introduction Radiotherapy is the primary treatment modality for non-disseminated nasopharyngeal carcinoma (NPC). The landmark Intergroup-0099 Study was the first randomised trial to achieve a 31% improvement in the 3year overall survival rate in the latter group by adding concurrent chemotherapy and adjuvant chemotherapy (AC) to radiotherapy, and, since 1998, this regimen has been deemed the standard of care for advanced NPC [1]. However, the Intergroup-0099 Study and subsequent three similar trials were unable to tease out the contribution of AC, as the control arm was radiotherapy alone [1e4]. In addition, there were three pure phase 3 ‘AC trials’ for NPC, in which AC was used alone, and all these trials failed to demonstrate a positive impact on survival [5e7]. Based on the results of above trials, the role of the addition of AC to concurrent chemoradiotherapy (CCRT) is questionable. We therefore performed a phase 3 trial to compare CCRT plus AC with CCRT alone, to appraise the contribution of AC in locoregionally advanced NPC. After a median follow-up period of 37.8 months, the 2year results had been published and demonstrated that adjuvant cisplatin and fluorouracil chemotherapy did not significantly improve failure-free survival after CCRT in locoregionally advanced NPC [8]. However, it should be noted that the follow-up period is relatively short, especially for overall survival, and there were no data on detailed late toxicities at that time. Thereafter, meta-analyses which involved our trial and focused on
AC in advanced NPC, unanimously failed to demonstrate a significant advantage from using AC to treat advanced NPC [9e11]. Hence, the purpose of this progress report is to verify the long-term survival and late toxicities and to further assess the ultimate therapeutic index of AC in patients with locoregionally advanced NPC. 2. Patients and methods 2.1. Participants Between 1st June 2006 and 5th March 2010, we did an open-label phase 3 multicentre randomised controlled trial at seven institutions in China. Eligible patients were aged 18e70 years with non-metastatic, histologically proven non-keratinising stage III or IV NPC, except T3-4N0 (6th American Joint Commission on Cancer staging system) [8]. All participants provided written informed consent. Our protocol was approved by the ethics committee or institutional review board at each centre. 2.2. Randomisation and masking Random assignment was done (via sealed envelopes) by the Clinical Trials Centre, Sun Yat-sen University Cancer Centre, with a computer-generated random number code. Participants were stratified according to treatment centre and randomly assigned in blocks of four based on a one-to-one treatment allocation (the
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block size was known only by the statistician). Treatment allocation was not masked. Investigators of each centre enrolled participants and assigned them to interventions. 2.3. Procedures We compared CCRT plus three cycles of cisplatin and fluorouracil AC with CCRT alone. The chemotherapy component of the CCRT regimen consisted of 40 mg/m2 cisplatin given as a 2 h intravenous infusion every week for a maximum of seven cycles, beginning on the first day of radiotherapy [4,12]. Dose modifications were not permitted during concurrent chemotherapy. All patients were treated with 2.0e2.27 Gy per fraction with five daily fractions per week for 6e7 weeks, administered as megavoltage photons using either two-dimensional radiotherapy (2DRT), intensity-modulated radiotherapy (IMRT) or three-dimensional conformal radiotherapy (3DCRT), in accordance with the treatment policy adopted by each centre. The cumulative radiation doses were 66 Gy or greater to the primary tumour and 60e66 Gy to the involved neck area. All potential sites of local infiltration and bilateral cervical lymphatics were irradiated to 50 Gy or greater. Three cycles of AC were given to patients in the CCRT plus AC group on days 29e33, 57e61 and 85e89 after radiotherapy, by intravenous infusion of 80 mg/m2 cisplatin on day 1 and 800 mg/m2 per day fluorouracil on days 1e5 (120-h infusion) [4]. Dose modifications during AC were based on the preceding cycle nadir blood counts and interim toxic effects [8]. Participants were assessed every 3 months during the first 3 years, and every 6 months thereafter until death [8]. Our primary end-point was failure-free survival, and our secondary end-points were overall survival, distant failure-free survival, locoregional failure-free survival, initial response rates after treatment and toxic effects. We calculated failure-free survival from the date of randomisation to the date of treatment failure or death from any cause, whichever was first. We calculated overall survival from randomisation to death. For locoregional and distant failure-free survival analyses, we recorded the latencies (ie, time from randomisation) to the first locoregional or remote failure, respectively. We graded chemotherapy-related toxic effects in accordance with Common Terminology Criteria for Adverse Events (version 3.0). We graded radiotherapy-related toxic effects in accordance with both the Acute and the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group [13]. 2.4. Statistical analysis Our study had an 80% power to detect a treatment failure hazard ratio (HR) of 0.56 (two-sided log-rank test p Z 0.05), assuming a 2-year failure-free survival
rate of 85% in the CCRT plus AC group and 75% in the CCRT only group [4,12]. We anticipated that 96 events were needed from 480 patients (240 per treatment group), therefore we needed to recruit a maximum of 253 patients per group (total 506), assuming 5% early dropout or loss to follow-up [14]. Time-to-event data were described with the KaplaneMeier curves, time-to-event intervals compared with the log-rank test (primary analysis). We did multivariable analyses with the Cox proportional hazards model to test the independent significance of different factors. We compared toxicity rates and other categorical variables with the chi-squared test (or Fisher’s exact test, if indicated). All tests were two sided, we deemed p values of less than 0.05 to be significant. We reported the 2-year survival results after the prespecified number of events had occurred (98 patients experienced treatment failure; July 2011) [8]. The cutoff date for the analysis of long-term survival presented here was 30th April 2015, with the median follow-up of 68.4 months. We did all efficacy analyses in our intention-to-treat population, and only patients who received their randomly assigned treatments were included in adverse events analyses. All analyses were done with Stata (version 10).
3. Results Between 1st June 2006 and 5th March 2010, a total of 508 patients were randomly assigned, to receive CCRT plus AC (251) or CCRT alone (257). In total, 477 (94%) of the 508 patients received regular follow-up until death or the latest scheduled assessment (Fig. 1). The last follow-up was 30th April 2015, and the median followup for the entire cohort was 68.4 months (range, 1.3e104.7 months). The two treatment groups were well balanced according to baseline demographic, clinical characteristics and radiotherapy technique (Table 1). Two hundred fourty-seven (98%) of 251 participants in the CCRT plus AC group and 252 (98%) of 257 in the CCRT only group completed the scheduled total radiation dose. One hundred fourteen (45%) of 251 patients in the CCRT plus AC group and 105 (41%) of 257 in the CCRT only group completed all protocol-defined concurrent chemotherapy, with a median of six cycles (interquartile range [IQR] 5e7) for both groups. Reduced concurrent chemotherapy cycles were mostly because of leucopenia, accounting for 98 (74%) of 133 reduced doses in the CCRT plus AC group and 112 (76%) of 148 in the CCRT only group. All three cycles of AC were completed by 158 (63%) of 251 participants in the concurrent chemotherapy plus AC group, with a median three cycles (IQR 1e3). The median total cisplatin doses were 220 mg/m2 (IQR 80e240; 92% of total scheduled doses) and fluorouracil doses were 8000 mg/m2 (4000e12,000; 67% of total scheduled doses). Refusal by patients was the primary
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508 Patients underwent randomization
251 were assigned to receive CCRT plus AC (intention-to-treat population) 2 did not receive CCRT 249 started CCRT (acute safety analysis population during CCRT and late safety analysis population) 2 discontinued radiotherapy 135 discontinued concurrent chemotherapy
257 were assigned to receive CCRT (intention-to-treat population) 3 did not receive CCRT 254 started CCRT (acute safety analysis population during CCRT and late safety analysis population)* 2 discontinued radiotherapy 149 discontinued concurrent chemotherapy
44 did not receive AC 205 started AC (acute safety analysis population during AC) 47 discontinued AC
14 lost to follow-up 188 were alive 170 were disease free 18 were alive with disease 49 were dead 41 died from disease progression 1 died from treatment toxicities 6 died from incident cause 1 died from unknown cause
17 lost to follow-up 182 were alive 164 were disease free 18 were alive with disease 58 were dead 50 died from disease progression 2 died from treatment toxicities 3 died from incident cause 3 died from unknown cause
Fig. 1. Flow diagram. CCRT denotes concurrent chemoradiotherapy and AC adjuvant chemotherapy. * Three patients were subsequently given AC at their request.
reason for uncompleted AC, accounting for 69 (76%) of 91 patients who did not complete AC in the CCRT plus AC group. All dose reductions were because of haematological toxic effects or mucositis. After a median follow-up of 68.4 months, estimated 5-year failure-free survival rate was 75% in the CCRT plus AC group and 71% in the CCRT only group (HR 0.88, 95% confidence interval [CI] 0.64e1.22; p Z 0.45) (Table 2; Fig. 2A). Moreover, two groups did not differ significantly in overall survival, distant failure-free survival or locoregional failure-free survival (Table 2; Fig. 2BeD). On multivariable analyses, treatment group was not a significant predictive factor for failurefree survival (HR 0.90, 0.65e1.25; p Z 0.53), overall survival, distant failure-free survival or locoregional
failure-free survival (Table 3). We did exploratory subset analyses by radiotherapy techniques (IMRT versus 2DRT/3DCRT), stage groups (III versus IVA-B), N classification (N1 versus N2-3) and actual treatments (patients who received CCRT and three cycles of AC versus patients who only received CCRT). The results showed that the effect of AC on failure-free survival, overall survival, distant failure-free survival and locoregional failure-free survival was insignificant in all subgroups (Supplementary Table 1e4). The CCRT plus AC group did not have a significant reduction in the 5-year actuarial incidence of death from disease progression compared with the CCRT only group (14% versus 18%; HR 0.81, 95% CI 0.54e1.22; p Z 0.31); furthermore, the 5-year actuarial incidence of
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death from treatment-related toxicities, incidental causes or unknown reasons were similar in both groups (3% versus 3%, respectively; HR 0.99, 95% CI 0.37e2.63; p Z 0.98). Of the 508 patients in the present study, four patients (0.8%) died from secondary malignancies, two (0.4%) died from infection, two (0.4%) died from cerebral vascular incidents and one (0.2%) died from cardiovascular disease. During CCRT, 156 (63%) of 249 patients in the CCRT plus AC group and 156 (61%) of 254 in the CCRT only group experienced grade 3e4 toxic effects (p Z 0.78); there were no treatment-related deaths. During AC, 87 (42%) of 205 patients in the CCRT plus AC group experienced grade 3e4 toxic effects, and there were no treatment-related deaths (Table 4). Overall, 119 (24%) of 503 patients developed one or more late grade 3e4 toxicities, including 66 (27%) of 249 patients in the CCRT plus AC group and 53 (21%) of 254 patients in the CCRT only group (p Z 0.14). One (0.4%) of 249 patient in the CCRT plus AC group died from temporal lobe necrosis, and two (0.8%) of 254 patient in the CCRT only group died from temporal lobe necrosis and cranial neuropathy, respectively (p Z 0.57). The incidence of grade 3e4 peripheral neuropathy was higher in the CCRT plus AC group compared with the CCRT only group (2% versus 0.4%), and the difference was of borderline significance (p Z 0.05); other late toxicities were not significantly different between two groups (Table 4). Moreover, the incidence of late grade 3e4 toxicities according to
Table 1 Characteristics of the patients. Characteristic
CCRT plus AC CCRT only Total group (N Z 251) group (N Z 257) (N Z 508)
Male sexdno. (%) 192 (77) Agedyear Median 44 Range 19e68 Karnofsky scaledno. (%) 100 17 (7) 90 186 (74) 70e80 48 (19) T classificationdno. (%)a T1 15 (6) T2 57 (23) T3 111 (44) T4 68 (27) N classificationdno. (%)a N1 82 (33) N2 141 (56) N3 28 (11) Stagingdno. (%)a III 162 (65) IVA 61 (24) IVB 28 (11) RT techniquedno. (%) 2DRT 131 (52) IMRT 108 (43) 3DCRT 12 (5)
188 (73)
380 (75)
46 18e68
45 18e68
21 (8) 168 (65) 68 (26)
38 (8) 354 (70) 116 (23)
11 (4) 57 (22) 124 (48) 65 (25)
26 (5) 114 (22) 235 (46) 133 (26)
74 (29) 156 (61) 27 (11)
156 (31) 297 (59) 55 (11)
171 (67) 59 (23) 27 (11)
334 (66) 120 (24) 55 (11)
137 (53) 107 (42) 13 (5)
268 (53) 215 (42) 25 (5)
Abbreviations: CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; RT, radiotherapy; 2DRT, two-dimensional radiotherapy; IMRT, intensity-modulated radiotherapy; 3DCRT, threedimensional conformal radiotherapy. a The 6th American Joint Commission on Cancer staging system.
Table 2 Survival. Variable
CCRT plus AC group (N Z 251)
Failure-free survival Eventdno. (%) 69 Rated% At 3-year 82 At 5-year 75 Overall survival Eventdno. (%) 49 Rated% At 3 years 91 At 5 years 83 Distant failure-free survival Eventdno. (%) 41 Rated% At 3 years 86 At 5 years 85 Locoregional failure-free survival Eventdno. (%) 23 Rated% At 3 years 96 At 5 years 91
(27)
CCRT only group (N Z 257)
Hazard ratioa (95% CI)
p valueb
0.88 (0.64e1.22)
0.45
0.83 (0.57e1.22)
0.35
0.81 (0.53e1.22)
0.30
0.91 (0.51e1.60)
0.73
77 (30) 77 71
(20)
58 (23) 89 80
(16)
51 (20) 84 80
(9)
25 (10) 93 90
Abbreviations: CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; CI, confidence interval. a Hazard ratios were calculated by the unadjusted Cox proportional hazards model. b p values were calculated by the unadjusted log-rank test.
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Fig. 2. KaplaneMeier survival curves for the CCRT plus AC group and the CCRT only group. (A) Failure-free survival, (B) overall survival, (C) distant failure-free survival, (D) locoregional failure-free survival. CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy; HR, hazard ratio and CI, confidence interval. HRs were calculated by the unadjusted Cox proportional hazards model. p values were calculated by the unadjusted log-rank test.
radiotherapy techniques (IMRT versus 2DRT/3DCRT) were presented in Supplementary Table 5. 4. Discussion In this trial, we focused on stage IIIeIVB NPC patients, except T3-4N0 patients and would like to include only the patients who had a relatively higher risk of distant metastasis. However, routine delivery of AC after CCRT for ‘all’ advanced-stage NPC patients should be reconsidered. In the present study, only 20% (51/257) patients in the CCRT alone group developed distant failure, which implied that unnecessary AC is frequently used. Thus, the key to effective AC should be the patients’ selection, which means individualising AC. These findings highlight the importance of improving patient selection beyond the TNM staging system. For example, AC guided by post-radiation detectable plasma EpsteineBarr virus (EBV) DNA is more reasonable [15]. In present, several ongoing trials are designed to investigate the utility of post-chemoradiotherapy plasma EBV DNA in individualising AC (NCT00370890, NCT02135042 and NCT02363400). Before our trial started, the quantitative plasma EBV DNA assay was not widely used at most cancer centres in China. Moreover, quantitative
polymerase chain reaction assays, even when performed in experienced clinical labs, can yield large variability in plasma EBV DNA copy numbers. Therefore, we did not incorporate this biomarker in our trial at that time. Delightedly, an international collaboration has harmonised the quantitative plasma EBV DNA assay for current biomarker-guided trials [16]. Adjuvant cisplatin and fluorouracil chemotherapy is the recommended regimen for advanced NPC [1]. However, this combination perhaps benefits only those with lower distant tumour burden. A subgroup analysis of the Taiwanese chemoradiotherapy trial showed that concurrent cisplatin and fluorouracil chemotherapy was only beneficial in patients without high-risk features such as N3 or T4N2 disease or bulky nodal metastases [17]. Therefore, it is possible that adjuvant cisplatin and fluorouracil is not a truly effective enough combination for the eradication of micrometastases in NPC. Intriguingly, newer drugs, such as taxanes and gemcitabine, have shown promising results in the settings of neoadjuvant and palliative chemotherapy in NPC [18,19]. An ongoing trial is designed to compare which AC regimen (cisplatin and fluorouracil or docetaxel and gemcitabine) is the best one in patients at high risk of disease recurrence (NCT02135042).
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Table 3 Summary of prognostic factors multivariable analyses. End-point
Variable
HR
95% CI for HR
p valuea
Failure-free survival
Sex, women versus men Age, 45 years versus <45 years Karnofsky scale, 100 versus 90 versus 70e80 T classification, T3-4 versus T1-2 N classification, N2 versus N1 N classification, N3 versus N1 RT technique, IMRT versus 2DRT/3DCRT Treatment group, CCRT plus AC versus CCRT Sex, women versus men Age, 45 years versus <45 years Karnofsky scale, 100 versus 90 versus 70e80 T classification, T3-4 versus T1-2 N classification, N2 versus N1 N classification, N3 versus N1 RT technique, IMRT versus 2DRT/3DCRT Treatment group, CCRT plus AC versus CCRT Sex, women versus men Age, 45 years versus <45 years Karnofsky scale, 100 versus 90 versus 70e80 T classification, T3-4 versus T1-2 N classification, N2 versus N1 N classification, N3 versus N1 RT technique, IMRT versus 2DRT/3DCRT Treatment group, CCRT plus AC versus CCRT Sex, women versus men Age, 45 years versus <45 years Karnofsky scale, 100 versus 90 versus 70e80 T classification, T3-4 versus T1-2 N classification, N2 versus N1 N classification, N3 versus N1 RT technique, IMRT versus 2DRT/3DCRT Treatment group, CCRT plus AC versus CCRT
0.84 1.34 0.99 1.19 1.25 2.20 0.87 0.90 0.77 1.45 0.98 1.26 1.26 2.75 0.93 0.84 0.68 1.22 0.99 1.21 1.28 2.39 0.89 0.82 0.99 1.13 1.05 1.12 0.97 1.81 0.68 0.88
0.56e1.26 0.96e1.87 0.96e1.02 0.97e1.47 0.83e1.88 1.26e3.85 0.62e1.23 0.65e1.25 0.47e1.26 0.98e2.15 0.95e1.02 0.98e1.62 0.78e2.04 1.48e5.14 0.63e1.38 0.57e1.23 0.40e1.17 0.80e1.85 0.95e1.03 0.93e1.58 0.76e2.15 1.21e4.74 0.58e1.36 0.54e1.23 0.51e1.94 0.64e2.02 0.99e1.11 0.78e1.62 0.49e1.92 0.64e5.08 0.37e1.24 0.50e1.57
0.39 0.08 0.55 0.10 0.28 0.01 0.43 0.53 0.30 0.06 0.31 0.07 0.35 <0.01 0.71 0.37 0.16 0.36 0.56 0.15 0.35 0.01 0.59 0.33 0.98 0.67 0.10 0.55 0.92 0.26 0.21 0.67
Overall survival
Distant failure-free survival
Locoregional failure-free survival
Abbreviations: HR, hazard ratio; CI, confidence interval; RT, radiotherapy; IMRT, intensity-modulated radiotherapy; 2DRT, two-dimensional radiotherapy; 3DCRT, three-dimensional conformal radiotherapy; CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy. a p values were calculated using an adjusted Cox proportional hazards model. The following parameters were included in the model as the covariates for each analysis: sex, age (<45 years versus 45 years), Karnofsky scale (70e80 versus 90 versus 100), T classification (T1-2 versus T3-4), N classification (N1, N2, N3), RT technique (2DRT/3DCRT versus IMRT) and treatment group (CCRT versus CCRT plus AC).
Moreover, compliance of AC was a problem; only 63% (158/251) of patients could complete the planned AC, which was similar to other studies (52e61%) [1e4]. It was obvious that acute toxicities during CCRT decreased patient tolerance to AC. Therefore, induction chemotherapy was thought to be a potentially more feasible and effective strategy of treatment intensification than adjuvant sequencing. In recent years, our team conducted two phase 3 trials to assess the contribution of induction chemotherapy to CCRT (NCT01245959 and NCT01536223). One of these trials has finished and the results indicated that addition of cisplatin, fluorouracil and docetaxel induction chemotherapy to CCRT significantly improved failure-free survival in locoregionally advanced NPC [18]. Another trial on gemcitabine and cisplatin induction chemotherapy is ongoing and the results are eagerly awaited. The incidence of peripheral neuropathy showed a trend to increase in the CCRT plus AC group (p Z 0.05). This trend may be attributed to the larger doses of cisplatin in the CCRT plus AC group, since the
accumulation of cisplatin in the nervous system, particularly the dorsal root ganglia, can result in neurotoxicity [20]. For most late toxicities, radiation parameters probably remain the key determinants of damage. However, it should be noted that 18% (46/251) of patients in the CCRT plus AC group did not receive any AC, and 49% (100/205) of patients receiving AC had dose reductions. Thus, underestimation of increased late toxicities caused by AC can not be excluded. To our knowledge, the progress report of this trial is the first study to confirm the ultimate therapeutic index of AC in addition to CCRT in locoregionally advanced NPC. However, it should be noted that this trial was not designed as a non-inferiority trial, so the negative results should be interpreted with caution. One could argue that the magnitude of any theoretic gain from AC would be small, and this implies that a much larger phase 3 study is needed. Moreover, the different radiotherapy techniques used in this trial might have confounded the findings. Nevertheless, two treatment groups were well balanced according to radiotherapy technique (Table 1),
L. Chen et al. / European Journal of Cancer 75 (2017) 150e158
Table 4 Adverse events. CCRT plus AC group Grade 3e4 acute adverse events No. of safety analysis population Anaemia Thrombocytopaenia Neutropenia Leukopenia Dermatitis Stomatitis (mucositis) Oesophagitis, dysphagia or odynophagia Nausea Vomiting Dry mouth Ototoxicity Neurotoxicity Grade 3e4 acute adverse events No. of safety analysis population Anaemia Thrombocytopaenia Neutropenia Leukopenia Stomatitis (mucositis) Oesophagitis, dysphagia or odynophagia Nausea Vomiting Diarrhoea Ototoxicity Nephrotoxicity Neurotoxicity Grade 3e4 late adverse events No. of safety analysis population Symptomatic brain damage Temporal lobe necrosis Cranial neuropathy Peripheral neuropathy Eye damage Ear (deafness/otitis) Bone necrosis Neck tissue damage Trismus Dry mouth
CCRT only group
p valuea
during CCRT 249 254 3 (1%) 14 (6%) 25 (10%) 59 (24%) 25 (10%) 76 (31%) 8 (3%)
6 (2%) 16 (6%) 29 (11%) 65 (26%) 29 (11%) 82 (32%) 13 (5%)
0.33 0.75 0.62 0.62 0.62 0.67 0.29
32 (13%) 29 (12%) 13 (5%) 2 (1%) 1 (0.4%) during AC 205
37 (15%) 33 (13%) 21 (8%) 1 (0.4%) 1 (0.4%)
0.75 0.63 0.17 0.55 0.99
157
demonstrate significant survival benefit over CCRT alone in locoregionally advanced NPC based on the data of this long-term update. Although addition of adjuvant cisplatin and fluorouracil chemotherapy did not significantly increase late toxicities, a definitive recommendation regarding such regimen should not be allowed. Funding This work was supported by the Sun Yat-sen University Clinical Research 5010 Programme [2007037]; the National Science & Technology Pillar Program during the Twelfth Five-year Plan Period [2014BAI09B10]; the Science and Technology Project of Guangzhou City, China [14570006]; the Planned Science and Technology Project of Guangdong Province [2013B020400004]; and the Health & Medical Collaborative Innovation Project of Guangzhou City, China [201400000001]. Role of the funding source
3 (2%) 8 (4%) 21 (10%) 29 (14%) 43 (21%) 9 (4%)
Our study was mainly funded by the Sun Yat-sen University Clinical Research 5010 Programme (No. 2007037), which was involved in trial management and audit.
23 (11%) 20 (10%) 6 (3%) 6 (3%) 1 (0.5%) 2 (1%)
Writing assistance None. Conflict of interest statement
249
254
3 (1%) 8 (3%) 5 (2%) 6 (2%) 2 (1%) 33 (13%) 1 (0.4%) 5 (2%) 3 (1%) 18 (7%)
5 (2%) 8 (3%) 6 (2%) 1 (0.4%) 2 (1%) 29 (11%) 0 3 (1%) 1 (0.4%) 16 (6%)
0.49 0.97 0.79 0.05 0.98 0.53 0.31 0.46 0.31 0.68
Abbreviations: CCRT, concurrent chemoradiotherapy; AC, adjuvant chemotherapy. a p values were calculated by the chi-squared test.
and subset analyses by radiotherapy techniques showed no differences in the effect of AC (Supplementary Table 1). Therefore, different radiotherapy techniques had a limited impact in our results, but these findings can not be directly extrapolated to IMRT-treated patients. Finally, the data of late toxicities were based largely on clinical observations, and regular audiometry and/or imaging were not specified in the protocol, thus, the underestimation can not be excluded. In conclusion, addition of three cycles of adjuvant cisplatin and fluorouracil chemotherapy still failed to
None declared.
Acknowledgements The authors thank Fei Han, Yong-Hong Hu, ZhenYu He, Qiao-Qiao Li, Yan Xu, Xiao-Fen Xiao, XiaoQing Hu and Hui-Xia Feng (Department of Radiation Oncology, Sun Yat-sen University Cancer Centre) for contributing their patients to the study, assistance with the data management and logistic support. They thank the Clinical Trials Centre, Sun Yat-sen University Cancer Centre, for trial monitoring, data management and statistical assistance. They also thank the patients and their families for their willingness to participate in this trial. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejca.2017.01.002.
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