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IJC International Journal of Cancer

Concurrent chemoradiotherapy with/without induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma: Long-term results of phase 3 randomized controlled trial Wen-Fei Li1†, Nian-Yong Chen2†, Ning Zhang3†, Guo-Qing Hu4†, Fang-Yun Xie1†, Yan Sun5†, Xiao-Zhong Chen6, Jin-Gao Li7, Xiao-Dong Zhu8, Chao-Su Hu9, Xiang-Ying Xu10, Yuan-Yuan Chen6, Wei-Han Hu1, Ling Guo11, Hao-Yuan Mo 11, Lei Chen1, Yan-Ping Mao1, Rui Sun1, Ping Ai2, Shao-Bo Liang3, Guo-Xian Long4, Bao-Min Zheng5, Xing-Lai Feng6, Xiao-Chang Gong7, Ling Li8, Chun-Ying Shen9, Jian-Yu Xu10, Ying Guo12, Yu-Ming Chen13, Fan Zhang1, Li Lin1, Ling-Long Tang 1, Meng-Zhong Liu1, Jun Ma 1 and Ying Sun 1 Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, People’s Republic of China 2 Department of Radiation Oncology, Cancer Centre, West China Hospital, Sichuan University, Chengdu, China 3 Department of Radiation Oncology, The First People’s Hospital of Foshan, Foshan, People’s Republic of China 4 Department of Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People’s Republic of China 5 Department of Radiation Oncology, Peking University School of Oncology, Beijing, People’s Republic of China 6 Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China 7 Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang, People’s Republic of China 8 Department of Radiation Oncology, Cancer Hospital of Guangxi Medical University, Nanning, People’s Republic of China 9 Department of Radiation Oncology, Fudan University Shanghai Cancer Centre, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, People’s Republic of China 10 Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China 11 Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, People’s Republic of China 12 Clinical Trials Centre, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Centre for Cancer Medicine, Guangzhou, People’s Republic of China 13 Department of Medical Statistics and Epidemiology, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China

Key words: nasopharyngeal carcinoma, induction chemotherapy, concurrent chemoradiotherapy, randomized clinical trial Abbreviations: CCRT: concurrent chemoradiotherapy; CI: confidence interval; D-FFS: distant failure-free survival; EBV: Epstein–Barr Virus; FFS: failure-free survival; HR: hazard ratio.; IC: induction chemotherapy; IMRT: intensity-modulated radiotherapy; IQR: interquartile range; LDH: lactate dehydrogenase; LR-FFS: locoregional failure-free survival; NPC: nasopharyngeal carcinoma; OS: overall survival Additional Supporting Information may be found in the online version of this article. † W.-F.L., N.-Y.C., N.Z., G.-Q.H., F.-Y.X. and Y.S. contributed equally to this study. Conflict of interest: The authors declare that they have no competing interests. Grant sponsor: Shenzhen Main Luck Pharmaceuticals Inc., Sun Yat-sen University Clinical Research 5010 Program; Grant number: 2007037; Grant sponsor: National Natural Science Foundation of China; Grant number: 81702682; Grant sponsor: Special support program of Sun Yat-sen University Cancer Center; Grant number: 16zxtzlc06; Grant sponsor: Natural Science Foundation of Guang Dong Province; Grant number: 2017A030312003; Grant sponsor: Health & Medical Collaborative Innovation Project of Guangzhou City; Grant number: 201803040003; Grant sponsor: Innovation Team Development Plan of the Ministry of Education; Grant number: IRT_17R110; Grant sponsor: Overseas Expertise Introduction Project for Discipline Innovation; Grant number: 111 Project, B14035 DOI: 10.1002/ijc.32099 History: Received 12 Oct 2018; Accepted 19 Dec 2018; Online 6 Jan 2019 Correspondence to: Ying Sun, Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Centre of Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China, Tel.: +86-20-87342253, Fax: +86-20-87343295, E-mail: [email protected]; or Jun Ma, Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Centre of Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, People’s Republic of China, E-mail: [email protected]

Int. J. Cancer: 145, 295–305 (2019) © 2019 UICC

Cancer Therapy and Prevention

1

296

Induction chemotherapy for NPC

To report long-term results of a randomized controlled trial that compared cisplatin/fluorouracil/docetaxel (TPF) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC). Patients with stage III–IVB (except T3–4 N0) NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239). IC included three cycles of docetaxel (60 mg/m2 d1), cisplatin (60 mg/m2 d1), and fluorouracil (600 mg/m2/d civ d1–5) every 3 weeks. Patients from both groups received intensity-modulated radiotherapy concurrently with three cycles of 100 mg/m2 cisplatin every 3 weeks. After a median follow-up of 71.5 months, the IC plus CCRT group showed significantly better 5-year failure-free survival (FFS, 77.4% vs. 66.4%, p = 0.019), overall survival (OS, 85.6% vs. 77.7%, p = 0.042), distant failure-free survival (88% vs. 79.8%, p = 0.030), and locoregional failure-free survival (90.7% vs. 83.8%, p = 0.044) compared to the CCRT alone group. Post hoc subgroup analyses revealed that beneficial effects on FFS were primarily observed in patients with N1, stage IVA, pretreatment lactate dehydrogenase ≥170 U/l, or pretreatment plasma Epstein–Barr virus DNA ≥6000 copies/mL. Two nomograms were further developed to predict the potential FFS and OS benefit of TPF IC. The incidence of grade 3 or 4 late toxicities was 8.8% (21/239) in the IC plus CCRT group and 9.2% (22/238) in the CCRT alone group. Long-term follow-up confirmed that TPF IC plus CCRT significantly improved survival in locoregionally advanced NPC with no marked increase in late toxicities and could be an option of treatment for these patients.

Cancer Therapy and Prevention

What’s new? Despite advances in the treatment of nasopharyngeal carcinoma, approximately 30% of high-risk patients experience recurrence after treatment. Here the authors find that combining the conventional chemoradiotherapy with a triple induction chemotherapy (cisplatin/fluorouracil/docetaxel) prolonged survival of patients with locoregionally advanced cancer, even after more than 70 months of follow-up. The combination treatment increased acute, but not late, toxicities, and the authors propose that it could present a new treatment option for this patient group.

Introduction Nasopharyngeal carcinoma (NPC) is a unique head and neck cancer with an unbalanced endemic distribution, and China has one of the highest incidence rates of NPC in the world, particularly the southern regions.1 Over 70% of patients with NPC present with locoregionally advanced disease, and concurrent chemoradiotherapy (CCRT) is the standard treatment. Despite advances in diagnosis and multimodality treatment, approximately 30% of high-risk patients still experience tumor recurrence, with distant metastasis as the primary failure pattern.2,3 Various strategies such as addition of adjuvant and/or induction chemotherapy (IC) to CCRT have been explored to improve survival in patients with locoregionally advanced NPC. Compared to adjuvant chemotherapy, IC offers the advantages of early eradication of micrometastases, tumor downstaging, and better tolerability. For head and neck cancer, cisplatin/fluorouracil/docetaxel (TPF) is the recommended induction regimen based on its superiority over cisplatin and fluorouracil (PF) IC.4–6 Several phase 2 trials have reported promising results with manageable toxicities for TPF IC in NPC.7–9 However, whether the addition of TPF IC to CCRT provides additional survival benefits in NPC remains unclear. Therefore, we conducted a phase 3 trial to compare the efficacy of TPF IC plus CCRT with that of CCRT alone in

locoregionally advanced NPC (NCT01245959), and 3-year follow-up results showed significant improvement in survival in patients treated with TPF IC plus CCRT.10 Nevertheless, it is imperative to determine whether this survival benefit is durable. Hence, the purpose of this progress report is to assess long-term outcomes and late toxicities of TPF IC in patients with locoregionally advanced NPC.

Materials and Methods Eligibility

Our study was an open-label, multicenter, phase 3, randomized controlled trial conducted at 10 hospitals in China. Eligible patients were those with previously untreated, histologically confirmed, non-keratinizing, locoregionally advanced NPC (stage III-IVB except T3-4 N0; 7th American Joint Commission on Cancer staging system). Patients had to be 18–59 years old with Karnofsky scores of at least 70, and adequate bone marrow, liver, and renal function. Exclusion criteria included treatment with palliative intent, a history of previous radiotherapy, chemotherapy, or surgery (except diagnostic) to the primary tumor or nodes, previous malignancy, pregnancy or lactation, or any severe coexisting disease. The study protocol was approved by the institutional review board at each center, and all patients provided written informed consent.

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Randomization

Prognostic marker analysis

Eligible patients were randomly assigned (1:1 ratio) to receive three cycles of TPF IC followed by CCRT or CCRT alone. Random assignment was conducted (via sealed envelopes) by the Clinical Trials Centre, Sun Yat–sen University Cancer Centre, by means of computer-generated random number codes. Patients were stratified according to treatment center and disease stage (III or IV) and randomly assigned in blocks of four (one-to-one treatment allocation; block size known only to statistician). Treatment allocation was not masked. Investigators of each center enrolled patients and assigned them to the interventions.

Pretreatment plasma Epstein–Barr Virus (EBV) DNA levels were retrospectively collected in patients at the Sun Yat-sen University Cancer Centre, Guangzhou, China, and the methodology for detecting plasma EBV DNA has been described previously.15,16 In addition, pretreatment serum lactate dehydrogenase (LDH) levels were retrospectively collected from all participating centers.

For IC, TPF was administered as 60 mg/m2 docetaxel intravenously on day 1, 60 mg/m2 cisplatin intravenously on day 1, and 600 mg/m2/d fluorouracil as continuous infusion on days 1–5; three cycles were administered at intervals of 3 weeks.11,12 For CCRT, 100 mg/m2 cisplatin was administered intravenously every 3 weeks on days 1, 22, and 43 concurrently with radiotherapy. During the induction and concurrent phases, chemotherapy was withheld until nadir values were ≥ 1500/μL for neutrophils and ≥ 100,000/μL for platelets. Dose modifications for hematologic and nonhematologic toxic effects during IC or CCRT were based on nadir blood counts and interim toxicities of the preceding cycle.10 All patients were irradiated with intensity-modulated radiotherapy (IMRT), based on previously published guidelines for IMRT.10 Cumulative doses were ≥ 66 Gy to the primary tumor and ≥ 50 Gy to bilateral cervical lymph nodes and potential sites of local infiltration. The recommended radiotherapy dose was 68–70 Gy in 2.0–2.27 Gy per fraction with five daily fractions per week for 6–7 weeks; a moderate dose escalation to ≤74 Gy or dose increase per fraction to ≤2.35 Gy could be considered for some patients. Protocol was previously published10 and described in the Supporting Information. Treatment responses were assessed 1 week after completion of the third cycle of IC and 16 weeks after radiotherapy, according to the Response Evaluation Criteria in Solid Tumors (version 1.1).13 Acute toxic effects during IC and CCRT were graded according to the Common Terminology Criteria for Adverse Events (version 3.0); late radiotherapy-related toxic effects were graded according to the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group.14 Patients were assessed every 3 months during the first 3 years, and every 6 months thereafter until death. The primary end point was failure-free survival (FFS), which was calculated from the date of randomization to the date of locoregional failure, distant failure, or death from any cause, whichever occurred first. Secondary end points included overall survival (OS), distant failure-free survival (D-FFS), locoregional failure-free survival (LR-FFS), response rates, toxicity profile, compliance to treatment, and quality of life. OS was calculated from date of randomization to death; moreover, LR-FFS and D-FFS were calculated from date of randomization to first locoregional and distant failure, respectively. Int. J. Cancer: 145, 295–305 (2019) © 2019 UICC

Our study had an 80% power to detect a treatment failure hazard ratio (HR) of 0.52 (two-sided log-rank test; p = 0.05), assuming a 3-year FFS of 88% in the IC plus CCRT group and 78% in the CCRT alone group.2,17 We anticipated that 77 events were required in 452 patients (226 per treatment group); therefore, a minimum of 238 patients had to be recruited per group (total 476), assuming a 5% early dropout or loss to follow-up rate.18 All efficacy analyses were performed in the intention-totreat population, and only those patients who received their randomly assigned treatments were included in adverse events analyses. Time-to-event data were described using Kaplan– Meier curves; time-to-event intervals were compared using the log-rank test. HRs and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards model.19 Multivariate analyses were performed using the Cox proportional hazards model to test the independent significance of various factors.19 Initial response rates, toxicity rates, and other categorical variables were compared using the Chi-square test (or Fisher’s exact test, if indicated). Subgroup analyses were exploratory, and the tests for treatment–subgroup interactions were performed using interaction terms in the Cox model without corrected for multiple comparisons. Two nomograms were further formulated to predict 5-year FFS and OS using the rms package in R. The performance of the nomograms were evaluated by the concordance index (C-index) and calibration curve, and bootstraps with 1000 resamples were applied to these activities. All analyses were performed using SPSS (version 22.0) and R (version 3.4.4). Two-sided p values <0.05 were considered statistically significant.

Results Patient characteristics and treatment delivery

From March 1, 2011, to August 22, 2013, 480 patients with locoregionally advanced NPC were randomly assigned to receive IC plus CCRT (n = 241) or CCRT alone (n = 239; Supporting Information Fig. S1). Both treatment groups were well balanced in baseline demographic and clinical characteristics (Table 1). In all, 236/241 (97.9%) patients in the IC plus CCRT group and 239/239 (100%) patients in the CCRT group completed IMRT. The median radiotherapy dose was 70 Gy (interquartile range [IQR], 70–70), and the median dose per fraction was 2.19 Gy (IQR, 2.12–2.26). Overall, 212/241 (88%) patients from the IC plus CCRT group completed three cycles

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Procedures

Statistical analysis

298

of TPF IC. During CCRT, 30.3% (73/241) of patients completed three concurrent cycles of cisplatin and 85.9% (207/241) received ≥200 mg/m2 concurrent cisplatin in the IC plus CCRT group; in the CCRT alone group, these proportions were 56.1% (134/239) and 98.3% (235/239), respectively (Supporting Information Table S1). The median cumulative cisplatin dose was 500 mg/m2 (IQR, 500–580) for the IC plus CCRT group and 300 mg/m2 (IQR, 200–300) for the CCRT alone group.

Cancer Therapy and Prevention

Clinical outcomes

One week after completion of TPF IC, 27 (11.2%) of the 241 patients had achieved complete response (CR) and 189 (78.4%) achieved partial response (PR) considering the primary tumor and neck together. The proportion of patients achieving an overall response (CR + PR) with TPF IC was 89.6% (216/241). Sixteen weeks after completion of radiotherapy, the CR rate was 98.3% (237/241) in the IC plus CCRT group and 97.1% (232/239) in the CCRT alone group (p = 0.353). The last date of data collection was August 31, 2018, and the median follow-up duration was 71.5 (range, 0.8–90) months. Overall, 138/480 (28.8%) patients experienced treatment failure or died. The 5-year FFS rate was 77.4% (95% CI, 71.5%–82.2%) in the IC plus CCRT group and 66.4% (60.1%– 72.1%) in the CCRT alone group (HR = 0.67, 95% CI: 0.48–0.94; p = 0.019). Ninety-four patients died; of these, 82 were cancer-specific deaths (31/241 [12.9%] in the IC plus CCRT group vs. 51/239 [21.3%] in the CCRT alone group), and 12 patients died of noncancer-related causes (7/241 [2.9%] in the IC plus CCRT group vs. 5/239 [2.1%] in the CCRT alone group). The 5-year OS rate was 85.6% (80.4%– 89.5%) in the IC plus CCRT group and 77.7% (71.9%–82.5%) in the CCRT alone group (HR = 0.65, 95% CI: 0.43–0.98; p = 0.042). Patients from the IC plus CCRT group showed significantly better 5-year D-FFS (88% [83.1%–91.6%] vs. 79.8% [74%–84.4%], HR = 0.60, 95% CI: 0.38–0.95; p = 0.030) and 5-year LR-FFS (90.7% [86.1%–93.9%] vs. 83.8% [78.2%– 88.1%], HR = 0.58, 95% CI: 0.34–0.99; p = 0.044) compared to patients from the CCRT alone group (Figs. 1a–1d). Prognostic analysis

Of the 480 patients, pretreatment lactate dehydrogenase (LDH) levels were retrospectively collected in 460 (95.8%) patients, and the median LDH level was 173 U/l (IQR, 153–202). Of the 257 patients from the Sun Yat-sen University Cancer Centre, 243 (94.6%) patients had undergone pretreatment plasma Epstein–Barr Virus (EBV) DNA assay, and the median concentration was 5700 copies/mL (IQR, 626–33,400). Elevated pretreatment LDH levels (≥170 vs. <170 U/l) and EBV DNA levels (≥6000 vs. <6000 copies/mL) were significantly associated with poorer FFS and OS in univariate analysis. In multivariate analysis of all 480 patients, treatment group and T category were independently associated with FFS and OS; N category was an

Induction chemotherapy for NPC

independent prognostic factor for OS and a marginally significant factor for FFS (Table 2). In the other two cohorts of patients mentioned above, pretreatment LDH level was independently correlated with FFS and OS, while EBV DNA level was not an independent prognosticator (Table 2). Subgroup analysis

Post hoc exploratory analysis was performed to assess the possible differential efficacy of TPF IC in a range of baseline subgroups. Adding TPF IC was associated with a trend toward improved FFS and OS in all subgroups, with HRs ranging from 0.43 to 0.85 (Figs. 2a–2b). Statistically significant improvement in FFS was achieved by male patients (HR = 0.65, 95% CI: 0.45–0.95; p = 0.025), patients aged <45 years (HR = 0.55, 95% CI: 0.34–0.87; p = 0.010), and those with Karnofsky scores of 90–100 (HR = 0.69, 95% CI: 0.48–0.99; p = 0.045), N1 category (HR = 0.48, 95% CI: 0.27–0.88; p = 0.017), stage IVA (HR = 0.51, 95% CI: 0.30–0.87; p = 0.013), pretreatment LDH ≥170 U/l (HR = 0.60, 95% CI: 0.39–0.93; p = 0.021), or

Table 1. Baseline characteristics IC plus CCRT group (n = 241)

Characteristic

CCRT group (n = 239)

0.4142

Age, years Median

42

44

18–59

18–59

Male

193 (80.1)

174 (72.8)

Female

48 (19.9)

65 (27.2)

Rang Sex, No. (%)

0.060

Karnofsky score, No. (%)

0.536

90–100

217 (90)

211 (88.3)

24 (10)

28 (11.7)

T1

15 (6.2)

6 (2.5)

T2

27 (11.2)

19 (7.9)

T3

112 (46.5)

121 (50.6)

T4

87 (36.1)

93 (38.9)

97 (40.2)

107 (44.8)

70–80 T category, No. (%)

0.122

N category, No. (%) N1

p Value1

0.307

N2

105 (43.6)

106 (44.4)

N3a

13 (5.4)

11 (4.6)

N3b

26 (10.8)

15 (6.3)

III

129 (53.5)

133 (55.6)

IVA

73 (30.3)

80 (33.5)

IVB

39 (16.2)

26 (10.9)

Stage, No. (%)

0.226

Abbreviations: IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy. 1 p Values were calculated by Chi-square test. 2 Comparison of patients younger than 45 years of age and 45 years or older.

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(a)

(b) IC+CCRT CCRT

100

100 90

80

80 Overall survival(%)

70 60 50 40

IC+CCRT CCRT 5y FFS 77.4% 66.4% HR 0.67 (95% CI 0.48-0.94) P=0.019

30 20 10

Number at risk CCRT 239 IC+CCRT 241

96

210 225

0 0

170 191

161 181

152 169

96 113

17 20

IC+CCRT CCRT 5y OS 85.6% 77.7% HR 0.65 (95% CI 0.43-0.98) P=0.042

30

0 0 Number at risk CCRT 239 IC+CCRT 241

12 24 36 48 60 72 84 Time Since Random Assignment (months)

96

231 234

0 0

221 223

205 216

187 207

178 186

108 124

20 21

(d)

(c)

Locoregional failure-free survival(%)

100 Distant failure-free survival(%)

50 40 20

12 24 36 48 60 72 84 Time Since Random Assignment (months) 181 203

60

10

0 0

70

90 80 70 60 50

IC+CCRT CCRT 5y D-FFS 88% 79.8% HR 0.60 (95% CI 0.38-0.95) P=0.030

40 30 20 10 0 0

Number at risk CCRT 239 IC+CCRT 241

12 24 36 48 60 72 84 Time Since Random Assignment (months)

96

215 228

0 0

197 214

185 204

176 194

168 179

103 118

19 21

100 90 80 70 60 50 40

IC+CCRT CCRT 5y LR-FFS 90.7% 83.8% HR 0.58 (95% CI 0.34-0.99) P=0.044

30 20 10 0 0

Number at risk CCRT 239 IC+CCRT 241

12 24 36 48 60 72 84 Time Since Random Assignment (months)

96

225 231

0 0

201 212

188 203

171 193

162 175

101 118

18 20

Figure 1. Kaplan–Meier survival curves for IC plus CCRT and CCRT groups. Failure-free survival (a), overall survival (b), distant failure-free survival (c), and locoregional failure-free survival (d). Hazard ratios (HRs) were calculated using the unadjusted Cox proportional hazards model; p values were calculated using the unadjusted log-rank test. IC = induction chemotherapy; CCRT = concurrent chemoradiotherapy; FFS = failure-free survival; OS = overall survival; D-FFS = distant failure-free survival; LR-FFS = locoregional failure-free survival.

pretreatment EBV DNA ≥6000 copies/mL (HR = 0.45, 95% CI: 0.23–0.87; p = 0.017). Moreover, significant improvement in OS was noted in patients aged <45 years (HR = 0.55, 95% CI: 0.31–0.98; p = 0.043) or those with Karnofsky scores 90–100 (HR = 0.64, 95% CI: 0.41–1.00; p = 0.049). However, no interactions were noted between patient characteristics and treatment effects in terms of FFS or OS. Nomogram development and validation

Based on the results of multivariate analyses, we built nomogram A to predict 5-year FFS and nomogram B to predict 5-year OS, using the variables of treatment group, T category, N category, and pretreatment LDH levels (Figs. 3a–3b). The C-index of nomogram A for FFS prediction was 0.64 (95% CI: 0.593–0.687), and the C-index of nomogram B for predicting OS was 0.66 (0.609–0.711). The calibration curves for probability of survival showed good agreement between prediction by nomogram and actual observation (Figs. 3c–3d). Int. J. Cancer: 145, 295–305 (2019) © 2019 UICC

Treatment toxicities

During treatment, 72.8% (174/239) of patients from the IC plus CCRT group and 53.8% (128/238) from the CCRT alone group experienced grade 3 or 4 toxicities (p < 0.001, Table 3). The proportion of patients with any grade 4 acute toxicity was significantly higher in the IC plus CCRT group than the CCRT alone group (17.6% [42/239] vs. 1.3% [3/238], p < 0.001); major differences were observed in the incidences of grade 4 neutropenia and leucopenia. One TPF-related death occurred after one cycle of IC due to neutropenic infection and lack of timely medical care. During follow-up, 21 (8.8%) of 239 patients from the IC plus CCRT group and 22 (9.2%) of 238 patients from the CCRT alone group developed one or more grade 3 or 4 toxicities (p = 0.862). The incidence of grade 1 or 2 toxicities was 89.5% (214/239) in the IC plus CCRT group and 92.9% (221/238) in the CCRT alone group. No significant differences were noted in late toxicities between both groups (Table 3).

Cancer Therapy and Prevention

Failure-free survival(%)

90

300

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Table 2. Summary of multivariate analyses of prognostic factors Failure-free survival

Overall survival

HR

95% CI

p Value

HR

95% CI

0.70

0.46–1.07

0.096

0.63

0.37–1.07

1

p Value1

In all 480 patients Sex, females vs. males

0.089

Age, ≥ 45 yr vs. < 45 yr

1.04

0.74–1.45

0.839

1.18

0.78–1.77

0.438

Karnofsky score, 70–80 vs. 90–100

1.09

0.66–1.81

0.729

1.41

0.81–2.46

0.230

T category, T3 vs. T1-2

0.89

0.50–1.59

0.693

0.57

0.30–1.09

T category, T4 vs. T1-2

1.82

1.04–3.16

0.035

1.34

0.74–2.44

T category

<0.001

N category

0.001

0.055

0.087 0.334 0.049

N category, N2 vs. N1

1.54

1.05–2.25

0.027

1.74

1.08–2.80

0.024

N category, N3 vs. N1

1.63

0.97–2.75

0.065

1.89

1.01–3.54

0.047

Treatment group, IC plus CCRT vs. CCRT

0.64

0.46–0.91

0.011

0.61

0.40–0.92

0.019

Sex, females vs. males

0.72

0.47–1.10

0.131

0.66

0.39–1.13

0.126

Age, ≥ 45 yr vs. < 45 yr

1.03

0.73–1.46

0.862

1.15

0.75–1.75

0.516

Karnofsky score, 70–80 vs. 90–100

1.08

0.65–1.80

0.762

1.38

0.78–2.43

0.267

T category, T3 vs. T1-2

0.89

0.50–1.60

0.704

0.55

0.29–1.05

0.071

T category, T4 vs. T1-2

1.77

1.01–3.08

0.045

1.25

0.69–2.29

0.461

N category, N2 vs. N1

1.50

1.02–2.21

0.042

1.65

1.01–2.70

0.046

N category, N3 vs. N1

1.58

0.93–2.67

0.089

1.84

0.97–3.47

0.062

Treatment group, IC plus CCRT vs. CCRT

0.62

0.44–0.88

0.008

0.58

0.38–0.89

0.012

Pretreatment LDH, ≥ 170 U/l vs. < 170 U/l

1.54

1.08–2.20

0.017

1.69

1.09–2.63

0.019

Sex, females vs. males

1.08

0.56–2.08

0.808

1.00

0.43–2.32

0.999

Age, ≥ 45 yr vs. < 45 yr

1.19

0.72–1.97

0.488

1.56

0.86–2.84

0.144

Karnofsky score, 70–80 vs. 90–100

0.79

0.35–1.77

0.561

1.01

0.41–2.45

In 460 patients with pretreatment LDH

T category

0.001

Cancer Therapy and Prevention

N category

0.003

0.088

0.086

In 243 patients with pretreatment LDH and EBV DNA

T category

<0.001

T category, T3 vs. T1-2

1.10

0.37–3.23

0.864

0.65

0.21–2.03

T category, T4 vs. T1-2

3.32

1.13–9.81

0.030

2.87

0.94–8.72

N category

0.987 <0.001

0.012

0.461 0.063 0.001

N category, N2 vs. N1

1.74

1.03–2.95

0.038

2.34

1.20–4.57

0.013

N category, N3 vs. N1

3.30

1.40–7.79

0.006

6.16

2.41–15.78

<0.001

Treatment group, IC plus CCRT vs. CCRT

0.44

0.26–0.74

0.002

0.41

0.22–0.78

0.006

Pretreatment LDH, ≥ 170 U/l vs. < 170 U/l

1.83

1.10–3.03

0.020

1.91

1.02–3.57

0.044

Pretreatment EBV DNA, ≥ 6000 copies/mL vs. < 6000 copies/mL

1.43

0.86–2.39

0.168

1.37

0.71–2.66

0.345

Abbreviations: HR, hazard ratio; CI, confidence interval; IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy. 1 p Values were calculated using an adjusted Cox proportional-hazards model; all HRs presented in the table are adjusted for other covariates.

Discussion In this long-term analysis, patients from the TPF IC plus CCRT group showed significantly better 5-year FFS, OS, DFFS, and LR-FFS rates than did those treated with CCRT alone. No significant differences were noted in late toxic effects between both treatment groups. The efficacy of IC followed by CCRT in NPC remains controversial;20,21 however, accumulating evidence has revealed that patients with locoregionally advanced NPC can benefit from

IC.10,17,22–24 In our original report, TPF IC significantly improved 3-year FFS, OS, and D-FFS in patients with locoregionally advanced NPC.10 In another randomized trial (GORTEC 2006–02) which was prematurely closed owing to poor accrual, the TPF arm also showed a significant increase in 3-year progression-free survival and a trend toward better OS.23 Moreover, in the phase 3 study by Cao et al., addition of two cycles of induction PF to CCRT achieved significant improvement in disease-free survival and a marginally significant improvement in Int. J. Cancer: 145, 295–305 (2019) © 2019 UICC

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(a)

(b) IC+CCRT CCRT (events/total) (events/total)

HR (95% CI)

Subgroup

IC+CCRT CCRT (events/total) (events/total)

HR (95% CI)

38/241 /

56/239 /

0.65 (0.43, 0.98)

Female Male

5/48 / 33/193

12/65 / 44/174

0.56 (0.20, 1.58) 0.65 (0.42, 1.02)

0.55 (0.34, 0.87) 0.85 (0.52, 1.40)

Age < 45yrs > 45yrs

19/136 19/105

30/126 26/113

0.55 (0.31, 0.98) 0.79 (0.44, 1.43)

68/211 / 12/28

0.69 (0.48, 0.99) 0.53 (0.20, 1.42)

KPS score 90-100 70-80

32/217 / 6/24 /

47/211 / 9/28 /

0.64 (0.41, 1.00) 0.82 (0.29, 2.32)

8/42 / 22/112

9/25 / 29/121

0.47 (0.18, 1.22)

T category T1-2

28/87 /

42/93

0.79 (0.45, 1.37) 0.63 (0.39, 1.02)

T3 T4

33/107 37/106 10/26

0.48 (0.27, 0.88)

N category N1

N2 N3

16/97 / 30/105 12/39 /

0.76 (0.47, 1.22) 0.74 (0.32, 1.72)

N2 N3

Stage III IVA IVB

25/129 21/73 / 12/39 /

32/133 38/80 10/26

0.77 (0.46, 1.31) 0.51 (0.30, 0.87) 0.74 (0.32, 1.72)

Stage III IVA IVB

LDH < 170 U/L > 170 U/L

19/100 37/132

31/114 48/114

0.65 (0.37, 1.15) 0.60 (0.39, 0.93)

LDH < 170 U/L > 170 U/L

9/62 / 13/58 /

16/60 28/63

0.51 (0.22, 1.15)

EBV DNA < 6000 copies/mL

0.45 (0.23, 0.87)

> 6000 copies/mL

Overall

58/241

80/239 /

0.67 (0.48, 0.94)

Female Male

9/48 / 49/193

18/65 62/174

0.65 (0.29, 1.46) 0.65 (0.45, 0.95)

Age < 45yrs > 45yrs

30/136 28/105

45/126 35/113

KPS score 90-100 70-80

52/217 6/24 /

Sex

Sex

T category T1-2 T3 T4 N category N1

EBV DNA < 6000 copies/mL > 6000 copies/mL

Overall

.0625 .125

.25

.5

1

2

4

7/42 /

9/25 /

0.43 (0.16, 1.16)

12/112 19/87 /

18/121 29/93 /

0.71 (0.34, 1.47) 0.68 (0.38, 1.21)

9/97 /

20/107

0.46 (0.21, 1.01)

22/105 7/39 /

26/106 10/26 /

0.85 (0.48, 1.49) 0.46 (0.17, 1.20)

16/129

21/133

15/73 / 7/39 /

25/80 / 10/26 /

0.77 (0.40, 1.48) 0.62 (0.33, 1.18) 0.49 (0.17, 1.20)

10/100 26/132

21/114 34/114

0.52 (0.25, 1.11) 1.11) 0.64 (0.38, 1.06)

5/62 / 10/58 /

10/60 / 20/63 /

0.46 (0.16, 1.35)

.0625 .125

0.52 (0.24, 1.10)

.25

.5

1

2

4

Figure 2. Forest plots of treatment effects on survival within subgroups. Failure-free survival (a) and overall survival (b). The number of events and the number of patients were shown by arm. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated by univariate Cox proportional hazards model. IC = induction chemotherapy; CCRT = concurrent chemoradiotherapy.

distant control.22 Hong and colleagues did a randomized phase 3 trial comparing three cycles of induction mitomycin C, epirubicin, cisplatin, and 5-fluorouracil/leucovorin (MEPFL) followed by CCRT with CCRT alone in patients with stage IVA-B NPC, and induction MEPFL significantly improved disease-free survival and locoregional control, but not OS or distant control.24 In this updated report, the survival advantage seen in our original report 10 was sustained. The 5-year FFS and OS rates of the TPF IC plus CCRT group were 77.4% and 85.6%, respectively, which were comparable to those (74.4% and 87%, respectively) reported by Kong et al.9 The 5-year FFS and OS rates of the CCRT alone group were 66.4% and 77.7%, respectively, which were lower to those (71% and 80%, respectively) reported by Chen et al probably due to a higher percentage of patients with stage IVA-B disease (44.4% vs. 34%).25 Both LRFFS and D-FFS were significantly improved in this report; this new finding indicated that the positive effects of TPF IC on FFS and OS could be related to combined effects on local and distant control. Moreover, we developed two nomograms to provide individualized estimates of potential FFS and OS benefit from TPF IC for patients with locoregionally advanced NPC.

Int. J. Cancer: 145, 295–305 (2019) © 2019 UICC

Post hoc subgroup analyses suggest that IC plus CCRT probably works better for patients with N1 category, stage IVA (T4 N1–2), pretreatment LDH ≥170 U/l, or pretreatment EBV DNA ≥6000 copies/mL, while further treatment intensification might be needed in extreme high-risk subgroups (e.g., N3/stage IVB). In another phase 3 study focusing on patients with stage IVA-B NPC, addition of IC to CCRT achieved significant improvement in disease-free survival and locoregional control, but not OS or distant control.24 Several randomized trials are currently underway to evaluate therapeutic benefits of adding more potent systemic therapies such as anti-programmed death-1 (PD-1) antibody (e.g. NCT03427827, NCT03700476), anti-epidermal growth factor receptor (EGFR) antibody (e.g. NCT01074021), and maintenance chemotherapy (e.g. NCT02143388, NCT02958111, NCT03403829) in different high-risk subgroups of NPC receiving IC plus CCRT or CCRT, and the results are eagerly awaited. The overall response rate to TPF IC was 89.6% in our study, which is similar to that (87.5%) noted in the GORTEC study 23 and higher than that (72%–77%) reported in former studies wherein other induction regimens were used.17,20,24 Several studies have shown that tumor response to IC could serve as a prognostic

Cancer Therapy and Prevention

Subgroup

302

Induction chemotherapy for NPC

(b)

(a) Points

0

30

90

60

CCRT

Treatment

T3

>170

LDH (U/L) <170

<170 Total points

Total points

0

50

100

150

200

250

0.6

0.5 0.4

300

0

5-year FFS

50

100

150

200

250

300

350

5-year OS

0.85 0.8

0.7

0.9

(c)

0.85 0.8

0.7 0.6 0.5

(d) Actual 5-year OS (proportion)

Actual 5-year FFS (proportion)

N3

N1

>170

LDH (U/L)

T4 N2

N category N3

N1

Cancer Therapy and Prevention

T3 T1-2

T4 N2

90

60

CCRT

T category

T1-2 N category

30

Treatment IC+CCRT

IC+CCRT

T category

0

Points

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.4

0.5

0. 6 0.6

0.7

0.8

0.9

1.0

Nomogram-predicted probability of 5-year FFS

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.4

0.5

0.6

0.7

0.8

0.9

1.0

Nomogram-predicted probability of 5-year OS

Figure 3. Nomograms and calibration curves for predicting 5-year FFS and OS. (a) Nomogram A to predict 5-year FFS. (b) Nomogram B to predict 5-year OS. (c) Calibration curve of nomogram A for predicting 5-year FFS. (d) Calibration curve of nomogram B for predicting 5-year OS. The nomograms allow the user to obtain the probability of 5-year FFS and OS corresponding to a patient’s combination of covariates. To use, first determine the value for each variable by drawing a vertical line from that variable to the upper-most point scale, then sum all of the individual values and draw a vertical line from the total points scale to the bottom 5-year FFS or OS probability lines to obtain the probability estimates. In the calibration plots for the nomograms, the actual 5-year FFS or OS is plotted on the y-axis, and nomogram-predicted probability is plotted on the x-axis. The dashed line represents the ideal fit; black circles represent nomogram-predicted probabilities for each group, and crosses represent the bootstrap-corrected estimates. Error bars represent the 95% CIs of these estimates. IC = induction chemotherapy; CCRT = concurrent chemoradiotherapy; LDH = serum lactate dehydrogenase; FFS = failure-free survival; OS = overall survival.

predictor for NPC.26,27 Thus, with use of a more effective chemotherapy regimen, patients would obtain better tumor response and achieve better survival outcomes. Zhang et al. proved that gemcitabine plus cisplatin (GP) was better than the PF regimen in the first-line setting of recurrent or metastatic NPC.28 In the retrospective study by Zeng et al, no significant differences in treatment outcomes were found between the induction TPF and GP strategies for the treatment of locoregionally advanced NPC.29 Several ongoing trials are conducting to assess or compare the efficacy and safety of different IC regimens in locoregionally advanced NPC (e.g. NCT01872962, NCT02512315, NCT03503136, NCT03604965); hence, it remains to be determined whether TPF is the best induction regimen for NPC.

Acute grade 3 or 4 toxicities were significantly more frequent in the IC plus CCRT group, and the major hematological toxicities were neutropenia and leucopenia, which were uncomplicated and manageable. For late toxicities, radiation parameters probably remain the key determinants for NPC patients. In our study, the incidences of severe late radiationrelated toxicities were comparable with those in previous studies of patients with locoregionally advanced NPC treated with conformal radiotherapy.24,30 Although IC has the benefit of shrinking tumor volume before radiotherapy, the incidence of late radiation-related toxicities were similar between both groups, probably because of the inconsistency in target volume delineation based on pre-IC or post-IC images.31 For

Int. J. Cancer: 145, 295–305 (2019) © 2019 UICC

132 (55.2)

Any

Int. J. Cancer: 145, 295–305 (2019) © 2019 UICC 5 (2.1)

Thrombocytopenia

0

13 (5.4) 8 (3.3) 5 (2.1) 7 (2.9) 2 (0.8)

Dry mouth

Dermatitis

Esophagitis, dysphagia, or odynophagia

Hepatoxicity

102 (42.7) 6 (2.5) 13 (5.4)

Dry mouth

Neck tissue damage

Bone necrosis

Trismus

0

1 (0.4)

0

4 (1.7)

16 (6.7)

0

1 (0.4)

3 (1.3)

0

21 (8.8)

Grade 3–4 No. (%)

0

1 (0.4)

-

4 (1.7)

13 (5.5)

13 (5.5)

113 (47.5)

204 (85.7)

88 (37.0)

4 (1.7)

4 (1.7)

6 (2.5)

23 (9.7)

221 (92.9)

Grade 1–2 No. (%)

0

2 (0.8)

9 (3.8)

10 (4.2)

13 (5.5)

40 (16.8)

45 (18.9)

82 (34.5)

2 (0.8)

5 (2.1)

40 (16.8)

0

0

16 (6.7)

125 (52.5)

Grade 3 No. (%)

1

Cancer Therapy and Prevention

0

1 (0.4)

0

2 (0.8)

15 (6.3)

0

0

4 (1.7)

0

22 (9.2)

Grade 3–4 No. (%)

0

0

0

0

-

0

0

2 (0.8)

0

0

1 (0.4)

0

0

1 (0.4)

3 (1.3)

Grade 4 No. (%)

CCRT group (n = 238)

Abbreviations: IC, induction chemotherapy; CCRT, concurrent chemoradiotherapy. There were no grade 3–4 acute adverse events for nephrotoxicity, ototoxicity, and neurotoxicity. p Values were calculated using the Chi-square test (or Fisher’s exact test).

80 (33.5) 195 (81.6)

Ear (deafness/otitis)

8 (3.3)

5 (2.1)

Cranial neuropathy 1 (0.4)

19 (7.9)

Symptomatic temporal lobe necrosis

Eye damage

214 (89.5)

Any

Peripheral neuropathy

Grade 1–2 No. (%)

Maximum-grade late adverse events

Allergic reaction

0

46 (19.2)

Nausea

4 (1.7)

96 (40.2) 52 (21.8)

Vomiting

2 (0.8)

1 (0.4)

0

12 (5)

0

2 (0.8)

37 (15.5)

42 (17.6)

Grade 4 No. (%)

Stomatitis (mucositis)

Nonhematologic

86 (36) 4 (1.7)

1 (0.4)

Neutropenic infection

Anemia

5 (2.1)

Febrile neutropenia

Leukopenia

64 (26.8)

Neutropenia

Hematologic

Grade 3 No. (%)

IC plus CCRT group (n = 239)

Maximum-grade acute adverse events during treatment

Table 3. Adverse events

0.991

0.099

0.292

0.223

0.423

0.216

0.245

0.755

0.509

0.201

-

1.000

-

0.686

0.862

-

1.000

0.724

-

0.862

p Value for grade 3–4 adverse events1

0.499

-

-

1.000

-

0.123

0.123

1.000

1.000

-

0.002

-

0.499

<0.001

<0.001

p Value for grade 4 adverse events1

p Value for grade 1–2 adverse events1

0.176

0.274

0.624

0.991

0.488

0.439

0.197

0.450

0.751

<0.001

1.000

0.061

<0.001

0.553

p Value for grade 3 adverse events1

p Value

Li et al.

303

304

Induction chemotherapy for NPC

chemotherapy-related toxicities, the incidence and severity of long-term paresthesias are determined mainly by cumulative cisplatin dose and dose intensity.32 In our study, the median cumulative cisplatin dose was 500 mg/m2 (IQR, 500–580) for the IC plus CCRT group, but only 3.7% of patients developed peripheral neurotoxicity; thus, the subjective toxicities may be under-reported. The present study had several limitations. First, we did not include prognostic biomarkers such as EBV DNA and LDH level for participant selection.33–35 Several clinical trials have included pre-treatment EBV DNA or post-radiotherapy EBV DNA level as the selection factor for systemic therapy in NPC (e.g. NCT02143388, NCT00370890, NCT02135042), which may help identifying patients most likely to benefit from therapeutic interventions. Second, patients aged ≥60 years were excluded in consideration of safety; therefore, the results lack generalizability to “elderly” patients. Older patients have decreased tolerance to chemotherapy, and clinical trials should be conducted to test the efficacy and safety of IC in elderly patients. Third, during design of the trial, there was no consensus on dose fractionation of IMRT in NPC, with the daily fraction dose ranging from 2.0 to 2.34 Gy.30,36–38 Thus, we adopted the daily fraction of 2.0–2.27 Gy, and a moderate dose increase per fraction to ≤2.35 Gy could be considered for some patients with T1-2 NPC. Although the optimal dose

schedule of IMRT in NPC still needs further evaluation, IMRT dose fractionation should be strictly unified in clinical trials to ensure consistency of radiotherapy treatment across all participating centers. Fourth, reliable data for late toxic effects were difficult to obtain for all patients, and underestimation of late toxicities could not be excluded. Implementation of improved adverse event data capture with Internet and mobile devices is suggested for future clinical trials. In conclusion, our long-term analysis confirms the efficacy of adding TPF IC to CCRT in patients with locoregionally advanced NPC from endemic regions of China. Combination treatment induces more acute toxicities but does not increase late toxicities. These results suggest that TPF IC plus CCRT could be an option of treatment for locoregionally advanced NPC.

Acknowledgements This work was supported by Shenzhen Main Luck Pharmaceuticals Inc., Sun Yat-sen University Clinical Research 5010 Program (2007037), National Natural Science Foundation of China (81702682), Special support program of Sun Yat-sen University Cancer Center (16zxtzlc06), Natural Science Foundation of Guang Dong Province (2017A030312003), Health & Medical Collaborative Innovation Project of Guangzhou City (201803040003), Innovation Team Development Plan of the Ministry of Education (IRT_17R110), and Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B14035).

Cancer Therapy and Prevention

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Int. J. Cancer: 145, 295–305 (2019) © 2019 UICC