This study was a prospective, single-arm, phase 2 trial conducted in a single institute in China. Eligibility was defined as newly diagnosed, previously untreated, histologically confirmed non-keratinizing NPC, stage III-IVB disease as per the 7th edition of the American Joint Committee on Cancer–Union for International Cancer Control (AJCC-UICC TNM-7) for patients diagnosed before 2018 or stage III-IVA disease as per AJCC-UICC TNM-8 for patients diagnosed on or after 2018 (except T3N0). Re-staging was performed using AJCC-UICC TNM-8 for patients enrolled prior to 2018 by two independent oncologists before the final analyses of this study. Any discrepancy in staging was resolved by consensus. Other inclusion criteria were age 18 to 75 years, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2, adequate hematologic, hepatic, and renal function. Key exclusion criteria were the following: treatment for palliative intent; a history of prior malignancy; a history of previous chemotherapy, radiotherapy, or surgery (except diagnostic procedures) to the primary tumor or nodes; pregnancy or lactation; or any severe comorbidity. The local institutional ethics committee approved the trial protocol (reference number 201627). The trial was conducted according to the Declaration of Helsinki and Good Clinical Practice guidelines. All patients provided written informed consent before enrollment. Patients could withdraw consent at any time after enrollment. This trial is registered on clinicaltrials.gov as NCT03427359, (https://clinicaltrials.gov/ct2/show/NCT03427359?term=NCT03427359&draw=2&rank=1).

Pre-treatment assessment included the following: complete history and physical examination; complete blood count, renal and liver function tests; Epstein-Barr virus- deoxyribonucleic acid (EBV-DNA) test; dental, audiometric, and nutritional assessment; fiberoptic nasopharyngoscopy; magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT) of the head and neck region (if MRI was contraindicated) for primary tumor staging; contrast-enhanced CT of the chest and abdomen, together with skeletal scintigraphy for distant metastasis staging. 18F-fluorodeoxyglucose-positron-emission tomography with integrated computed tomography (PET-CT) scan was recommended though not mandatory.

Patients received induction PX with cisplatin at a dose of 80 mg/m² as an intravenous infusion on day 1 plus oral capecitabine at a dose of 1000 mg/m² twice daily from day 1 to 14 every 21 days for 3 cycles. In the CCRT phase, cisplatin was delivered concurrently with radiotherapy (RT) and administered intravenously at a dose of 100 mg/m² on days 1 and 22 for 2 cycles. Details of the chemotherapy dose modifications are available in the Supplementary Appendix.

Treatment with intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) was mandatory for all patients. Doses of 70 Gy, 63 Gy, and 56 Gy were delivered to planning target volumes (PTV) at three levels (high, intermediate, and low risk, respectively) in 35 fractions over 7 weeks. An optional RT boost was allowed for patients with residual disease after CCRT. The details regarding RT are provided in the Supplementary Appendix. It was recommended that patients commence CCRT within 3 to 4 weeks after the first day of the last cycle of IC.

After completing IC and 16 weeks following RT, tumor responses were assessed with complete physical examination, fiberoptic nasopharyngoscopy, and MRI of the head and neck region, according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) (15). Further investigations with contrast-enhanced CT scan of the thorax and abdomen (or PET-CT) were arranged when indicated. Complete physical examination at the end of RT and fiberoptic nasopharyngoscopy with random nasopharyngeal biopsies 8 weeks after the completion of RT were recommended to assess if RT boost was needed. Persistent primary or lymph node disease 16 weeks after the completion of RT was considered a locoregional failure. Acute toxicities during IC and CCRT were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCEA v4.0). Late RT-related toxicities were graded according to the Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group (16).

In the first 3 years of follow-up, all the patients had regular assessments every 3 months and every 6 months thereafter until death. Whenever possible, locoregional or distant recurrences were confirmed by fine-needle aspiration or biopsy. All endpoints were assessed or confirmed by the primary treating physician.

The primary endpoint was progression-free survival (PFS), defined as the time from the start of IC to the first failure at any site (either distant metastasis or locoregional recurrence) or death from any cause, whichever occurred first. Secondary endpoints included overall survival (OS) (the time from the start of IC to death from any cause), locoregional recurrence-free survival (LRFS) (the time from the start of IC to first locoregional failure), distant metastasis-free survival (DMFS) (the time from the start of IC to distant failure), tumor response, compliance to treatment, and severe (grade ≥ 3) acute and late toxicities.

This non-inferiority trial aimed to evaluate whether the PFS of induction PX-CCRT with reduced cumulative cisplatin dose in LA NPC was not inferior to PFS reported in the NPC-0501 trial. The reported 3-year PFS in the induction PX-CCRT group (Arm 3A) in the NPC-0501 trial was 81% (7). Given the threshold of non-inferior effect δL= -10%, we estimated that 101 NPC cases could achieve 80.1% power by one-side log-rank test at the significance level of 0.05 (17, 18). Assuming 5% early dropout or loss to follow-up, the target accrual was a minimum of 107 patients.

Efficacy analyses were done in both intention-to-treat and per-protocol populations (see the Supplementary Appendix). Only patients who received at least 1 cycle of induction PX were included in the safety analyses. Patient demographics, clinicopathologic, and treatment-related factors were reported by descriptive statistics. For each chemotherapy drug of PX, the dose intensity (DI) was calculated as the ratio of the total dose per square meter of the patient, divided by the total treatment duration (mg/m²/week). The relative DI was calculated as the ratio of the DI delivered to the DI planned by the protocol. Kaplan–Meier curves were used to describe time-to-event data, and the subgroups were compared with the log-rank tests. All statistical analyses were performed by R software version 3.6.1 and SPSS software version 26.0 (IBM). A two-sided P-value less than 0.05 was considered clinically significant.

From January 2015 to September 2019, 135 eligible patients were accrued (Figure 1). The median age was 45 years (range 19-70), and 95 (70.4%) patients were male. The detailed characteristics of the patients are shown in Table 1.

All 135 patients started protocol-defined induction IC (Figure 1). A total of 128 patients (94.8%) completed 3 cycles of induction PX. 7 patients (5.2%) failed to complete 3 cycles of induction PX. 2 (1.5%) patients received only one cycle, and 5 (3.7%) patients received two cycles. The reasons for discontinuing PX were shown in Figure 1. During IC, 7 patients (5.2%) required dose reductions of cisplatin and/or capecitabine because of neutropenia (n= 1 patient), severe vomiting (n= 2 patients), renal impairment (n= 1 patient), electrolyte disturbance (n= 1 patient), legs edema (n= 1 patient), and common cold (n=1 patient). 1 patient forgot to take the medication. Overall, the median relative DI was 96.2% (interquartile range [IQR], 91.2% to 99.0%) for cisplatin and 93.1% (IQR, 88.7% to 97.2%) for capecitabine (Table 2).

Regarding concurrent cisplatin, 125 patients (92.6%) started protocol-defined Q3W cisplatin, 7 patients (5.2%) started weekly cisplatin (at 40mg/m²) due to deterioration in renal function or performance status (PS) after IC. Additionally, three patients (2.2%) received no chemotherapy, one patient received RT alone due to a single kidney, and two patients declined RT. A total of 115 of the 135 patients (85.2%) completed 2 cycles of concurrent Q3W cisplatin, and ten patients (7.4%) received only one cycle of concurrent Q3W cisplatin (Figure 1). Only one patient (0.7%) switched to concurrent carboplatin due to deterioration in renal function. Overall, 97 of 135 patients (71.9%) received at least 200mg/m² of concurrent cisplatin (including Q3W and weekly cisplatin). 93 patients (68.9%) received the full protocol-defined cumulative cisplatin dose of 440mg/m2 (Table 2). However in practice, when we calculate chemotherapy doses based on body surface area, we would round to the nearest whole number. The actual median cumulative dose of cisplatin in the overall patient population was 430mg/m² (IQR, 410 to 440).

Regarding RT, 133 patients (98.5%) started RT, and the remaining 2 patients (1.5%) declined RT after completing 3 cycles of induction PX. A total of 130 patients (96.3%) completed protocol-defined IMRT/VMAT, and another 3 patients (2.2%) declined treatment after 18Gy, 30Gy, and 40 Gy of RT, respectively. On completion of RT, one patient (0.7%) had residual disease of cervical metastatic lymph nodes and received an electron boost to the residual disease. At eight weeks after RT, the pathology-proven residual disease of primary tumor of nasopharynx was detected in one patient (0.7%), and a VMAT boost was delivered. The median time from the start of the last cycle of IC to the commencement of RT was 21 days (IQR, 21 to 24). The median time from the start of the first cycle of IC to the completion of RT was 116 days (IQR, 113 to 121).

Among the 135 patients recruited to the study, 127 patients (94.1%) achieved a response after IC before the commencement of RT. 15 patients (11.1%) had a complete response (CR), 112 patients (83.0%) had a partial response (PR), and 8 patients (5.9%) had stable disease (SD). No patients had disease progression after IC. At 16 weeks after radiotherapy, all 130 patients (96.3%) who completed the entire course of RT achieved CR. The response of 5 patients (3.8%) who did not complete RT was unavailable (Table S1 in the Supplementary Appendix).

At the last follow-up on April 4, 2021, the median follow-up duration was 36.2 months (IQR, 26.1 to 51.8). Twenty-two patients (16.3% of the trial population) experienced disease recurrence, and 8 patients died. Details regarding the patterns of relapse and cause of death are provided in Table S2 in the Supplementary Appendix.

For the intention-to-treat population, the 3-year PFS, OS, LRFS, and DMFS were 83.7% (95% confidence interval [CI], 76.4% to 89.5%), 94.1% (95% CI, 88.7% to 97.4%), 94.1% (95% CI, 88.7% to 97.4%), and 85.9% (95% CI, 78.9% to 91.3%), respectively (Table 3 and Figures 2A-D).

For per-protocol population, the 3-year PFS, OS, LRFS, and DMFS were 85.5% (95% CI, 77.5% to 91.5%), 94.5% (95% CI, 88.5% to 98.0%), 94.5% (95% CI, 88.5% to 98.0%), and 87.3% (95% CI, 79.6% to 92.9%), respectively (Figures S1A-D in the Supplementary Appendix).

During IC, 29 patients (21.5%) experienced acute grade 3 or 4 (G3-4) adverse events (AEs). Neutropenia was the most common G3-4 AEs (14.8%), followed by electrolyte disturbance (8.9%) and anemia (7.4%). G3-4 capecitabine-related hand-foot syndrome was uncommon (0.7%). During CCRT, 74.1% of patients reported G3-4 AEs. Leukopenia was the most common G3-4 AEs (43.7%), followed by mucositis (28.9%) and anemia (25.9%) (Table 4). As for any late toxicity, only 2 out of 135 patients (1.5%) had ≥ G3-4 late RT toxicities (Table 4). There was no treatment-related death.

With the short follow-up, only univariate and multivariate analyses of PFS rather than OS were performed. As shown in Figure 3.

Significant factors of PFS indentified by univariate analyses included tumor stage (IVA/III) and cumulative concurrent cisplatin dose, either as continuous or categorical (reduced-dose/standard-dose) variable (hazard ratio [HR] 3.157, 95% CI 1.287-7.745, P = 0.012; HR 0.989, 95% CI 0.982-0.996, P = 0.003; and HR 2.384, 95% CI 1.006-5.649, P = 0.048; respectively). On multivariate analyses, cumulative concurrent cisplatin dose as categorical variable (HR 2.242, 95% CI 0.943- 5.333, P = 0.068) remained significant when adjusted for tumor stage (HR 3.036, 95% CI 1.236- 7.461, P = 0.015).