A, Failure-free survival. B, Distant failure–free survival. C, Locoregional failure–free survival. D, Overall survival. sHR indicates stratified hazard ratio.
eTable 1. List of Participating Centers
eTable 2. Treatment Compliance
eTable 3. Distribution of Disease Recurrence or Death in the Two Treatment Groups
eTable 4. Summary of Salvage Treatments After Disease Recurrence
eTable 5. Treatment-Related Acute Adverse Events During Induction Chemotherapy
eTable 6. Treatment-Related Acute Adverse Events During Concurrent Chemoradiotherapy
eTable 7. Late Radiotherapy Toxicities After Treatment
eFigure 1. Study Design
eFigure 2. The Relative Dose Intensity of Chemotherapy Drugs in the Two Treatment Groups During Induction Chemotherapy and Concurrent Chemotherapy
eFigure 3. The Proportional-Hazards Assumption for Failure-Free Survival Was Tested Using Schoenfeld Residuals Test
eFigure 4. The Estimated Restricted Mean Survival Time for Failure-Free Survival at Truncation Time of 36 Months in the Intention-to-Treat Population
eFigure 5. Kaplan-Meier Analysis of Failure-Free Survival (A), Distant Metastasis-Free Survival (B), Locoregional Relapse-Free Survival (C), and Overall Survival (D) in the Two Treatment Groups in Per-Protocol Population
eFigure 6. The Estimated Restricted Mean Survival Time for Failure-Free Survival at Truncation Time of 36 Months in the Per-Protocol Population
eFigure 7. Subgroup Analysis of Failure-Free Survival in the Intention-to-Treat Population
eFigure 8. Kaplan-Meier Analysis of Failure-Free Survival in the Treatment Groups Stratified by the TNM Staging Classifications: (A) T1-3, (B) T4, (C) N0-1, (D) N2-3, (E) IVA, and (F) IVB
eFigure 9. Kaplan-Meier Analysis of Failure-Free Survival in the Treatment Groups Stratified by the Baseline EBV DNA: (A) ≤ 1500 copies/mL, (B) > 1500 copies/mL
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Li W, Lv X, Hu D, et al. Effect of Induction Chemotherapy With Paclitaxel, Cisplatin, and Capecitabine vs Cisplatin and Fluorouracil on Failure-Free Survival for Patients With Stage IVA to IVB Nasopharyngeal Carcinoma: A Multicenter Phase 3 Randomized Clinical Trial. JAMA Oncol. 2022;8(5):706–714. doi:10.1001/jamaoncol.2022.0122
Does chemotherapy with paclitaxel, cisplatin, and capecitabine (TPC) improve failure-free survival compared with cisplatin and fluorouracil (PF) as induction treatment prior to concurrent chemoradiotherapy for patients with stage IVA to IVB nasopharyngeal carcinoma?
In this phase 3 randomized clinical trial of 238 patients with stage IVA to IVB nasopharyngeal carcinoma, induction chemotherapy with 2 cycles of TPC followed by 2 cycles of concurrent chemoradiotherapy resulted in a statistically significant improvement in failure-free survival compared with 2 cycles of PF followed by 2 cycles of concurrent chemoradiotherapy, with no increase in the toxicity profile.
Induction chemotherapy with TPC is more efficacious than that with PF for patients with stage IVA to IVB nasopharyngeal carcinoma.
Induction chemotherapy added to concurrent chemoradiotherapy significantly improves survival for patients with locoregionally advanced nasopharyngeal carcinoma, but the optimal induction regimen remains unclear.
To determine whether induction chemotherapy with paclitaxel, cisplatin, and capecitabine (TPC) improves survival vs cisplatin and fluorouracil (PF) prior to chemoradiotherapy for patients with stage IVA to IVB nasopharyngeal carcinoma.
Design, Setting, and Participants
This randomized, open-label, phase 3 clinical trial recruited 238 patients at 4 hospitals in China from October 20, 2016, to August 29, 2019. Patients were 18 to 65 years of age with treatment-naive, nonkeratinizing stage IVA to IVB nasopharyngeal carcinoma and an Eastern Cooperative Oncology Group performance status of 0 to 1.
Patients were randomly assigned (1:1) to receive induction chemotherapy with two 21-day cycles of TPC (intravenous paclitaxel [150 mg/m2, day 1], intravenous cisplatin [60 mg/m2, day 1], and oral capecitabine [1000 mg/m2 orally twice daily, days 1-14]) or PF (intravenous cisplatin [100 mg/m2, day 1] and fluorouracil [800 mg/m2 daily, days 1-5]), followed by chemoradiotherapy.
Main Outcomes and Measures
The primary end point was failure-free survival in the intention-to-treat population. Secondary end points included distant metastasis–free survival, locoregional relapse–free survival, overall survival, tumor response, and safety.
Overall, 238 eligible patients (187 men [78.6%]; median age, 45 years [range, 18-65 years]) were randomly assigned to receive TPC (n = 118) or PF (n = 120). The median follow-up duration was 48.4 months (IQR, 39.6-53.3 months). Failure-free survival at 3 years was 83.5% (95% CI, 77.0%-90.6%) in the TPC group and 68.9% (95% CI, 61.1%-77.8%) in the PF group (stratified hazard ratio [HR] for recurrence or death, 0.47; 95% CI, 0.28-0.79; P = .004). Induction with the TPC regimen resulted in a significant reduction in the risk of distant metastases (stratified HR, 0.49 [95% CI, 0.24-0.98]; P = .04) and locoregional recurrence (stratified HR, 0.40 [95% CI, 0.18-0.93]; P = .03) compared with the PF regimen. However, there was no effect on early overall survival (stratified HR, 0.45 [95% CI, 0.17-1.18]; P = .10). The incidences of grade 3 to 4 acute adverse events and late-onset toxicities were 57.6% (n = 68) and 13.6% (16 of 118), respectively, in the TPC group and 65.8% (n = 79) and 17.9% (21 of 117), respectively, in the PF group. One treatment-related death occurred in the PF group.
Conclusions and Relevance
This randomized clinical trial found that induction chemotherapy with 2 cycles of TPC for patients with stage IVA to IVB nasopharyngeal carcinoma improved failure-free survival compared with 2 cycles of PF, with no increase in the toxicity profile.
ClinicalTrials.gov Identifier: NCT02940925
Nasopharyngeal carcinoma (NPC) is a malignant neoplasm originating from the nasopharynx epithelium.1 Platinum-based concurrent chemoradiotherapy (CRT) represents the treatment backbone for locoregionally advanced NPC. Intensified chemotherapy in the induction or adjuvant setting, added to CRT, has improved survival outcomes.2 In the past decade, induction chemotherapy (IC) has regained the spotlight, with a series of randomized clinical trials demonstrating its clinical benefit.3-8 Induction chemotherapy in combination with CRT is the new standard of care recommended by the treatment guidelines for nonmetastatic stage III to IV NPC.9,10
Taxanes have shown promise in IC for advanced head and neck cancer, including NPC.3,11-15 A triplet induction regimen with cisplatin, fluorouracil, and a taxane might be more efficacious than cisplatin and fluorouracil (PF).13-18 Furthermore, replacing continuous fluorouracil infusion with oral capecitabine during IC has the advantages of convenience, good compliance, and favorable efficacy and safety.19 Capecitabine has shown robust antitumor activity against advanced NPC with fewer toxicities compared with fluorouracil, representing a promising chemotherapeutic agent for IC.20-23
After the landmark Intergroup 0099 trial,24 the PF regimen has emerged as the most used combination. This regimen is one of the treatment options in the guidelines.9,10 To date, the optimal induction regimen for NPC remains unclear. There is a lack of prospective data comparing 2 different IC regimens. Thus, we initiated a multicenter, open-label, randomized clinical phase 3 trial to compare the efficacy and safety of a paclitaxel, cisplatin, and capecitabine (TPC) regimen with that of a PF regimen as IC combined with CRT for patients with locoregionally advanced NPC. Given that the 5-year failure-free survival (FFS) of patients with stage III NPC exceeds 80%, we recruited only patients with stage IVA to IVB disease for this trial.25,26
This multicenter, randomized, clinical, open-label, phase 3 trial (protocol in Supplement 1) recruited patients at 4 hospitals in China (eTable 1 in Supplement 2) from October 20, 2016, to August 29, 2019. A study design diagram is provided in eFigure 1 in Supplement 2. The Chinese Ethics Committee of Registering Clinical Trials approved the trial protocol. Written informed consent was obtained from all participating patients before enrollment. This trial was conducted according to the Declaration of Helsinki27 and the standards of Good Clinical Practice. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Patients who met the following criteria were eligible: aged 18 to 65 years, nonkeratinizing NPC, treatment naive, stage IVA to IVB disease according to the 7th edition of the American Joint Committee on Cancer staging system,28 Eastern Cooperative Oncology Group performance status of 0 or 1, and sufficient organ function. Key exclusion criteria included a history of other malignant neoplasms, previous anticancer treatment, distant metastasis, severe coexisting illness, and pregnancy or lactation. More information regarding inclusion and exclusion criteria are detailed in the trial protocol in Supplement 1.
Randomization was performed centrally at the Sun Yat-sen University Cancer Center. A computer-generated randomization list was created using stratified block randomization. Blocks of variable size were adopted to guard against guessing.29 At study entry, patients were stratified by disease stage (IVA or IVB). Competitive recruitment was applied in this trial. After obtaining informed consent from eligible patients, an independent study coordinator unblinded treatment allocation information and notified investigators of interventions accordingly.
All patients underwent comprehensive pretreatment evaluations within 4 weeks before randomization. Patients were randomly assigned (1:1) to receive IC with two 21-day cycles of either TPC or PF, followed by 6 to 7 weeks of CRT. The patients in the TPC group received the following regimen as induction therapy: paclitaxel was administered intravenously at a dose of 150 mg/m2 over 3 hours on day 1, cisplatin was administered at a dose of 60 mg/m2 on day 1, and capecitabine was taken orally twice a day at a dose of 1000 mg/m2 on days 1 to 14.11,12,18,22,23,30 The patients in the PF group received the following regimen as induction therapy: cisplatin was administered intravenously at a dose of 100 mg/m2 on day 1, and fluorouracil was administered as a continuous 120-hour infusion at a dose of 800 mg/m2 per day on days 1 to 5.23,31 Induction chemotherapy was administered every 3 weeks for 2 cycles. After completing 2 cycles of IC, both groups were to receive 2 cycles of concurrent chemotherapy (CC) with cisplatin, 100 mg/m2. All patients received intensity-modulated radiotherapy. Detailed information on dose modifications, and concomitant medication, and radiotherapy is listed in the trial protocol in Supplement 1.
Tumor responses were assessed using physical examination, flexible nasopharyngoscopy, and enhanced magnetic resonance imaging or computed tomographic scan of the nasopharynx and neck 1 week after IC and 12 weeks after CRT. Tumor responses were evaluated based on the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).32 Acute toxic effects during treatment were graded with the Common Terminology Criteria for Adverse Events, version 4.0.33 Late radiation toxicities (complications occurring 3 months after radiotherapy) were assessed with the Late Radiation Morbidity Scoring Scheme of the Radiation Therapy Oncology Group.34 After completing scheduled treatment, each patient underwent assessment every 3 months in the first 3 years, every 6 months in the next 2 years, and annually after that until death.
The primary end point was FFS in the intention-to-treat population, defined as the interval between randomization and the first documented tumor recurrence (locoregional relapse or distant metastasis), death, or the last follow-up, whichever occurred first. Secondary end points included distant metastasis–free survival (the interval between randomization and distant metastasis), locoregional relapse–free survival (the interval between randomization and locoregional relapse), overall survival (OS; the interval between randomization and death from any cause), overall response rate after IC and after radiotherapy according to RECIST v1.1, safety profile, and treatment compliance.
The trial sought to assess whether IC with the TPC regimen improved FFS compared with the PF regimen. We calculated that approximately 220 patients (110 patients per group) would need to undergo randomization, providing 80% power to detect the underlying hazard ratio (HR) of 0.50 for the primary analysis of FFS at a 2-sided α level of 5%.35 After allowing for an 8% dropout rate, we estimated that approximately 238 patients were needed.
The intention-to-treat population was used for efficacy analyses. We also performed efficacy analyses in the per-protocol population, including patients who completed 2 cycles of IC and 2 cycles of CC. We reported safety data for all patients who had started their randomly assigned treatment. Categorical variables were compared using the χ2 test or the Fisher exact test. Continuous variables were compared using the Mann-Whitney test. Time-to-event data were estimated using the Kaplan-Meier approach. Treatment groups were compared for time-to-event data stratified by disease stage using stratified log-rank tests. Hazard ratios and corresponding 95% CIs were calculated using a stratified Cox proportional hazards regression model to estimate the effect of the experimental treatment, stratified by disease stage. The proportional hazards assumption was examined using Schoenfeld residuals. Complementary analyses, such as those using restricted mean survival time, would be performed if the proportional hazards assumption was unmet.36 We also performed post hoc exploratory analyses to examine whether the treatment effect varied in specific subgroups. Statistical analyses were conducted with R software, version 4.1.0 (R Group for Statistical Computing) and were 2-sided at a significance level of P < .05.
Between October 20, 2016, and August 29, 2019, 238 eligible patients (187 men [78.6%]; median age, 45 years [range, 18-65 years]) with stage IVA to IVB NPC were recruited and randomly assigned to receive TPC (n = 118) or PF (n = 120) (Figure 1) as IC. Patient characteristics were balanced between groups (Table 1).
The relative dose intensity of chemotherapy in the 2 treatment groups is shown in eFigure 2 in Supplement 2. Overall, treatment groups were relatively comparable concerning treatment compliance (eTable 2 in Supplement 2). In the TPC group, 113 patients (95.8%) completed 2 cycles of IC, 3 patients (2.5%) received 1 cycle owing to adverse events, and 2 patients received 3 cycles. In the PF group, 113 patients (94.2%) completed 2 cycles of IC, 6 patients (5.0%) received 1 cycle (3 owing to adverse events, 2 owing to treatment withdrawal, and 1 owing to death caused by treatment-related acute renal failure), and 1 patient received 3 cycles. Protocol-defined IC doses were administered to 107 patients (90.7%) in the TPC group and 104 patients (86.7%) patients in the PF group. Dose reductions or cancellations of IC were more commonly seen in the PF group than in the TPC group (16 [13.3%] vs 7 [5.9%]; P = .05).
After completing IC, 111 patients (94.1%) in the TPC group started concurrent cisplatin chemotherapy: 106 patients completed 2 cycles of cisplatin, 3 received 1 cycle, 1 received carboplatin, and 1 received radiotherapy alone (eTable 2 in Supplement 2). In the PF group, 113 patients (94.2%) started CRT: 103 patients completed 2 cycles of cisplatin, 8 received 1 cycle, and 2 received 3 cycles. Protocol-defined concurrent cisplatin was administered to 101 of 111 patients (91.0%) in the TPC group and 95 of 113 patients (84.1%) in the PF group. Cisplatin dose reductions or cancellations were similar in the TPC and PF groups (10 of 111 [9.0%] vs 16 of 113 [14.2%]; P = .23). All 118 patients in the TPC group and 117 of 120 patients (97.5%) in the PF group completed protocol-defined intensity-modulated radiotherapy. The reasons for not receiving radiotherapy included treatment withdrawal (2 patients) and chemotherapy-related death (1 patient). No significant differences in radiotherapy parameters or treatment durations were observed. Finally, 106 of 118 patients (89.8%) in the TPC group and 103 of 120 patients (85.8%) in the PF group were included in the per-protocol population.
The response rates after IC and after the whole treatment are summarized in Table 2. There were no significant differences in the overall response rate at 1 week after IC between the TPC and PF groups (104 [88.1%] vs 96 [80.0%]; P = .09). At 12 weeks after CRT, more patients in the TPC group than in the PF group showed a complete response (111 of 118 [94.1%] vs 102 of 120 [85.0%]; P = .04).
At the data cutoff date (August 28, 2021), the median follow-up time was 48.4 months (IQR, 39.6-53.3 months). Overall, 63 patients had disease recurrence or died (TPC group, 22; and PF group, 41). Information regarding disease failure patterns and subsequent salvage therapies are detailed in eTables 3 and 4, respectively, in Supplement 2. In the intention-to-treat population, the 3-year FFS rate was 83.5% (95% CI, 77.0%-90.6%) in the TPC group, compared with 68.9% (95% CI, 61.1%-77.8%) in the PF group (stratified HR, 0.47; 95% CI, 0.28-0.79; P = .004) (Table 2 and Figure 2A). The prespecified statistical criteria for the superiority of TPC vs PF were met. Treatment with the TPC regimen resulted in a reduction of 53% in the risk of disease failure, compared with treatment with PF. However, the proportional hazards assumption for FFS was unmet (eFigure 3 in Supplement 2); as additional analysis, the post hoc exploratory restricted mean survival time analysis was conducted to verify the clinical advantage of the TPC regimen. The estimated restricted mean survival time for FFS at the truncation time of 36 months was significantly longer in the TPC group than in the PF group (33.4 months [95% CI, 32.1-34.6 months] vs 29.1 months [95% CI, 27.1-31.1 months]; P < .001) (eFigure 4 in Supplement 2). In the per-protocol population, the clinical benefit of the TPC regimen vs the PF regimen was evident (eFigures 5A and 6 in Supplement 2). In the post hoc subgroup analysis for FFS, we observed a consistent benefit favoring the TPC regimen across all patient subgroups (eFigures 7, 8, and 9 in Supplement 2).
In the intention-to-treat population, the 3-year distant metastasis–free survival rate was significantly higher in the TPC group (91.4% [95% CI, 86.4%-96.6%]) than in the PF group (80.4% [95% CI, 73.6%-87.9%]) (Table 2); 12 of 118 patients (10.2%) in the TPC group and 23 of 120 patients (19.2%) in the PF group showed distant metastasis (stratified HR, 0.49 [95% CI, 0.24-0.98]; P = .04) (Figure 2B). Similarly, the 3-year locoregional relapse–free survival rate was significantly higher in the TPC group than in the PF group (93.8% [95% CI, 89.5%-98.4%] vs 87.4% [95% CI, 81.4%-93.8%]) (Table 2); 18 of 120 patients (15.0%) in the PF group and 8 of 118 patients (6.8%) in the TPC group showed locoregional relapse (stratified HR, 0.40 [95% CI, 0.18-0.93]; P = .03) (Figure 2C). However, the 3-year OS rate was not significantly different between the TPC and PF groups (94.7% [95% CI, 90.6%-98.9%] vs 88.9% [95% CI, 83.4%-94.8%]) (Table 2); 6 of 118 patients (5.1%) in the TPC group and 13 of 120 patients (10.8%) in the PF group died (stratified HR, 0.45 [95% CI, 0.17-1.18]; P = .10) (Figure 2D). We observed similar results in the per-protocol analysis for the above-mentioned secondary end points (eFigure 4B, 4C, and 4D in Supplement 2).
During the entire treatment course, acute adverse events occurred in all patients. Details concerning adverse events during treatment are summarized in Table 3. The incidence of grade 2 or higher acute toxic effects was similar between the 2 groups. Grade 3 to 4 acute adverse events were reported in 68 patients (57.6%) in the TPC group compared with 79 patients (65.8%) in the PF group. The most frequent grade 3 to 4 adverse events were mucositis (TPC, 33 [28.0%] vs PF, 34 [28.3%]), nausea (TPC, 18 [15.3%] vs PF, 25 [20.8%]), vomiting (TPC, 22 [18.6%] vs PF, 19 [15.8%]), and neutropenia (TPC, 15 [12.7%] vs PF, 22 [18.3%]). We recorded 1 grade 5 adverse event in the PF group: death caused by treatment-related acute renal failure. The incidences of acute adverse events during IC and CC are summarized in eTables 5 and 6, respectively, in Supplement 2. The prevalence of late-onset toxicities was similar between the treatment groups (TPC, 16 of 118 [13.6%]; and PF, 21 of 117 [17.9%]; eTable 7 in Supplement 2).
To our knowledge, this phase 3 randomized clinical trial of patients with stage IVA to IVB NPC is the first study to show the advantage of IC with TPC followed by CRT compared with IC with PF followed by CRT. Our study showed that IC with TPC improved FFS with no increase in toxicity. The TPC group had a lower incidence of distant metastases and locoregional relapse than the PF group, but the effect of TPC on early OS was not significant.
Induction chemotherapy in combination with CRT has become the new standard of care for locoregionally advanced NPC.9,10 The latest guidelines have provided more than 5 different induction regimens for patients with stage III to IVA NPC. There are no prospective trials available that compare 2 induction regimens head-to-head in a superiority design. Recently, an individual patient data meta-analysis involving 8214 patients indicated that IC with a taxane-based regimen ranked better than IC without taxanes for OS.37 Our trial suggested that the TPC regimen provided better disease control than the PF regimen did. Our findings are consistent with several trials that showed survival superiority of cisplatin and fluorouracil with a taxane compared with a PF regimen for advanced head and neck cancer.13,14,16
The cycles of IC and CC in this trial were deintensified from the traditional 3 cycles. The optimal cycle number of IC and CC when used in combination has not yet been established.1 The latest guideline recommends 2 or 3 cycles.10 Five randomized trials have used 2 cycles of IC in NPC.3,8,38-40 Two cycles of IC were well tolerated and associated with satisfactory subsequent delivery of cumulative concomitant cisplatin, 200 mg/m2.3,8,40 Furthermore, several retrospective studies also indicated that 2 and 3 cycles of IC were associated with similar survival in the era of intensity-modulated radiotherapy.41,42 Apart from IC, increasing evidence also indicates that 2 cycles of CC (cumulative cisplatin dose of 200 mg/m2) might be adequate for locoregionally advanced NPC. In the pooled analyses of NPC-9901 and NPC-9902 trials, there was no difference between cohorts receiving 2 cycles of concurrent cisplatin, 100 mg/m2, vs cohorts receiving 3 cycles.43 A series of subsequent studies also had similar findings.44-49 Given this evidence, updated reviews and guidelines recommended that a cumulative cisplatin dose of 200 mg/m2 may be the optimal threshold.1,10,50-52 A recent study has shown that 2 cycles of triweekly cisplatin, 100 mg/m2, was noninferior to standard weekly cisplatin, 40 mg/m2, for patients with locoregionally advanced NPC.53 Another updated randomized phase 2 noninferiority trial also revealed that 2 cycles of triweekly cisplatin, 100 mg/m2, was noninferior to 3 cycles for patients with Epstein-Barr virus DNA levels of less than 4000 copies/mL.54
This trial recorded similar acute toxicities and late radiotherapy toxicities in both the TPC and PF groups. When we designed and initiated this trial, there were no available standard doses of the TPC regimen. The dose and dosing schedule were based on several phase 2 studies investigating the efficacy of paclitaxel-based regimens in advanced NPC.11,12,22 The doses of 135 to 175 mg/m2 of paclitaxel were frequently used in these trials. Considering that the intensified triplet combination was used, a dose of 150 mg/m2 was selected. The cisplatin dose of 60 mg/m2 and capecitabine dose of 1000 mg/m2 twice daily on days 1 to 14 were used in previous trials.23,30 In our trial, adding the paclitaxel and replacing the fluorouracil with capecitabine did not increase toxicity. The FFS rate at 3 years was similar to that reported in the landmark trials examining the benefit of IC (docetaxel, cisplatin, and fluorouracil; and gemcitabine and cisplatin) when added to CRT in NPC,4,7 while we observed fewer grade 3 to 4 acute toxic effects in our trial. Patients with more advanced diseases were recruited in our trial, and they received fewer protocol-defined cycles of IC and CC. However, because of the absence of direct head-to-head comparative data, prospective randomized clinical trials are needed to define the best choice among these 3 regimens.
This study has several limitations. First, all study participants came from endemic areas in China, where nonkeratinizing NPC accounts for more than 95% of cases.1 Whether the findings can be generalizable to nonendemic regions warrants further validation. Second, children, adolescents, and elderly patients with NPC were excluded from the current study. Therefore, our results should not be applied to these patients directly. Third, although the current trial has met the primary end point of FFS, the effect of the TPC regimen on early OS was not significant. A longer follow-up is needed to confirm whether there is a benefit of OS. Fourth, although 2 or 3 cycles of IC are recommended, 3 cycles are more commonly used.10 To date, the optimal cycle number of IC remains unclear. To address this issue, in 2018, we initiated a noninferiority phase 3 trial (ChiCTR1800018417) to compare 2 vs 3 cycles of IC followed by CRT for locoregionally advanced NPC.
This phase 3 randomized clinical trial found that IC with 2 cycles of TPC for patients with stage IVA to IVB NPC improved FFS compared with 2 cycles of PF, with no increase in toxicity profiles.
Accepted for Publication: January 5, 2022.
Published Online: March 24, 2022. doi:10.1001/jamaoncol.2022.0122
Corresponding Authors: Yan-Qun Xiang, MD (email@example.com) and Wei-Xiong Xia, MD (firstname.lastname@example.org), Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, 651 Dongfeng Rd E, Guangzhou 510060, China.
Author Contributions: Drs Li and Xiang had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Li, X. Lv, Hu, S.-H. Lv, G.-Y. Liu, Liang, Ye, Yang, and Zhang contributed equally to this study. Drs Mai, X. Guo, Xiang, and Xia were joint senior authors.
Concept and design: X. Guo, Xiang, Xia.
Acquisition, analysis, or interpretation of data: Li, X. Lv, Hu, S.-H. Lv, G.-Y. Liu, Liang, Ye, Yang, Zhang, Yuan, D.-S. Wang, Lu, Ke, W.-B. Tang, Tong, Z.-J. Chen, T. Liu, Cao, Mo, L. Guo, Zhao, M.-Y. Chen, Q.-Y. Chen, Huang, Sun, Qiu, Luo, L. Wang, Hua, L.-Q. Tang, Qian, Mai, Xiang, Xia.
Drafting of the manuscript: Li, X. Lv, Hu, S.-H. Lv, Ye, Yang, Zhang, Lu, Xiang, Xia.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Li, X. Lv, Hu, S.-H. Lv, G.-Y. Liu, Liang, Ye, Yang, Zhang, Yuan, Lu, W.-B. Tang, Tong, Z.-J. Chen, T. Liu, Cao, Mo, L. Guo, Zhao, Q.-Y. Chen, Huang, Sun, Qiu, Luo, L. Wang, Hua, Mai, X. Guo, Xiang, Xia.
Obtained funding: Liang, X. Guo, Xiang, Xia.
Administrative, technical, or material support: Ke, L.-Q. Tang, X. Guo, Xiang, Xia.
Supervision: D.-S. Wang, M.-Y. Chen, Qian, Xiang, Xia.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported by grant 81672680 from the National Natural Science Foundation of China.
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the patients and their families for participating in the study. We also thank Changqing Xie, MD, Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, for his help in English editing; he was not compensated for his contribution.