Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma
Yuan Zhang, M.D., Ph.D., Lei Chen, M.D., Ph.D., Guo-Qing Hu, M.D., Ning Zhang, M.D., Xiao-Dong Zhu, M.D., Ph.D., Kun-Yu Yang, M.D., Feng Jin, M.D., Mei Shi, M.D., Ph.D., Yu-Pei Chen, M.D., Wei-Han Hu, M.D., Zhi-Bin Cheng, M.D., Si-Yang Wang, M.D., et al.
https://www.nejm.org/doi/full/10.1056/NEJMoa1905287?query=oncology-hematology
Abstract
BACKGROUND
Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials.
METHODS
In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety.
RESULTS
A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P=0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group.
CONCLUSIONS
Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.)
Nasopharyngeal carcinoma is a head and neck cancer with a specific geographic distribution. It affected an estimated 130,000 patients worldwide in 2018, with the highest rates occurring in regions in South China, Southeastern Asia, and North Africa.1 More than 70% of patients receive a diagnosis of locoregionally advanced disease at presentation,2 and in this subgroup of patients with an unfavorable prognosis, concurrent chemoradiotherapy with a platinum-based agent constitutes the backbone of treatment, with the chemotherapy sensitizing the tumor to the toxic effects of the radiotherapy. Distant metastasis predominates as the pattern of disease relapse, and it accounts for cancer-specific mortality among approximately 70% of patients.3,4
The addition of chemotherapy as an induction or adjuvant regimen to chemoradiotherapy has been investigated with mixed results.5-9 The toxicity of systemic therapy after chemoradiotherapy remains a pertinent issue.6,10 The use of induction chemotherapy is supported by the long-term results of a randomized, controlled trial in which docetaxel, cisplatin, and fluorouracil were added to chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma; patients had prolonged overall survival with this regimen.7,9
Previous phase 2 trials have shown that gemcitabine plus cisplatin is an effective chemotherapy in patients with nasopharyngeal carcinoma11-13 and has been established as the first-line treatment of choice over cisplatin plus fluorouracil in patients with recurrent or metastatic disease.14 However, in the context of newly diagnosed, nonmetastatic, locoregionally advanced disease, the efficacy and safety profile of induction therapy with gemcitabine plus cisplatin to chemoradiotherapy is unclear. We therefore conducted a multicenter, randomized, controlled, phase 3 clinical trial to investigate the efficacy and safety of adding gemcitabine plus cisplatin to chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.
Methods
TRIAL DESIGN AND PARTICIPANTS
This open-label, parallel-group, randomized, phase 3 trial enrolled patients from 12 hospitals in China (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The institutional ethics review board at each participating center approved the trial protocol, available at NEJM.org. The trial was performed according to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. Written informed consent was obtained from all the patients before enrollment. Patients could withdraw consent at any time after enrollment and could discontinue the trial if disease progression or severe coexisting conditions occurred during treatment.
This was an investigator-initiated trial. The last author designed, wrote, and implemented the trial protocol and managed the trial. Lead investigators from each center gathered the data and ensured its accuracy and completeness. One of the authors conducted the statistical analyses. No one who is not an author contributed to the writing of the manuscript. The first author wrote the first draft of manuscript, which was reviewed by all the authors. All the authors approved the final content of the manuscript. The trial sponsors had no access to the data and were not involved in the data interpretation or the manuscript preparation or review. Qilu Pharmaceutical provided gemcitabine and cisplatin free of charge and was not involved in the trial design, data collection or analysis, or manuscript preparation or review. The last author vouches for the completeness and accuracy of the data and for the adherence of the trial to the protocol.
Eligibility criteria included the following: an age between 18 and 64 years; histologic confirmation of nonkeratinizing nasopharyngeal carcinoma; no previous treatment for cancer; nondistant metastatic, newly diagnosed stage III to IVB disease (excluding subgroups of patients with low risk of metastasis; i.e., those with bulky primary tumor with no nodal involvement) that was staged according to the American Joint Committee on Cancer–Union for International Cancer Control 7th edition stage-classification system15; a Karnofsky performance-status score of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability); and adequate hematologic, renal, and hepatic function. Key exclusion criteria were the following: receipt of treatment with palliative intent; a history of cancer; receipt of previous treatment (radiotherapy, chemotherapy, or surgery [except diagnostic procedures]) to the nasopharynx or neck; lactation or pregnancy; or severe coexisting illness.
For this trial, essential pretreatment evaluations included the following: complete history; physical examination; hematologic and biochemical analyses; flexible nasopharyngoscopy; histopathological diagnosis; and magnetic resonance imaging (MRI) or enhanced computed tomography (CT) (if patients had contraindications to MRI) of the nasopharynx and neck for primary tumor staging. Distant metastasis staging was completed with CT examination of the chest and abdomen and with skeletal scintigraphy. The use of 18F-fluorodeoxyglucose–positron-emission tomography was recommended for patients with advanced node stage or if there was a clinical suspicion of distant metastases.16
RANDOMIZATION AND MASKING
The randomization procedure was carried out by telephone from the Clinical Trials Center of the Sun Yat-sen University Cancer Center. A computer program was used to generate the assignment list. Randomization was stratified according to treatment center and tumor–node–metastasis (TNM) stage (III or IV), and patients were randomly assigned in a 1:1 ratio in blocks of four to receive either three cycles of induction chemotherapy plus chemoradiotherapy (induction chemotherapy group) or chemoradiotherapy alone (standard-therapy group). Treatment group assignment was not masked.
PROCEDURES
Gemcitabine at a dose of 1 g per square meter of body-surface area on days 1 and 8 and cisplatin at a dose of 80 mg per square meter on day 1 were administered intravenously once every 3 weeks for three cycles.14 Cisplatin that was concurrent with radiotherapy was then administered intravenously at a dose of 100 mg per square meter every 3 weeks on days 1, 22, and 43. Details of the chemotherapy dose modifications and supportive measures are provided in the Supplementary Appendix.
For radiotherapy, an intensity-modulated technique was mandatory in both groups. The guidelines regarding radiotherapy3,17 are provided in the Supplementary Appendix. It was recommended that patients in the induction chemotherapy group commence chemoradiotherapy within 21 to 28 days after the first day of the last cycle of induction chemotherapy.
Tumors were assessed with the use of flexible nasopharyngoscopy and MRI of the nasopharyngeal and neck areas at 1 week after the completion of induction chemotherapy and 16 weeks after chemoradiotherapy. We used the Common Terminology Criteria for Adverse Events, version 4.0, to grade acute toxic effects during treatment, and late toxic effects that were associated with radiotherapy were graded according to the Late Radiation Morbidity Scoring Scheme of the Radiation Therapy Oncology Group.18
In the first 3 years of follow-up, all the patients underwent assessment every 3 months and then every 6 months thereafter until death. All end points were assessed or confirmed by the physician in charge. Fine-needle aspiration or biopsy of suspected lesions was performed if deemed necessary in order to confirm locoregional or distant disease progression.
END POINTS
The primary end point was recurrence-free survival, which was defined as the time from randomization to documented disease recurrence (either distant metastasis or locoregional disease recurrence) or death from any cause, whichever occurred first. Secondary end points included overall survival, distant recurrence–free survival (freedom from documented distant metastasis or death from any cause), locoregional recurrence–free survival (freedom from documented locoregional recurrence or death from any cause), treatment response, treatment adherence, and safety. (Definitions of the end points are provided in the Supplementary Appendix.) Patients who were lost to follow-up or were still alive without distant metastasis or locoregional recurrence at the end of the trial had their data censored at the date of last follow-up.
STATISTICAL ANALYSIS
This trial aimed to evaluate whether the addition of induction chemotherapy to chemoradiotherapy improved recurrence-free survival as compared with chemoradiotherapy alone. We estimated that approximately 452 patients would need to undergo randomization in a 1:1 ratio (226 patients per group) in order for 77 events to be observed for the primary analysis of recurrence-free survival. We estimated that the trial would have 80% power to detect a hazard ratio for disease recurrence or death of 0.52 using a log-rank test with a two-sided significance level of 0.05. We further assumed that 5% of the patients would be lost to follow-up or would prematurely discontinue the trial. This yielded a final sample size of 476 (238 patients per group).19
Efficacy analyses were performed in both the intention-to-treat and per-protocol trial populations (see the Supplementary Appendix). The safety population comprised patients who started treatment in each group. Kaplan–Meier curves were used to present time-to-event data, and the two treatment groups were compared by means of log-rank tests that were stratified according to trial center and disease stage (primary analysis).20 The stratified Cox proportional-hazards model, with treatment as a single covariate, was used to calculate the hazard ratios and 95% confidence intervals, and the proportional-hazards assumption was tested with Schoenfeld residuals.21
We further performed an interaction analysis to explore whether the effect of the experimental treatment varied in the subgroups defined according to sex, age, Karnofsky performance-status score, tumor category, node category, and TNM stage (see the Supplementary Appendix). The interaction analysis was conducted by means of a test of treatment-by-covariate interaction on the basis of the Cox proportional-hazards model.22 For each chemotherapy drug, we calculated the relative dose intensity as the total dose actually received during treatment, divided by the dose defined by the protocol. Dose intensity in the two groups was compared with the use of the Wilcoxon rank-sum test.
An independent data monitoring committee monitored the trial and made decisions regarding possible early trial stoppage. An interim analysis was performed on October 30, 2016, when the trial reached approximately half the expected number of disease recurrences or deaths (i.e., 38 events). To preserve an overall type I error rate of 0.05 for the entire trial, the O’Brien–Fleming type boundary (alpha of 0.003) was used for early trial stoppage. The data monitoring committee reviewed the analyses and approved the continuation of the trial. Separately, we implemented a central safety monitoring committee to monitor unexpected adverse events and treatment-related death. The database was locked on April 15, 2019, and here we report the survival and toxicity analyses. Analyses were conducted with the use of SPSS software, version 22.0 (IBM), and Stata software, version 14.2 (StataCorp). The type I error rate was set to 0.05 for the primary end point, and all tests were two-sided.
Results
PATIENTS AND TREATMENT
Figure 1.
Enrollment, Randomization, and Follow-up.
Table 1.
Characteristics of the Patients at Baseline.
From December 2013 through September 2016, we enrolled 480 patients across 12 sites. The induction chemotherapy group comprised 242 patients, and the standard-therapy group comprised 238 patients (Figure 1). The characteristics of the patients at baseline were well balanced between the two groups (Table 1).
Of the 242 patients who had been randomly assigned to undergo induction chemotherapy plus chemoradiotherapy, 239 (98.8%) started protocol-defined induction chemotherapy and were included in the safety population (Figure 1). A total of 3 patients withdrew from the trial before the initiation of trial treatment (1 patient received chemoradiotherapy alone, and 2 received different induction chemotherapy plus chemoradiotherapy). A total of 231 of the 239 patients (96.7%) completed three cycles of induction chemotherapy; 8 patients (3.3%) did not complete all three cycles of induction chemotherapy (3 patients received two cycles and 5 received one cycle; the reasons included a case of the patient declining the treatment, a case of disease progression, and discontinuation due to adverse events in the remaining six cases) (Table S2 in the Supplementary Appendix). A total of 31 of the 239 patients (13.0%) had dose reductions of gemcitabine or cisplatin, mainly because of hematologic toxic effects (in 21 patients). Overall, the median relative dose intensity was 100% (interquartile range, 100 to 100) for gemcitabine and 100% (interquartile range, 100 to 100) for cisplatin.
In the induction chemotherapy group, 234 of 239 patients (97.9%) received concurrent chemoradiotherapy after induction chemotherapy, and 5 patients (2.1%) did not (Figure 1). A total of 93 patients (38.9%) completed three cycles of concurrent cisplatin, 127 (53.1%) received two cycles, and 14 (5.9%) received one cycle.
In the standard-therapy group, of the 238 patients who had undergone randomization, 237 received the protocol-defined concurrent chemoradiotherapy and were included in the safety population; 1 patient who deviated from the protocol received weekly cisplatin (Table S3 in the Supplementary Appendix). A total of 177 of 237 patients (74.7%) completed three cycles of concurrent cisplatin, 56 (23.6%) received two cycles, and 4 (1.7%) received one cycle.
Overall, 191 of 239 patients (79.9%) in the induction chemotherapy group and 227 of 237 patients (95.8%) in the standard-therapy group received at least 200 mg per square meter of concurrent cisplatin. The median dose intensity for concurrent cisplatin, which had been administered every 3 weeks, was 200 mg per square meter (interquartile range, 200 to 300) in the induction chemotherapy group and 300 mg per square meter (interquartile range, 200 to 300) in the standard-therapy group (P<0.001). The median cumulative dose of cisplatin was 440 mg per square meter (interquartile range, 440 to 540) in the induction chemotherapy group; only 63 of 239 patients (26.4%) received the full cumulative dose of 540 mg per square meter.
Regarding radiotherapy, all 239 patients in the induction chemotherapy group completed protocol-defined intensity-modulated radiotherapy. The median time from the start of the last induction chemotherapy cycle to the commencement of chemoradiotherapy was 25 days (interquartile range, 22 to 28). In the standard-therapy group, radiotherapy was discontinued in 2 of 237 patients (0.8%) because the patients declined the treatment. The time to the completion of radiotherapy and the radiotherapy doses received were similar in the two groups (Table S3 in the Supplementary Appendix).
EFFICACY
Table 2.
Survival and Response to Treatment.
Overall, 94.6% of the patients (226 of 239) had a response after induction chemotherapy before the start of chemoradiotherapy; 24 patients (10.0%) had a complete response, and 202 (84.5%) had a partial response. At 16 weeks after radiotherapy, 97.1% of the patients (235 of 242) in the induction chemotherapy group had a complete response, as did 96.6% of the patients (230 of 238) in the standard-therapy group (Table 2).
Figure 2.
Kaplan–Meier Analysis of Recurrence-free Survival, Overall Survival, Distant Recurrence–free Survival, and Locoregional Recurrence–free Survival (Intention-to-Treat Population).
At the last follow-up on April 15, 2019, the median follow-up was 42.7 months (range, 3.5 to 65.0). A total of 296 of the 427 patients who were alive (69.3%) as of this date had follow-up records of at least 36 months, and the last patient who had enrolled in the trial had a follow-up of 31.2 months. We recorded a total of 100 events of recurrence or death (20.8% of the patients in the overall trial population), including events in 37 of 242 patients (15.3%) in the induction chemotherapy group and in 63 of 238 (26.5%) in the standard-therapy group. Details regarding the patterns of relapse and subsequent therapies after relapse are provided in Tables S5 and S6 in the Supplementary Appendix. The 3-year recurrence-free survival was 85.3% (95% confidence interval [CI], 80.0 to 89.3) in the induction chemotherapy group, as compared with 76.5% (95% CI, 70.4 to 81.5) in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% CI, 0.34 to 0.77; P=0.001) (Table 2 and Figure 2A).
Table 3.
Adverse Events, According to Trial Group and Grade.
At the time of analysis, 18 of 242 patients (7.4%) in the induction chemotherapy group and 35 of 238 patients (14.7%) in the standard-therapy group had died. Details regarding the cause of death are provided in Table S5 in the Supplementary Appendix. Patients in the induction chemotherapy group had better 3-year overall survival than those in the standard-therapy group (94.6% [95% CI, 90.6 to 96.9] vs. 90.3% [95% CI, 85.6 to 93.5]; stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77) (Table 2 and Figure 2B). The 3-year distant recurrence–free survival was better in the induction chemotherapy group than in the standard-therapy group (91.1% [95% CI, 86.4 to 94.2] vs. 84.4% [95% CI, 79.1 to 88.5]; stratified hazard ratio for distant recurrence or death, 0.43; 95% CI, 0.25 to 0.73) (Table 2 and Figure 2C). However, the 3-year locoregional recurrence–free survival was similar in the induction chemotherapy group and the standard-therapy group (91.8% [95% CI, 87.3 to 94.7] and 91.0% [95% CI, 86.2 to 94.0], respectively; stratified hazard ratio for locoregional recurrence or death, 0.77; 95% CI, 0.42 to 1.41) (Table 3 and Figure 2D).
ADVERSE EVENTS
During induction chemotherapy, 93 of 239 patients (38.9%) had acute adverse events of grade 3 or 4 (Table S4 in the Supplementary Appendix). Neutropenia was the most common event (in 49 patients [20.5%]), followed by leukopenia (in 26 [10.9%]) and vomiting (in 26 [10.9%]). Over the entire treatment course, 181 patients (75.7%) in the induction chemotherapy group and 132 (55.7%) in the standard-therapy group reported adverse events of grade 3 or 4 (Table 3). Mucositis was the most common adverse event of grade 3 or 4 (in 69 patients [28.9%] in the induction chemotherapy group and in 76 [32.1%] in the standard-therapy group). The induction chemotherapy group had a higher incidence than the standard-therapy group of grade 3 or 4 neutropenia (67 patients [28.0%] vs. 25 [10.5%]), thrombocytopenia (27 [11.3%] vs. 3 [1.3%]), anemia (23 [9.6%] vs. 2 [0.8%]), nausea (55 [23.0%] vs. 33 [13.9%]), and vomiting (54 [22.6%] vs. 33 [13.9%]). The induction chemotherapy group also had a higher incidence than the standard-therapy group of grade 1 or 2 nephrotoxic effects (46 patients [19.2%] vs. 27 [11.4%]) but not of ototoxic effects such as deafness or otitis (172 [72.0%] and 178 [75.1%], respectively).
The incidence of all late toxic effects of grade 1 or 2 was 84.9% (203 of 239 patients) in the induction chemotherapy group and 87.8% (208 of 237) in the standard-therapy group. A total of 9.2% of the patients (22 of 239) in the induction chemotherapy group and 11.4% of the patients (27 of 237) in the standard-therapy group had one or more late toxic effects of grade 3 or 4 (Table 3). The incidence of late toxic effects was similar in the treatment groups, with the exception of grade 1 or 2 peripheral neuropathy, the incidence of which was higher in the induction chemotherapy group than in the standard-therapy group (8.8% vs. 1.7%).
Discussion
We report the results of a randomized, controlled, phase 3 trial that showed the superior tumor control and survival with the addition of induction chemotherapy to chemoradiotherapy in a selected cohort of patients with high-risk locoregionally advanced nasopharyngeal carcinoma. The majority of patients had unfavorable prognostic features of N2 or N3 disease or bulky primary tumors (T3 or T4), all of which are surrogates for occult metastasis.23 The efficacy of induction chemotherapy was due to the lower incidence of distant metastatic recurrences in the induction chemotherapy group than in the standard-therapy group, which probably explained the early overall survival advantage in the patients treated in the induction chemotherapy group. The 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group, which corresponded to overall survival at 3 years that was 4.3 percentage points higher with induction chemotherapy than with standard therapy. This clinical advantage was evident when the outcomes of the two treatment groups were analyzed in patients who completed the planned course of treatment (three cycles of chemotherapy plus two or three cycles of concurrent cisplatin and radiotherapy vs. three cycles of concurrent cisplatin and radiotherapy alone) (see the Supplementary Appendix).
Among patients with recurrent or metastatic disease, objective response rates of 64% and 91% (including complete and partial responses) have been observed with gemcitabine plus cisplatin alone and together with camrelizumab (an anti–programmed death 1 antibody), respectively.24 Likewise, in patients with locoregionally advanced disease, Yau and colleagues found that three cycles of induction therapy with gemcitabine plus cisplatin yielded high percentages (>90%) of patients with a clinical response.12 Our results contrast with those from a similar trial conducted by Tan et al., in which a combination of gemcitabine, carboplatin, and paclitaxel did not prolong progression-free survival or overall survival.25 Several explanations may be offered for the conflicting results, including a cohort with more favorable characteristics in the trial conducted by Tan et al. (fewer patients with N2 or N3 disease than in the present trial) and the use of low-dose carboplatin (area under the curve, 2.0) that could have compromised the synergy with gemcitabine. The improvements in recurrence-free survival at 3 years are similar among patients who received induction therapy with gemcitabine plus cisplatin (difference vs. standard therapy, 8.8 percentage points) and those who received docetaxel plus cisplatin and fluorouracil (difference vs. standard therapy, 8.0 percentage points).7 It remains unclear whether these regimens differ significantly with regard to efficacy or toxicity.
We noted a higher overall incidence of acute adverse events among patients treated with induction chemotherapy than among those treated with chemoradiotherapy alone; in particular, the incidence of severe neutropenia, thrombocytopenia, anemia, nausea, and vomiting was higher in the induction chemotherapy group. The incidence of acute grade 1 or 2 nephrotoxic effects was also greater with the higher cumulative dose of cisplatin in the induction chemotherapy group, although the frequencies of late nephrotoxic effects and ototoxic effects were similar in the treatment groups, with the exception of grade 1 or 2 peripheral neuropathy. The incidence of severe late complications was low in both groups, and we did not find any treatment-related deaths. In our previous chemotherapy trial (which investigated docetaxel plus cisplatin plus fluorouracil),7 a high incidence of grade 3 or 4 acute adverse events such as neutropenia (35.5%), leukopenia (27.2%), and diarrhea (8.0%) was observed despite the modified doses (a 20% reduction of each drug as compared with the other trials26,27); in that trial, four patients (2%) had leukopenic fever, and one patient died from neutropenic sepsis (Table S7 in the Supplementary Appendix). Given the paucity of comparative data, the choice of either a gemcitabine-based or taxane-based induction chemotherapy regimen could be made on the basis of the expected toxic effects matched against the patient’s status with regard to coexisting conditions.
In conclusion, the addition of induction therapy with gemcitabine plus cisplatin to a backbone of chemoradiotherapy with cisplatin, administered every 3 weeks, improved recurrence-free survival among patients with high-risk locoregionally advanced nasopharyngeal cancer. This result translated into a 4.3-percentage-point advantage in survival over standard therapy at 3 years, at the cost of a higher incidence of acute adverse events.
Supported by grants from the Innovation Team Development Plan of the Ministry of Education (IRT_17R110), the Natural Science Foundation of Guangdong Province (2017A030312003), the Planned Science and Technology Project of Guangdong Province (2019B020230002), the Health and Medical Collaborative Innovation Project of Guangzhou City, China (201803040003), the Sun Yat-Sen University Clinical Research 5010 Program (2014009), and the Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B14035) and by a National Medical Research Council Singapore Clinician-Scientist Award (NMRC/CSA/0027/2018) and the Duke–NUS Oncology Academic Program Proton Research Program (EX/42-A92) (both to Dr. Chua).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. Y. Zhang, L. Chen, G.-Q. Hu, N. Zhang, Zhu, Yang, Jin, Shi, and Y.-P. Chen and Drs. Chua, Xie, Ying Sun, and Ma contributed equally to this article.
This article was published on May 31, 2019, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the patients who participated in this study, their families, and the medical, nursing, and research staff at the study centers; Xiao-Qing Hu, Xiao-Dan Jiang, Xiao-Fen Xiao, Qiu-Hui Zheng, and Hui-Xia Feng (Department of Radiation Oncology, Sun Yat-sen University Cancer Center) for assistance with data management and logistic support; the staff of the National Clinical Study Center for Anticancer Drugs, Sun Yat-sen University Cancer Center, for trial monitoring, data management, and statistical analysis; and Tan Sze Huey (Division of Clinical Trials and Epidemiologic Sciences, National Cancer Center Singapore) for assistance with statistics.
Author Affiliations
From the Departments of Radiation Oncology (Y.Z., L.C., Y.-P.C., W.-H.H., W.-F.L., L.-L.T., Y.-P.M., G.-Q.Z., R.S., X.L., R.G., F.H., J.-W.L., X.-J.D., C.X., N.L., Y.-Q.L., F.-Y.X., Ying Sun, J.M.), Medical Oncology (Y.-H.L.), and Nasopharyngeal Carcinoma (H.-Y.M.) and the Clinical Trials Center (Y.G.), Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy (Y.Z., L.C., Y.-P.C., W.-H.H., W.-F.L., L.-L.T., Y.-P.M., G.-Q.Z., R.S., X.L., R.G., F.H., J.-W.L., X.-J.D., C.X., N.L., Y.-Q.L., F.-Y.X., Ying Sun, J.M.), and the Department of Radiation Oncology, First Affiliated Hospital of Guangdong Pharmaceutical University (X.-C.W., Q.-F.S.), Guangzhou, the Cancer Center, Tongji Hospital Affiliated to Tongji Medical College (G.-Q.H., G.-X.L.), and the Cancer Center, Union Hospital, Tongji Medical College (K.-Y.Y., J.H.), Huazhong University of Science and Technology, Wuhan, the Department of Radiation Oncology, First People’s Hospital of Foshan, Foshan (N.Z., S.-Q.L.), the Department of Radiation Oncology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning (X.-D.Z., L.L.), the Department of Head and Neck Oncology, Affiliated Hospital of Guizhou Medical University, Guizhou Cancer Hospital, Guiyang (F.J., J.-H.L.), the Department of Radiation Oncology, XiJing Hospital of Fourth Military Medical University, Xi’an (M.S., J.Z.), the Cancer Center (Z.-B.C.), and the Department of Head and Neck Oncology (S.-Y.W., Q.-D.L.), Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, the Department of Radiation Oncology, Second Affiliated Hospital of Soochow University, Suzhou (Y.T., L.Z.), the Department of Radiation Oncology, Peking University Cancer Hospital, Beijing (Yan Sun, B.-M.Z.), and the Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang (J.-G.L., Y.X.) — all in China; and the Divisions of Radiation Oncology and Medical Sciences, National Cancer Center Singapore, and the Oncology Academic Program, Duke–National University of Singapore Medical School — both in Singapore (M.L.K.C.).
Address reprint requests to Dr. Ma at the Department of Radiation Oncology, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Rd. E., Guangzhou 510060, China, or at majun2@mail.sysu.edu.cn.
Figures/Media
Figure 1.
Enrollment, Randomization, and Follow-up.
The induction chemotherapy group received gemcitabine and cisplatin plus concurrent chemoradiotherapy, and the standard-therapy group received chemoradiotherapy alone. Other induction chemotherapy regimens included docetaxel, cisplatin plus fluorouracil, and docetaxel plus cisplatin.
Table 1.
Characteristics of the Patients at Baseline.*
Table 2.
Survival and Response to Treatment.*
Figure 2.
Kaplan–Meier Analysis of Recurrence-free Survival, Overall Survival, Distant Recurrence–free Survival, and Locoregional Recurrence–free Survival (Intention-to-Treat Population).
Hazard ratios and 95% confidence intervals were calculated by a stratified Cox proportional-hazards model. The primary end point was recurrence-free survival, defined as the time from randomization to documented disease recurrence (either distant metastasis or locoregional disease recurrence) or death from any cause, whichever occurred first. Secondary end points included overall survival, distant recurrence–free survival, and locoregional recurrence–free survival. Tick marks indicate censored data.
Table 3.
Adverse Events, According to Trial Group and Grade.*
Article
Figures/Media
More aboutTREATMENTS IN ONCOLOGYOTOLARYNGOLOGY
Yuan Zhang, M.D., Ph.D., Lei Chen, M.D., Ph.D., Guo-Qing Hu, M.D., Ning Zhang, M.D., Xiao-Dong Zhu, M.D., Ph.D., Kun-Yu Yang, M.D., Feng Jin, M.D., Mei Shi, M.D., Ph.D., Yu-Pei Chen, M.D., Wei-Han Hu, M.D., Zhi-Bin Cheng, M.D., Si-Yang Wang, M.D., et al.
https://www.nejm.org/doi/full/10.1056/NEJMoa1905287?query=oncology-hematology
Abstract
BACKGROUND
Platinum-based concurrent chemoradiotherapy is the standard of care for patients with locoregionally advanced nasopharyngeal carcinoma. Additional gemcitabine and cisplatin induction chemotherapy has shown promising efficacy in phase 2 trials.
METHODS
In a parallel-group, multicenter, randomized, controlled, phase 3 trial, we compared gemcitabine and cisplatin as induction chemotherapy plus concurrent chemoradiotherapy with concurrent chemoradiotherapy alone. Patients with locoregionally advanced nasopharyngeal carcinoma were randomly assigned in a 1:1 ratio to receive gemcitabine (at a dose of 1 g per square meter of body-surface area on days 1 and 8) plus cisplatin (80 mg per square meter on day 1), administered every 3 weeks for three cycles, plus chemoradiotherapy (concurrent cisplatin at a dose of 100 mg per square meter every 3 weeks for three cycles plus intensity-modulated radiotherapy) or chemoradiotherapy alone. The primary end point was recurrence-free survival (i.e., freedom from disease recurrence [distant metastasis or locoregional recurrence] or death from any cause) in the intention-to-treat population. Secondary end points included overall survival, treatment adherence, and safety.
RESULTS
A total of 480 patients were included in the trial (242 patients in the induction chemotherapy group and 238 in the standard-therapy group). At a median follow-up of 42.7 months, the 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% confidence interval [CI], 0.34 to 0.77; P=0.001). Overall survival at 3 years was 94.6% and 90.3%, respectively (stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77). A total of 96.7% of the patients completed three cycles of induction chemotherapy. The incidence of acute adverse events of grade 3 or 4 was 75.7% in the induction chemotherapy group and 55.7% in the standard-therapy group, with a higher incidence of neutropenia, thrombocytopenia, anemia, nausea, and vomiting in the induction chemotherapy group. The incidence of grade 3 or 4 late toxic effects was 9.2% in the induction chemotherapy group and 11.4% in the standard-therapy group.
CONCLUSIONS
Induction chemotherapy added to chemoradiotherapy significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone, among patients with locoregionally advanced nasopharyngeal carcinoma. (Funded by the Innovation Team Development Plan of the Ministry of Education and others; ClinicalTrials.gov number, NCT01872962.)
Nasopharyngeal carcinoma is a head and neck cancer with a specific geographic distribution. It affected an estimated 130,000 patients worldwide in 2018, with the highest rates occurring in regions in South China, Southeastern Asia, and North Africa.1 More than 70% of patients receive a diagnosis of locoregionally advanced disease at presentation,2 and in this subgroup of patients with an unfavorable prognosis, concurrent chemoradiotherapy with a platinum-based agent constitutes the backbone of treatment, with the chemotherapy sensitizing the tumor to the toxic effects of the radiotherapy. Distant metastasis predominates as the pattern of disease relapse, and it accounts for cancer-specific mortality among approximately 70% of patients.3,4
The addition of chemotherapy as an induction or adjuvant regimen to chemoradiotherapy has been investigated with mixed results.5-9 The toxicity of systemic therapy after chemoradiotherapy remains a pertinent issue.6,10 The use of induction chemotherapy is supported by the long-term results of a randomized, controlled trial in which docetaxel, cisplatin, and fluorouracil were added to chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma; patients had prolonged overall survival with this regimen.7,9
Previous phase 2 trials have shown that gemcitabine plus cisplatin is an effective chemotherapy in patients with nasopharyngeal carcinoma11-13 and has been established as the first-line treatment of choice over cisplatin plus fluorouracil in patients with recurrent or metastatic disease.14 However, in the context of newly diagnosed, nonmetastatic, locoregionally advanced disease, the efficacy and safety profile of induction therapy with gemcitabine plus cisplatin to chemoradiotherapy is unclear. We therefore conducted a multicenter, randomized, controlled, phase 3 clinical trial to investigate the efficacy and safety of adding gemcitabine plus cisplatin to chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.
Methods
TRIAL DESIGN AND PARTICIPANTS
This open-label, parallel-group, randomized, phase 3 trial enrolled patients from 12 hospitals in China (Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). The institutional ethics review board at each participating center approved the trial protocol, available at NEJM.org. The trial was performed according to the principles of the Declaration of Helsinki and Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. Written informed consent was obtained from all the patients before enrollment. Patients could withdraw consent at any time after enrollment and could discontinue the trial if disease progression or severe coexisting conditions occurred during treatment.
This was an investigator-initiated trial. The last author designed, wrote, and implemented the trial protocol and managed the trial. Lead investigators from each center gathered the data and ensured its accuracy and completeness. One of the authors conducted the statistical analyses. No one who is not an author contributed to the writing of the manuscript. The first author wrote the first draft of manuscript, which was reviewed by all the authors. All the authors approved the final content of the manuscript. The trial sponsors had no access to the data and were not involved in the data interpretation or the manuscript preparation or review. Qilu Pharmaceutical provided gemcitabine and cisplatin free of charge and was not involved in the trial design, data collection or analysis, or manuscript preparation or review. The last author vouches for the completeness and accuracy of the data and for the adherence of the trial to the protocol.
Eligibility criteria included the following: an age between 18 and 64 years; histologic confirmation of nonkeratinizing nasopharyngeal carcinoma; no previous treatment for cancer; nondistant metastatic, newly diagnosed stage III to IVB disease (excluding subgroups of patients with low risk of metastasis; i.e., those with bulky primary tumor with no nodal involvement) that was staged according to the American Joint Committee on Cancer–Union for International Cancer Control 7th edition stage-classification system15; a Karnofsky performance-status score of at least 70 (on a scale from 0 to 100, with lower scores indicating greater disability); and adequate hematologic, renal, and hepatic function. Key exclusion criteria were the following: receipt of treatment with palliative intent; a history of cancer; receipt of previous treatment (radiotherapy, chemotherapy, or surgery [except diagnostic procedures]) to the nasopharynx or neck; lactation or pregnancy; or severe coexisting illness.
For this trial, essential pretreatment evaluations included the following: complete history; physical examination; hematologic and biochemical analyses; flexible nasopharyngoscopy; histopathological diagnosis; and magnetic resonance imaging (MRI) or enhanced computed tomography (CT) (if patients had contraindications to MRI) of the nasopharynx and neck for primary tumor staging. Distant metastasis staging was completed with CT examination of the chest and abdomen and with skeletal scintigraphy. The use of 18F-fluorodeoxyglucose–positron-emission tomography was recommended for patients with advanced node stage or if there was a clinical suspicion of distant metastases.16
RANDOMIZATION AND MASKING
The randomization procedure was carried out by telephone from the Clinical Trials Center of the Sun Yat-sen University Cancer Center. A computer program was used to generate the assignment list. Randomization was stratified according to treatment center and tumor–node–metastasis (TNM) stage (III or IV), and patients were randomly assigned in a 1:1 ratio in blocks of four to receive either three cycles of induction chemotherapy plus chemoradiotherapy (induction chemotherapy group) or chemoradiotherapy alone (standard-therapy group). Treatment group assignment was not masked.
PROCEDURES
Gemcitabine at a dose of 1 g per square meter of body-surface area on days 1 and 8 and cisplatin at a dose of 80 mg per square meter on day 1 were administered intravenously once every 3 weeks for three cycles.14 Cisplatin that was concurrent with radiotherapy was then administered intravenously at a dose of 100 mg per square meter every 3 weeks on days 1, 22, and 43. Details of the chemotherapy dose modifications and supportive measures are provided in the Supplementary Appendix.
For radiotherapy, an intensity-modulated technique was mandatory in both groups. The guidelines regarding radiotherapy3,17 are provided in the Supplementary Appendix. It was recommended that patients in the induction chemotherapy group commence chemoradiotherapy within 21 to 28 days after the first day of the last cycle of induction chemotherapy.
Tumors were assessed with the use of flexible nasopharyngoscopy and MRI of the nasopharyngeal and neck areas at 1 week after the completion of induction chemotherapy and 16 weeks after chemoradiotherapy. We used the Common Terminology Criteria for Adverse Events, version 4.0, to grade acute toxic effects during treatment, and late toxic effects that were associated with radiotherapy were graded according to the Late Radiation Morbidity Scoring Scheme of the Radiation Therapy Oncology Group.18
In the first 3 years of follow-up, all the patients underwent assessment every 3 months and then every 6 months thereafter until death. All end points were assessed or confirmed by the physician in charge. Fine-needle aspiration or biopsy of suspected lesions was performed if deemed necessary in order to confirm locoregional or distant disease progression.
END POINTS
The primary end point was recurrence-free survival, which was defined as the time from randomization to documented disease recurrence (either distant metastasis or locoregional disease recurrence) or death from any cause, whichever occurred first. Secondary end points included overall survival, distant recurrence–free survival (freedom from documented distant metastasis or death from any cause), locoregional recurrence–free survival (freedom from documented locoregional recurrence or death from any cause), treatment response, treatment adherence, and safety. (Definitions of the end points are provided in the Supplementary Appendix.) Patients who were lost to follow-up or were still alive without distant metastasis or locoregional recurrence at the end of the trial had their data censored at the date of last follow-up.
STATISTICAL ANALYSIS
This trial aimed to evaluate whether the addition of induction chemotherapy to chemoradiotherapy improved recurrence-free survival as compared with chemoradiotherapy alone. We estimated that approximately 452 patients would need to undergo randomization in a 1:1 ratio (226 patients per group) in order for 77 events to be observed for the primary analysis of recurrence-free survival. We estimated that the trial would have 80% power to detect a hazard ratio for disease recurrence or death of 0.52 using a log-rank test with a two-sided significance level of 0.05. We further assumed that 5% of the patients would be lost to follow-up or would prematurely discontinue the trial. This yielded a final sample size of 476 (238 patients per group).19
Efficacy analyses were performed in both the intention-to-treat and per-protocol trial populations (see the Supplementary Appendix). The safety population comprised patients who started treatment in each group. Kaplan–Meier curves were used to present time-to-event data, and the two treatment groups were compared by means of log-rank tests that were stratified according to trial center and disease stage (primary analysis).20 The stratified Cox proportional-hazards model, with treatment as a single covariate, was used to calculate the hazard ratios and 95% confidence intervals, and the proportional-hazards assumption was tested with Schoenfeld residuals.21
We further performed an interaction analysis to explore whether the effect of the experimental treatment varied in the subgroups defined according to sex, age, Karnofsky performance-status score, tumor category, node category, and TNM stage (see the Supplementary Appendix). The interaction analysis was conducted by means of a test of treatment-by-covariate interaction on the basis of the Cox proportional-hazards model.22 For each chemotherapy drug, we calculated the relative dose intensity as the total dose actually received during treatment, divided by the dose defined by the protocol. Dose intensity in the two groups was compared with the use of the Wilcoxon rank-sum test.
An independent data monitoring committee monitored the trial and made decisions regarding possible early trial stoppage. An interim analysis was performed on October 30, 2016, when the trial reached approximately half the expected number of disease recurrences or deaths (i.e., 38 events). To preserve an overall type I error rate of 0.05 for the entire trial, the O’Brien–Fleming type boundary (alpha of 0.003) was used for early trial stoppage. The data monitoring committee reviewed the analyses and approved the continuation of the trial. Separately, we implemented a central safety monitoring committee to monitor unexpected adverse events and treatment-related death. The database was locked on April 15, 2019, and here we report the survival and toxicity analyses. Analyses were conducted with the use of SPSS software, version 22.0 (IBM), and Stata software, version 14.2 (StataCorp). The type I error rate was set to 0.05 for the primary end point, and all tests were two-sided.
Results
PATIENTS AND TREATMENT
Figure 1.
Enrollment, Randomization, and Follow-up.
Table 1.
Characteristics of the Patients at Baseline.
From December 2013 through September 2016, we enrolled 480 patients across 12 sites. The induction chemotherapy group comprised 242 patients, and the standard-therapy group comprised 238 patients (Figure 1). The characteristics of the patients at baseline were well balanced between the two groups (Table 1).
Of the 242 patients who had been randomly assigned to undergo induction chemotherapy plus chemoradiotherapy, 239 (98.8%) started protocol-defined induction chemotherapy and were included in the safety population (Figure 1). A total of 3 patients withdrew from the trial before the initiation of trial treatment (1 patient received chemoradiotherapy alone, and 2 received different induction chemotherapy plus chemoradiotherapy). A total of 231 of the 239 patients (96.7%) completed three cycles of induction chemotherapy; 8 patients (3.3%) did not complete all three cycles of induction chemotherapy (3 patients received two cycles and 5 received one cycle; the reasons included a case of the patient declining the treatment, a case of disease progression, and discontinuation due to adverse events in the remaining six cases) (Table S2 in the Supplementary Appendix). A total of 31 of the 239 patients (13.0%) had dose reductions of gemcitabine or cisplatin, mainly because of hematologic toxic effects (in 21 patients). Overall, the median relative dose intensity was 100% (interquartile range, 100 to 100) for gemcitabine and 100% (interquartile range, 100 to 100) for cisplatin.
In the induction chemotherapy group, 234 of 239 patients (97.9%) received concurrent chemoradiotherapy after induction chemotherapy, and 5 patients (2.1%) did not (Figure 1). A total of 93 patients (38.9%) completed three cycles of concurrent cisplatin, 127 (53.1%) received two cycles, and 14 (5.9%) received one cycle.
In the standard-therapy group, of the 238 patients who had undergone randomization, 237 received the protocol-defined concurrent chemoradiotherapy and were included in the safety population; 1 patient who deviated from the protocol received weekly cisplatin (Table S3 in the Supplementary Appendix). A total of 177 of 237 patients (74.7%) completed three cycles of concurrent cisplatin, 56 (23.6%) received two cycles, and 4 (1.7%) received one cycle.
Overall, 191 of 239 patients (79.9%) in the induction chemotherapy group and 227 of 237 patients (95.8%) in the standard-therapy group received at least 200 mg per square meter of concurrent cisplatin. The median dose intensity for concurrent cisplatin, which had been administered every 3 weeks, was 200 mg per square meter (interquartile range, 200 to 300) in the induction chemotherapy group and 300 mg per square meter (interquartile range, 200 to 300) in the standard-therapy group (P<0.001). The median cumulative dose of cisplatin was 440 mg per square meter (interquartile range, 440 to 540) in the induction chemotherapy group; only 63 of 239 patients (26.4%) received the full cumulative dose of 540 mg per square meter.
Regarding radiotherapy, all 239 patients in the induction chemotherapy group completed protocol-defined intensity-modulated radiotherapy. The median time from the start of the last induction chemotherapy cycle to the commencement of chemoradiotherapy was 25 days (interquartile range, 22 to 28). In the standard-therapy group, radiotherapy was discontinued in 2 of 237 patients (0.8%) because the patients declined the treatment. The time to the completion of radiotherapy and the radiotherapy doses received were similar in the two groups (Table S3 in the Supplementary Appendix).
EFFICACY
Table 2.
Survival and Response to Treatment.
Overall, 94.6% of the patients (226 of 239) had a response after induction chemotherapy before the start of chemoradiotherapy; 24 patients (10.0%) had a complete response, and 202 (84.5%) had a partial response. At 16 weeks after radiotherapy, 97.1% of the patients (235 of 242) in the induction chemotherapy group had a complete response, as did 96.6% of the patients (230 of 238) in the standard-therapy group (Table 2).
Figure 2.
Kaplan–Meier Analysis of Recurrence-free Survival, Overall Survival, Distant Recurrence–free Survival, and Locoregional Recurrence–free Survival (Intention-to-Treat Population).
At the last follow-up on April 15, 2019, the median follow-up was 42.7 months (range, 3.5 to 65.0). A total of 296 of the 427 patients who were alive (69.3%) as of this date had follow-up records of at least 36 months, and the last patient who had enrolled in the trial had a follow-up of 31.2 months. We recorded a total of 100 events of recurrence or death (20.8% of the patients in the overall trial population), including events in 37 of 242 patients (15.3%) in the induction chemotherapy group and in 63 of 238 (26.5%) in the standard-therapy group. Details regarding the patterns of relapse and subsequent therapies after relapse are provided in Tables S5 and S6 in the Supplementary Appendix. The 3-year recurrence-free survival was 85.3% (95% confidence interval [CI], 80.0 to 89.3) in the induction chemotherapy group, as compared with 76.5% (95% CI, 70.4 to 81.5) in the standard-therapy group (stratified hazard ratio for recurrence or death, 0.51; 95% CI, 0.34 to 0.77; P=0.001) (Table 2 and Figure 2A).
Table 3.
Adverse Events, According to Trial Group and Grade.
At the time of analysis, 18 of 242 patients (7.4%) in the induction chemotherapy group and 35 of 238 patients (14.7%) in the standard-therapy group had died. Details regarding the cause of death are provided in Table S5 in the Supplementary Appendix. Patients in the induction chemotherapy group had better 3-year overall survival than those in the standard-therapy group (94.6% [95% CI, 90.6 to 96.9] vs. 90.3% [95% CI, 85.6 to 93.5]; stratified hazard ratio for death, 0.43; 95% CI, 0.24 to 0.77) (Table 2 and Figure 2B). The 3-year distant recurrence–free survival was better in the induction chemotherapy group than in the standard-therapy group (91.1% [95% CI, 86.4 to 94.2] vs. 84.4% [95% CI, 79.1 to 88.5]; stratified hazard ratio for distant recurrence or death, 0.43; 95% CI, 0.25 to 0.73) (Table 2 and Figure 2C). However, the 3-year locoregional recurrence–free survival was similar in the induction chemotherapy group and the standard-therapy group (91.8% [95% CI, 87.3 to 94.7] and 91.0% [95% CI, 86.2 to 94.0], respectively; stratified hazard ratio for locoregional recurrence or death, 0.77; 95% CI, 0.42 to 1.41) (Table 3 and Figure 2D).
ADVERSE EVENTS
During induction chemotherapy, 93 of 239 patients (38.9%) had acute adverse events of grade 3 or 4 (Table S4 in the Supplementary Appendix). Neutropenia was the most common event (in 49 patients [20.5%]), followed by leukopenia (in 26 [10.9%]) and vomiting (in 26 [10.9%]). Over the entire treatment course, 181 patients (75.7%) in the induction chemotherapy group and 132 (55.7%) in the standard-therapy group reported adverse events of grade 3 or 4 (Table 3). Mucositis was the most common adverse event of grade 3 or 4 (in 69 patients [28.9%] in the induction chemotherapy group and in 76 [32.1%] in the standard-therapy group). The induction chemotherapy group had a higher incidence than the standard-therapy group of grade 3 or 4 neutropenia (67 patients [28.0%] vs. 25 [10.5%]), thrombocytopenia (27 [11.3%] vs. 3 [1.3%]), anemia (23 [9.6%] vs. 2 [0.8%]), nausea (55 [23.0%] vs. 33 [13.9%]), and vomiting (54 [22.6%] vs. 33 [13.9%]). The induction chemotherapy group also had a higher incidence than the standard-therapy group of grade 1 or 2 nephrotoxic effects (46 patients [19.2%] vs. 27 [11.4%]) but not of ototoxic effects such as deafness or otitis (172 [72.0%] and 178 [75.1%], respectively).
The incidence of all late toxic effects of grade 1 or 2 was 84.9% (203 of 239 patients) in the induction chemotherapy group and 87.8% (208 of 237) in the standard-therapy group. A total of 9.2% of the patients (22 of 239) in the induction chemotherapy group and 11.4% of the patients (27 of 237) in the standard-therapy group had one or more late toxic effects of grade 3 or 4 (Table 3). The incidence of late toxic effects was similar in the treatment groups, with the exception of grade 1 or 2 peripheral neuropathy, the incidence of which was higher in the induction chemotherapy group than in the standard-therapy group (8.8% vs. 1.7%).
Discussion
We report the results of a randomized, controlled, phase 3 trial that showed the superior tumor control and survival with the addition of induction chemotherapy to chemoradiotherapy in a selected cohort of patients with high-risk locoregionally advanced nasopharyngeal carcinoma. The majority of patients had unfavorable prognostic features of N2 or N3 disease or bulky primary tumors (T3 or T4), all of which are surrogates for occult metastasis.23 The efficacy of induction chemotherapy was due to the lower incidence of distant metastatic recurrences in the induction chemotherapy group than in the standard-therapy group, which probably explained the early overall survival advantage in the patients treated in the induction chemotherapy group. The 3-year recurrence-free survival was 85.3% in the induction chemotherapy group and 76.5% in the standard-therapy group, which corresponded to overall survival at 3 years that was 4.3 percentage points higher with induction chemotherapy than with standard therapy. This clinical advantage was evident when the outcomes of the two treatment groups were analyzed in patients who completed the planned course of treatment (three cycles of chemotherapy plus two or three cycles of concurrent cisplatin and radiotherapy vs. three cycles of concurrent cisplatin and radiotherapy alone) (see the Supplementary Appendix).
Among patients with recurrent or metastatic disease, objective response rates of 64% and 91% (including complete and partial responses) have been observed with gemcitabine plus cisplatin alone and together with camrelizumab (an anti–programmed death 1 antibody), respectively.24 Likewise, in patients with locoregionally advanced disease, Yau and colleagues found that three cycles of induction therapy with gemcitabine plus cisplatin yielded high percentages (>90%) of patients with a clinical response.12 Our results contrast with those from a similar trial conducted by Tan et al., in which a combination of gemcitabine, carboplatin, and paclitaxel did not prolong progression-free survival or overall survival.25 Several explanations may be offered for the conflicting results, including a cohort with more favorable characteristics in the trial conducted by Tan et al. (fewer patients with N2 or N3 disease than in the present trial) and the use of low-dose carboplatin (area under the curve, 2.0) that could have compromised the synergy with gemcitabine. The improvements in recurrence-free survival at 3 years are similar among patients who received induction therapy with gemcitabine plus cisplatin (difference vs. standard therapy, 8.8 percentage points) and those who received docetaxel plus cisplatin and fluorouracil (difference vs. standard therapy, 8.0 percentage points).7 It remains unclear whether these regimens differ significantly with regard to efficacy or toxicity.
We noted a higher overall incidence of acute adverse events among patients treated with induction chemotherapy than among those treated with chemoradiotherapy alone; in particular, the incidence of severe neutropenia, thrombocytopenia, anemia, nausea, and vomiting was higher in the induction chemotherapy group. The incidence of acute grade 1 or 2 nephrotoxic effects was also greater with the higher cumulative dose of cisplatin in the induction chemotherapy group, although the frequencies of late nephrotoxic effects and ototoxic effects were similar in the treatment groups, with the exception of grade 1 or 2 peripheral neuropathy. The incidence of severe late complications was low in both groups, and we did not find any treatment-related deaths. In our previous chemotherapy trial (which investigated docetaxel plus cisplatin plus fluorouracil),7 a high incidence of grade 3 or 4 acute adverse events such as neutropenia (35.5%), leukopenia (27.2%), and diarrhea (8.0%) was observed despite the modified doses (a 20% reduction of each drug as compared with the other trials26,27); in that trial, four patients (2%) had leukopenic fever, and one patient died from neutropenic sepsis (Table S7 in the Supplementary Appendix). Given the paucity of comparative data, the choice of either a gemcitabine-based or taxane-based induction chemotherapy regimen could be made on the basis of the expected toxic effects matched against the patient’s status with regard to coexisting conditions.
In conclusion, the addition of induction therapy with gemcitabine plus cisplatin to a backbone of chemoradiotherapy with cisplatin, administered every 3 weeks, improved recurrence-free survival among patients with high-risk locoregionally advanced nasopharyngeal cancer. This result translated into a 4.3-percentage-point advantage in survival over standard therapy at 3 years, at the cost of a higher incidence of acute adverse events.
Supported by grants from the Innovation Team Development Plan of the Ministry of Education (IRT_17R110), the Natural Science Foundation of Guangdong Province (2017A030312003), the Planned Science and Technology Project of Guangdong Province (2019B020230002), the Health and Medical Collaborative Innovation Project of Guangzhou City, China (201803040003), the Sun Yat-Sen University Clinical Research 5010 Program (2014009), and the Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B14035) and by a National Medical Research Council Singapore Clinician-Scientist Award (NMRC/CSA/0027/2018) and the Duke–NUS Oncology Academic Program Proton Research Program (EX/42-A92) (both to Dr. Chua).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. Y. Zhang, L. Chen, G.-Q. Hu, N. Zhang, Zhu, Yang, Jin, Shi, and Y.-P. Chen and Drs. Chua, Xie, Ying Sun, and Ma contributed equally to this article.
This article was published on May 31, 2019, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the patients who participated in this study, their families, and the medical, nursing, and research staff at the study centers; Xiao-Qing Hu, Xiao-Dan Jiang, Xiao-Fen Xiao, Qiu-Hui Zheng, and Hui-Xia Feng (Department of Radiation Oncology, Sun Yat-sen University Cancer Center) for assistance with data management and logistic support; the staff of the National Clinical Study Center for Anticancer Drugs, Sun Yat-sen University Cancer Center, for trial monitoring, data management, and statistical analysis; and Tan Sze Huey (Division of Clinical Trials and Epidemiologic Sciences, National Cancer Center Singapore) for assistance with statistics.
Author Affiliations
From the Departments of Radiation Oncology (Y.Z., L.C., Y.-P.C., W.-H.H., W.-F.L., L.-L.T., Y.-P.M., G.-Q.Z., R.S., X.L., R.G., F.H., J.-W.L., X.-J.D., C.X., N.L., Y.-Q.L., F.-Y.X., Ying Sun, J.M.), Medical Oncology (Y.-H.L.), and Nasopharyngeal Carcinoma (H.-Y.M.) and the Clinical Trials Center (Y.G.), Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy (Y.Z., L.C., Y.-P.C., W.-H.H., W.-F.L., L.-L.T., Y.-P.M., G.-Q.Z., R.S., X.L., R.G., F.H., J.-W.L., X.-J.D., C.X., N.L., Y.-Q.L., F.-Y.X., Ying Sun, J.M.), and the Department of Radiation Oncology, First Affiliated Hospital of Guangdong Pharmaceutical University (X.-C.W., Q.-F.S.), Guangzhou, the Cancer Center, Tongji Hospital Affiliated to Tongji Medical College (G.-Q.H., G.-X.L.), and the Cancer Center, Union Hospital, Tongji Medical College (K.-Y.Y., J.H.), Huazhong University of Science and Technology, Wuhan, the Department of Radiation Oncology, First People’s Hospital of Foshan, Foshan (N.Z., S.-Q.L.), the Department of Radiation Oncology, Affiliated Cancer Hospital of Guangxi Medical University, Nanning (X.-D.Z., L.L.), the Department of Head and Neck Oncology, Affiliated Hospital of Guizhou Medical University, Guizhou Cancer Hospital, Guiyang (F.J., J.-H.L.), the Department of Radiation Oncology, XiJing Hospital of Fourth Military Medical University, Xi’an (M.S., J.Z.), the Cancer Center (Z.-B.C.), and the Department of Head and Neck Oncology (S.-Y.W., Q.-D.L.), Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, the Department of Radiation Oncology, Second Affiliated Hospital of Soochow University, Suzhou (Y.T., L.Z.), the Department of Radiation Oncology, Peking University Cancer Hospital, Beijing (Yan Sun, B.-M.Z.), and the Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang (J.-G.L., Y.X.) — all in China; and the Divisions of Radiation Oncology and Medical Sciences, National Cancer Center Singapore, and the Oncology Academic Program, Duke–National University of Singapore Medical School — both in Singapore (M.L.K.C.).
Address reprint requests to Dr. Ma at the Department of Radiation Oncology, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Rd. E., Guangzhou 510060, China, or at majun2@mail.sysu.edu.cn.
| Protocol | 1705KB | |
| Supplementary Appendix | 2139KB | |
| Disclosure Forms | 729KB | |
| Data Sharing Statement | 55KB |
Figures/Media
Figure 1.
Enrollment, Randomization, and Follow-up.
The induction chemotherapy group received gemcitabine and cisplatin plus concurrent chemoradiotherapy, and the standard-therapy group received chemoradiotherapy alone. Other induction chemotherapy regimens included docetaxel, cisplatin plus fluorouracil, and docetaxel plus cisplatin.
Table 1.
Characteristics of the Patients at Baseline.*
Table 2.
Survival and Response to Treatment.*
Figure 2.
Kaplan–Meier Analysis of Recurrence-free Survival, Overall Survival, Distant Recurrence–free Survival, and Locoregional Recurrence–free Survival (Intention-to-Treat Population).
Hazard ratios and 95% confidence intervals were calculated by a stratified Cox proportional-hazards model. The primary end point was recurrence-free survival, defined as the time from randomization to documented disease recurrence (either distant metastasis or locoregional disease recurrence) or death from any cause, whichever occurred first. Secondary end points included overall survival, distant recurrence–free survival, and locoregional recurrence–free survival. Tick marks indicate censored data.
Table 3.
Adverse Events, According to Trial Group and Grade.*
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