Key Points
Question
Is treatment with radiotherapy noninferior to chemoradiotherapy after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma?
Findings
In this noninferiority randomized clinical trial of 383 individuals with stage III to IVB nasopharyngeal cancer who received radiotherapy or chemoradiotherapy after induction chemotherapy, the 3-year progression-free survival rate was 76.2% and 76.8%, respectively. The noninferiority margin was established at 10%.
Meaning
The results of this trial suggest that after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma, radiotherapy alone was noninferior to chemoradiotherapy in terms of 3-year progression-free survival.
Abstract
Importance
Induction chemotherapy plus concurrent chemoradiotherapy is recommended for locoregionally advanced nasopharyngeal carcinoma but is associated with higher rates of acute toxic effects and low compliance. Evidence on de-escalating treatment intensity after induction chemotherapy is limited.
Objective
To assess if radiotherapy was noninferior to chemoradiotherapy after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma.
Design, Setting, and Participants
From April 2015 to March 2018, a multicenter, open-label, randomized, noninferiority, phase 3 trial was conducted at 5 Chinese hospitals. A total of 383 patients aged 18 to 70 years with an untreated histologically confirmed nonkeratinizing tumor, Karnofsky performance status score not worse than 70, proper organ function, and stage III to IVB nasopharyngeal cancer were enrolled. Data were analyzed from April 2023 to June 2023.
Interventions
Patients were assigned randomly. Both groups received 3 cycles of induction chemotherapy consisting of intravenous administration (on day 1) of cisplatin at 60 mg/m2 and docetaxel at 60 mg/m2 and continuous intravenous infusion (from day 1 to day 5) of daily fluorouracil (600 mg/m2), repeated every 21 days. Subsequently, the patients received radiotherapy alone (induction chemotherapy in combination with radiotherapy [IC-RT] group) or concomitant cisplatin (30 mg/m2/week) with radiotherapy for 6 to 7 weeks (induction chemotherapy combined with chemoradiotherapy [IC-CCRT] group).
Main Outcomes and Measures
The primary end point was 3-year progression-free survival (time from the initiation of therapy until the first indication of disease progression or death), with a noninferiority margin of 10%. The secondary end points included overall survival, locoregional failure-free survival, distant metastasis-free survival, response rate, and toxic effects.
Results
A total of 383 patients (median [range] age, 48 [19-70] years; 100 women [26%]). Median follow-up time was 76 months (IQR, 70-89 months). The 3-year progression-free survival was 76.2% and 76.8% in the IC-RT (n = 193) and IC-CCRT groups (n = 190), respectively, in the intention-to-treat population, showing a difference of 0.6% (95% CI, –7.9% to 9.1%; P = .01 for noninferiority). Identical outcomes were reported in the per-protocol population. The incidence of grade 3 to 4 short-term toxic effects in the IC-RT group was less than the IC-CCRT group. No differences were observed in late toxic effects.
Conclusions and Relevance
The results of this randomized clinical trial suggest that after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma, radiotherapy alone was noninferior to chemoradiotherapy in terms of 3-year progression-free survival.
Trial Registration
ClinicalTrials.gov Identifier: NCT02434614
This randomized clinical trial examines if radiotherapy is noninferior to chemoradiotherapy after induction chemotherapy for locoregionally advanced nasopharyngeal carcinoma.
Introduction
Nasopharyngeal carcinoma is an epithelial tissue-derived malignant neoplasm. It has a unique geographic distribution, with reports of high occurrence in Southeastern Asia, South China, and North Africa. Approximately 133 000 new cases of nasopharyngeal cancer were reported worldwide in 2020, and an initial diagnosis of locoregionally advanced disease was assigned to more than 70% of patients with nasopharyngeal carcinoma.
Concurrent chemoradiotherapy represents a new treatment era for locoregionally advanced nasopharyngeal carcinoma. Multiple large-scale randomized clinical trials have reported that the inclusion of induction chemotherapy is associated with good treatment adherence and eradicates the micrometastases. Moreover, induction chemotherapy in combination with concurrent chemoradiotherapy (IC-CCRT) achieves high rates of tumor remission and favorable long-term survival and is now recommended as a treatment strategy for locoregionally advanced nasopharyngeal carcinoma in current guidelines. Unfortunately, IC-CCRT is associated with high short-term toxic effects and low compliance with concomitant chemotherapy. Acute grade 3 adverse events or greater have been observed in more than 70% of patients receiving IC-CCRT, with only 30.0% to 57.2% of patients receiving concomitant cisplatin (100 mg/m2 dose/3 weeks) across 3 cycles. Chemotherapy-associated toxic effects are the leading cause of patients not completing treatment with concomitant chemotherapy.
With the wide application of different induction chemotherapy regimens and intensity-modulated radiation therapy in recent years, several studies have indicated that induction chemotherapy plus radiotherapy (IC-RT) may yield high efficacy and low toxic effects. A randomized clinical trial enrolling 408 individuals with locoregionally advanced nasopharyngeal carcinoma found that combining concomitant chemotherapy failed to offer additional benefit but was associated with increased toxic effects after induction chemotherapy. Identical outcomes have been reported in studies conducted by our and other groups. However, most of these studies were nonrandomized or based on 2-dimensional radiotherapy. Therefore, a noninferiority, randomized clinical trial was inaugurated to investigate the efficacy in terms of progression-free survival after IC-RT and IC-CCRT for locoregionally advanced nasopharyngeal carcinoma.
Methods
Study Design and Participants
The randomized, open-label, phase 3, noninferiority trial was conducted at 5 Chinese hospitals between April 1, 2015, and March 10, 2018 (Supplement 1; eTable 1 in Supplement 2). If patients met the following requirements they were considered eligible: age 18 to 70 years; presence of previously untreated, histologically confirmed nonkeratinizing stage III to IVB NPC (according to the seventh edition of the American Joint Committee on Cancer edition); nonpregnant female patient; normal blood count results (hemoglobin concentrations, ≥10 g/dL [to convert to g/L, multiply by 10]; white blood cell count, ≥4000/μL [to convert to ×109/L, multiply by 0.001]; and platelet count, ≥100 000/μL [to convert to ×109/L, multiply by 1]); satisfactory liver functions (total serum bilirubin, ≤1.6 mg/dL [to convert to μmol/L, multiply by 17.104]; serum transaminase, lower than 2.5 fold than the maximum normal limit); satisfactory kidney function (serum creatinine, ≤1.5 mg/dL [to convert to μmol/L, multiply by 88.4]; creatinine clearance, ≥60 mL/min [to convert to mL/s/m2, multiply by 0.0167]); a Karnofsky performance status score of 70 or greater; and no history of radiation therapy or chemotherapy. The exclusion criteria included disease progression during treatment, onset of uncontrollable potentially fatal diseases, a history of radiation or chemotherapy, pregnancy, or lactation. All eligibility criteria are shown in the protocol (Supplement 1). All participants provided written informed consent. The trial protocol was approved by the ethics committees of the Affiliated Hospital of Guilin Medical University and all the other participating centers. This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Randomization and Masking
Randomization was performed at the Guilin Medical University Affiliated Hospital with computer-generated random number codes and was based on the participating center and disease stage (known only to the statistician). An independent statistician provided opaque, sealed envelopes with a random number code generated by a computer. Patient assignment was performed using 1:1 randomization with a block size of 4. Every center’s investigator revealed the treatment assignment by opening the sequentially numbered envelopes after receiving the patient’s written informed consent.
Procedures
Pretreatment evaluations were performed in all patients. Nasopharyngeal biopsies were performed, and pathologic diagnoses were obtained before treatment. Additional pretreatment evaluations included full history-taking and physical examination, determination of the complete blood cell count, liver/kidney function tests, a serum biochemical profile test, magnetic resonance imaging (MRI) of the nasopharynx and neck, chest-area computed tomography (CT) scans, bone scans, and abdominal scans (sonography or CT). CT was performed for patients in whom MRI was contraindicated.18F-fluorodeoxyglucose (FDG) positron emission tomography was performed if metastases were highly suspected.
Patients received 3 cycles of fluorouracil, cisplatin, and docetaxel IC-RT or 3 cycles of the same induction chemotherapy combined with chemoradiotherapy (IC-CCRT group). Fluorouracil, 600 mg/m2, was continuously infused in both groups for 3 cycles of induction chemotherapy on days 1 to 5, 22 to 26, and 43 to 47, and 60 mg/m2 of cisplatin and docetaxel were intravenously delivered on days 1 and 2 and day 43. The IC-CCRT group received radiotherapy concomitantly with cisplatin, 30 mg/m2, administered intravenously at a 7-day interval, beginning on the first day of radiotherapy. The IC-RT group received radiotherapy alone. In the present trial, intensity-modulated radiotherapy was compulsorily administered. Details of radiotherapy and chemotherapy adjustment are shown in Supplement 1.
Therapeutic responses were evaluated according to the Response Evaluation Criteria in Solid Tumors (version 1.1) 1 week after induction chemotherapy and 12 weeks after radiotherapy. A physical examination, flexible nasopharyngoscopy, and enhanced MRI (or enhanced CT) of the neck and nasopharynx were all part of the evaluation. The Late Radiation Morbidity Scoring Criteria of the Radiation Therapy Oncology Group were used for determining the late toxic effects of radiation therapy, and the Common Terminology Criteria for Adverse Events (version 4.0) was used for grading acute toxic effects.
Evaluations were conducted weekly during radiation therapy. Patients underwent assessments at 3-month intervals during the initial 3 years after the completion of their treatment. Subsequently, follow-up evaluations were performed every 6 months for the following 4 to 5 years. Subsequently, patients were scheduled for annual assessments. Follow-up examinations consisting of flexible nasopharyngoscopy, enhanced MRI of the neck and nasopharynx (CT was performed instead when MRI was contraindicated), chest radiography (or an enhanced CT scan of the chest), and abdominal sonography (or enhanced CT scan of the abdomen) were performed. Tissue biopsy specimens were used to confirm recurrence or metastasis. When tissue biopsy specimens were difficult to obtain, diagnosis of recurrence or metastasis required at least 2 of the following imaging appearances: MRI, CT, abdominal sonography, or18F-FDG positron emission tomography. When feasible, salvage therapy was offered to patients who experienced a relapse or had persistent disease.
Outcomes
The primary end point was the 3-year progression-free survival, which was defined as the time from the beginning of therapy until the initial signs of disease progression (localized recurrence or distant metastasis) or death due to any reason. The secondary end points included overall survival, locoregional failure-free survival, distant metastasis-free survival, response rate, and toxic effects. Overall survival was the time from the initiation of therapy to the last follow-up or death attributable to any cause; locoregional failure-free survival was the interval from the initiation of treatment to the onset of locoregional progression; and distant metastasis-free survival was the time from the initiation of treatment to the occurrence of initial distant metastasis.
Sample Size Calculation
This trial aimed to assess whether the 3-year progression-free survival in the IC-RT group was noninferior to that in the IC-CCRT group. The 3-year progression-free survival was estimated for the IC-CCRT group to be 83% based on data from prior studies. The noninferiority margin was established at 10%. To demonstrate the noninferiority of IC-RT with a 5% 1-sided significance and 80% statistical power, 350 patients (175 per cohort) were needed. Considering a 5% loss to follow-up, the inclusion of 368 patients was needed (184 per cohort).
Statistical Analysis
Efficacy was evaluated using the intention-to-treat principle and per-protocol analysis. Noninferiority was determined if the upper limit of the 95% CI for the 3-year progression-free survival difference was not more than the noninferiority margin. Safety analyses included patients who underwent a minimum of 1 cycle of induction chemotherapy and initiated treatment with radiotherapy.
For categorical variables (including adverse events), the χ2 test, adjusted χ2 test, or Fisher exact test was used, and for continuous variables, Mann-Whitney U tests were used. The Kaplan-Meier method was used to plot survival curves and compared by the log-rank test. 95% CIs were calculated using the Greenwood formula.
The missing time-to-event data of patients who were lost to follow-up or had no event at the most recent follow-up time were censored. Hazard ratios (HRs) were created using the Cox proportional hazards model, with proportional hazards assumptions evaluated using Schoenfeld residuals.
The multivariable and univariable Cox proportional hazards models were used for investigating the independent importance of therapy. Various variables, which included age, sex, disease stage, Karnofsky performance status score, and tumor response to induction chemotherapy, were considered during the multivariate analysis.
The PASS software (version 11.0; NCSS) was used for sample size calculations. Stata, version 17.0 (StataCorp), and SAS, version 9.4 (SAS Institute), were used for statistical analysis. For 1-sided statistical tests, a 5% significance level was used, and for 2-sided statistical tests, a 5% significance level was used. The trial was registered on ClinicalTrials.gov with the registration number NCT02434614.
Results
From April 2015 through March 2018, 444 patients underwent the eligibility evaluation. Overall, 383 patients (86.3%) were assigned at random to the 2 groups: 193 (50.4%) to the IC-RT group and 190 (49.6%) to the IC-CCRT group (Figure 1). The cutoff date for the data was March 10, 2023. Two patients were lost to follow-up. Table 1 provides a list of baseline characteristics.
Figure 1. Trial Profile.
aFive patients without acceptable hematological function, 3 patients without satisfactory kidney function, and 3 patients without adequate liver functions, as well as 10 patients older than 70 years and 5 patients who underwent a previous neck surgery.
Table 1. Baseline Characteristics.
| Characteristic | No. (%) | |
|---|---|---|
| IC-RT group (n = 193) | IC-CCRT group (n = 190) | |
| Sex | ||
| Female | 51 (26) | 49 (26) |
| Male | 142 (74%) | 141 (74%) |
| Median (IQR) age, y | 48 (41-54) | 47 (40-53) |
| KPS score | ||
| 90-100 | 179 (93) | 174 (92) |
| 70-80 | 14 (7) | 16 (8) |
| T category | ||
| T1 | 7 (3) | 3 (2) |
| T2 | 28 (15) | 37 (19) |
| T3 | 95 (49) | 84 (44) |
| T4 | 63 (33) | 66 (35) |
| N category | ||
| N0 | 8 (4) | 9 (5) |
| N1 | 36 (19) | 31 (16) |
| N2 | 118 (61) | 121 (64) |
| N3 | 31 (16) | 29 (15) |
| Stage | ||
| III | 107 (55) | 101 (53) |
| IVA | 55 (29) | 60 (32) |
| IVB | 31 (16) | 29 (15) |
Abbreviations: IC-CCRT, induction chemotherapy combined with chemoradiotherapy; IC-RT, induction chemotherapy in combination with radiotherapy; KPS, Karnofsky performance status.
For the whole group, the median follow-up time was 76 months (IQR, 70-89 months). The 3-year progression-free survival was 76.2% for the IC-RT group vs 76.8% for the IC-CCRT group (HR, 0.92; 95% CI, 0.65- 1.32; log-rank P = .66; Figure 2A; eTable 2 in Supplement 2), with a 0.6% difference (95% CI, –7.9% to 9.1%; P = .01 value for noninferiority) according to the intention-to-treat analysis. The upper limit of the 95% CI of the difference was less than the 10% noninferiority criterion. In the per-protocol analysis, the corresponding 3-year progression-free survival was 76.6% in the IC-RT group and 75.7% in the IC-CCRT group (HR, 0.89; 95% CI, 0.62-1.28; log-rank P = .52; eTable 2 and eFigure 1 in Supplement 2), with a 0.9% difference (95% CI, –9.6% to 7.8%; P = .01 value for noninferiority).
Figure 2. Kaplan-Meier Survival Curves for the Induction Chemotherapy in Combination With Radiotherapy (IC-RT) and Induction Chemotherapy Combined With Chemoradiotherapy (IC-CCRT) Groups in the Intention-to-Treat Population.
DMFS indicates distant failure-free survival; HR, hazard ratio; LRFFS, locoregional metastasis-free survival; OS, overall survival; PFS, progression-free survival.
Regarding the secondary efficacy end points (intention-to-treat analysis), the 3-year overall survival, locoregional failure-free survival, and distant metastasis-free survival for the IC-RT group were 86.0%, 91.3%, and 83.7%, respectively. The corresponding values in the IC-CCRT group were 86.8%, 88.5%, and 85.1%. No significant differences were observed in the secondary end points among both groups in the intention-to-treat and per-protocol analyses (Figure 2; eTable 2 and eFigure 1 in Supplement 2). The results of 5-year survival analyses are listed in eTable 2 in Supplement 2. Multivariable analyses showed concurrent chemotherapy was not an independent prognostic factor (eTable 3 in Supplement 2). The distribution of disease failure is shown in eTable 4 in Supplement 2. Schoenfeld residuals suggested that the Cox models met the proportional hazard assumptions. No discernible difference was observed between the response rates 1 week following induction chemotherapy and 12 weeks following radiotherapy (eTable 5 in Supplement 2).
Safety evaluations were performed for 188 patients in the IC-CCRT group and 193 patients in the IC-RT groups. Throughout the treatments, grade 3 to 4 toxic effects could be seen in 105 patients (54%) from the IC-RT group and 137 patients (73%) from the IC-CCRT group. The most common grade 3 to 4 adverse reactions included neutropenia (73 of 193 [38%] in the IC-RT group vs 72 of 188 [38%] in the IC-CCRT group), leucopenia (40 [21%] vs 67 [36%]), and vomiting (22 [11%] vs 35 [19%]) (Table 2; eTable 6 in Supplement 2). The 2 therapy groups showed similar instances of late toxic effects (eTable 2 in Supplement 2).
Table 2. Summary of Adverse Events.
| Event | IC-RT group (n = 193) | IC-CCRT group (n = 188) | P value for events, grades 1-2 | P value for events, grades 3-4 | P value for events, grade ≥1 | ||||
|---|---|---|---|---|---|---|---|---|---|
| Grades 1-2 | Grade 3 | Grade 4 | Grades 1-2 | Grade 3 | Grade 4 | ||||
| Any acute adverse events | 88 (46) | 60 (31) | 45 (23) | 51 (27) | 97 (52) | 40 (21) | .001a | <.001a | NA |
| Hematological | |||||||||
| Leukopenia | 109 (56) | 31 (16) | 9 (5) | 104 (55) | 58 (31) | 9(5) | .82a | .001a | <.001a |
| Neutropenia | 57 (30) | 31 (16) | 42 (22) | 68 (36) | 35 (19) | 37 (20) | .17a | .92a | .13a |
| Thrombocytopenia | 16 (8) | 0 | 1 (<1) | 45 (24) | 4 (2) | 0 | <.001a | .21b | <.001a |
| Anemia | 123 (64) | 3 (2) | 0 | 153 (81) | 8 (4) | 0 | <.001a | .12a | <.001a |
| Nonhematological | |||||||||
| Nausea | 164 (85) | 10 (5) | 0 | 163 (87) | 18 (10) | 0 | .63a | .10a | .02a |
| Vomiting | 96 (50) | 22 (11) | 0 | 106 (56) | 35 (19) | 0 | .19a | .05a | .004a |
| Diarrhea | 29 (15) | 6 (3) | 0 | 22 (12) | 6 (3) | 0 | .34a | .96a | .40a |
| Stomatitis | 169 (88) | 21 (11) | 0 | 154 (82) | 32 (17) | 1 (<1) | .13a | .06a | .62b |
| Liver impairment | 44 (23) | 4 (2) | 2 (1) | 68 (36) | 6 (3) | 0 | .004a | .96a | .005a |
| Kidney impairment | 11 (6) | 0 | 0 | 14 (7) | 0 | 0 | .49a | NA | .49a |
| Weight loss | 102 (53) | 1 (<1) | 0 | 111 (59) | 7 (4) | 0 | .22a | .04b | .06a |
| Dysphagia | 135 (70) | 8 (4) | 0 | 122 (65) | 12 (6) | 0 | .29a | .33a | .54a |
| Dry mouth | 190 (98) | 0 | 0 | 187 (99) | 0 | 0 | .62b | NA | NA |
| Dermatitis | 176 (91) | 6 (3) | 1 (<1) | 170 (90) | 8 (4) | 3 (2) | .80a | .31a | .49a |
| Any late adverse events | 151 (78) | 26 (14) | 0 | 140 (74) | 32 (17) | 0 | .62a | .34a | .94a |
| Skin | 43 (22.2) | 0 | 0 | 47 (25) | 0 | 0 | .53a | >.99b | .53a |
| Dry mouth | 118 (61.1) | 10 (5.2) | 0 | 120 (63.8) | 13 (6.9) | 0 | .59a | .48a | .35a |
| Neck tissue damage | 64 (33.2) | 6 (3.1) | 0 | 66 (35.1) | 5 (2.7) | 0 | .69a | .79a | .76a |
| Trismus | 8 (4.1) | 1 (0.5) | 0 | 10 (5.3) | 1 (0) | 0 | .59a | >.99 | .60a |
| Dysphagia | 23 (11.9) | 0 | 0 | 29 (15.4) | 0 | 0 | .32a | .99>b | .32a |
| Deafness/otitis | 71 (36.8) | 9 (4.7) | 0 | 67 (35.6) | 11 (5.9) | 0 | .82a | .60a | .99a |
| Eye damage | 2 (1) | 0 | 0 | 2 (1) | 0 | 0 | >.99 | >.99b | >.99b |
| Bone necrosis | 2 (1) | 0 | 0 | 4 (2.1) | 0 | 0 | .44b | >.99b | .44b |
| Symptomatic temporal lobe necrosis | 28 (14.5) | 1 (0.5) | 0 | 33 (17.6) | 2 (1) | 0 | .42a | .62b | .35a |
Abbreviations: IC-CCRT, induction chemotherapy combined with chemoradiotherapy; IC-RT, induction chemotherapy in combination with radiotherapy; NA, not applicable.
P values were calculated with an unadjusted χ2 test.
P values were calculated with the Fisher exact test.
Induction chemotherapy was initiated in 381 of the 383 patients (99%) enrolled in both groups after randomization (Figure 1; eTable 7 in Supplement 2). Three cycles of induction chemotherapy were completed in 180 of 193 patients (93%) from the IC-RT group and 177 of 190 patients (93%) from the IC-CCRT group (eTable 7 in Supplement 2). In the IC-RT group, the mean (SD) relative dose intensity for cisplatin, docetaxel, and fluorouracil was 95.6% (1.39), 95.4% (1.47), and 89.6% (36.5); the corresponding values in the IC-CCRT group were 94.8% (1.53), 92.5% (2.93) and 84% (51.88) (eFigure 2 in Supplement 2). During radiation, radiotherapy was completed by 192 (99%) and 190 patients (100%) from the IC-RT group and the IC-CCRT group, respectively. The overall median radiotherapy duration and dose of radiation therapy are shown in eTable 7 in Supplement 2. The mean (SD) relative dose intensity for concomitant cisplatin reached 95% (2.31) in the IC-CCRT group (eFigure 2 in Supplement 2). Moreover, 190 patients (100%) from the IC-CCRT group began concomitant chemotherapy. In all, 163 patients (86%) underwent concomitant therapy for a minimum of 5 cycles (eTable 7 in Supplement 2).
Discussion
To our knowledge, this is the first noninferiority study that aimed to determine if IC-RT is noninferior to IC-CCRT for locoregionally advanced nasopharyngeal carcinoma. In this trial, we demonstrated that after induction chemotherapy, radiotherapy alone was noninferior to chemoradiotherapy in terms of the 3-year progression-free survival for locoregionally advanced nasopharyngeal carcinoma. Furthermore, the incidence of grade 3 to 4 short-term toxic effects in the IC-RT group was less than that in the IC-CCRT group.
During the last 2 decades, the contribution of concomitant chemotherapy has been repeatedly proven. In a meta-analysis incorporating 19 trials, the addition of concurrent chemotherapy to radiotherapy was associated with a substantial 10.1% absolute increase in the 5-year progression-free rate. This improvement elevated the survival rate from 59.8% to 69.9%. However, the studies included in this analysis were partially developed during the period when conventional 2-dimensional radiotherapy was prevalent. The effectiveness of 2-dimensional radiotherapy alone in achieving disease control and improving survival rates for advanced nasopharyngeal carcinoma was unsatisfactory. Additional concomitant chemotherapy can enhance radiation efficacy and offer additional survival benefits at the cost of increased severe toxic effects. Huang et al used methods similar to ours during the traditional radiation therapy era, randomly assigning 400 patients with locally advanced nasopharyngeal carcinoma to the IC-RT (199 patients) and the IC-CCRT (201 patients) arms. The 2 arms showed no notable differences in locoregional control, distant control, and failure-free survival. Carboplatin was proposed to be the leading reason for the negative outcomes. Besides, this study was conducted during the era of 2-dimensional radiotherapy planning. This trial aimed to reevaluate the value of concomitant chemotherapy in the era of intensity-modulated radiotherapy era. Unlike Huang et al, we used a triple-drug induction regimen that was recommended by current guidelines. The primary result confirmed that after triple-drug induction chemotherapy, omitting concomitant cisplatin during radiotherapy did not compromise clinical efficacy while reducing the toxic effect burden. This approach offered a potentially promising alternative choice for treating locoregionally advanced nasopharyngeal carcinoma.
Administration of radiotherapy and induction chemotherapy demonstrated favorable efficacy among patients with locoregionally advanced nasopharyngeal carcinoma. Several potential explanations may account for this result. First, advancements in radiation technique have facilitated local disease control. During the past decade, intensity-modulated radiotherapy has been gradually used instead of 2-dimensional radiotherapy and has become the most widely used radiation technique. Many studies confirmed that intensity-modulated radiotherapy was associated with better locoregional failure-free survival than 2-dimensional radiotherapy. Advancements in accurate radiotherapy may have diminished the role of concomitant chemotherapy. Second, the application of different chemotherapy regimens has further improved disease-free survival. Using chemotherapy before radiotherapy could eradicate micrometastases and reduce the tumor volume early. The results from multiple large randomized clinical trials have revealed better survival of the group receiving induction chemotherapy plus chemoradiotherapy compared with the group receiving chemoradiotherapy. The induction chemotherapy regimen used in our study included 3 chemotherapeutic drugs: docetaxel, cisplatin, and fluorouracil. After receiving induction chemotherapy, 87.5% of patients in the GORTEC 2006-02 study showed an objective response. Third, advances in imaging have contributed to nasopharyngeal carcinoma staging and radiotherapy. MRI showed advantages for its high-contrast resolution, while 18F-FDG positron emission tomography demonstrated greater sensitivity and specificity in detecting tumor lesions. Thus, the application of different imaging modalities leads to more accurate tumor staging and guides subsequent clinical decisions.
The completion rates in the IC-RT group were high, with more than 90% of all patients completing at least 3 cycles of induction chemotherapy. This outcome was identical to that reported by Frikha et al. The grade 3 to 4 toxic effect profile during induction chemotherapy was similar. However, the IC-RT group showed very low incidences of leukopenia and neutropenia. The primary adverse effect was radiotherapy-induced stomatitis, which was acceptable to patients. Thus, chemotherapy-related toxic effects, excess costs, and increased risk of infections during radiotherapy could be avoided in patients who underwent IC-RT.
In endemic areas of nasopharyngeal cancer, many factors contribute to the pathogenesis of nasopharyngeal carcinoma. Of these, host genetics and Epstein-Barr virus (EBV) infection are one of the important factors. At the present time, there is a lack of reliable evidence regarding nasopharyngeal carcinoma pathogenesis. Besides, more 90% of human adults are infected with EBV. However, the standards for detecting EBV DNA are lacking in various research institutions. Thus, we did not take the 2 factors into the randomization and statistical analysis.
Limitations
The limitations of this trial are worth consideration. First, this trial was conducted in endemic areas; thus, caution is needed when applying its results to nonendemic areas. Second, additional outcomes, such as quality of life, were not available in this trial. Further studies with longer follow-up times or other end points will be needed to test this inference further. Third, because EBV DNA data were not readily available at all centers several years ago, the present study did not include data for plasma EBV DNA, the most crucial prognostic factor. Several ongoing trials are evaluating the role of concomitant chemotherapy with various induction chemotherapy regimens (NCT04414566 and NCT03015727).
Conclusions
The results of this randomized clinical trial show that IC-RT is an effective alternative therapy for patients with locoregionally advanced nasopharyngeal carcinoma.
Trial protocol
eTable 1. List of participating centres
eTable 2. Survival analyses for intention-to-treat and per-protocol population
eTable 3. Summary of univariable and multivariable analyses of prognostic factors
eTable 4. Distribution of disease failure
eTable 5. Response to the treatment
eTable 6. Summary of acute adverse events according to treatment phase
eTable 7. Treatment compliance
eFigure 1. Kaplan-Meier survival curves for the IC-RT and IC-CCRT groups in the per-protocol population
eFigure 2. Mean relative dose intensity
Data sharing statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
eTable 1. List of participating centres
eTable 2. Survival analyses for intention-to-treat and per-protocol population
eTable 3. Summary of univariable and multivariable analyses of prognostic factors
eTable 4. Distribution of disease failure
eTable 5. Response to the treatment
eTable 6. Summary of acute adverse events according to treatment phase
eTable 7. Treatment compliance
eFigure 1. Kaplan-Meier survival curves for the IC-RT and IC-CCRT groups in the per-protocol population
eFigure 2. Mean relative dose intensity
Data sharing statement