Two or three cycles of induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma?

Abstract

Purpose

To investigate the optimal cycles of induction chemotherapy (IC) in patients with locoregionally advanced nasopharyngeal carcinoma (LANPC).

Methods

We included LANPC patients treated with two or three IC cycles from January 2015 to December 2021. The chi-square test, Kaplan-Meier method, propensity score matching (PSM), and Multivariate Cox regression analyses were used for statistical analysis.

Results

A total of 491 patients were included in this study, of whom 166 (33.8%) received two cycles and 325 (66.2%) received three cycles of IC. Patients with stage IVA disease (P < 0.001), advanced T stage (P = 0.011), and advanced N stage (P < 0.001) were more likely to receive three cycles of IC. Cox proportional hazards regression analyses showed that the number of IC cycles was not associated with better survival outcomes. Patients who received three cycles of IC had comparable LRFS (HR 0.992, 95% CI 0.525–1.875, P = 0.981), DMFS (HR 0.805, 95% CI 0.511–1.092, P = 0.351), PFS (HR 0.917, 95% CI 0.633–1.328, P = 0.645) and OS (HR 0.880, 95% CI 0.552–1.402, P = 0.590) compared to those with two cycles of IC. Similar results were found after PSM. No significant differences were found in the incidence of Grade 3–4 acute toxicities between the two and three-cycle groups. However, three cycles of IC significantly increased the incidence of Grade 1–2 leukopenia (P = 0.001), neutropenia (P = 0.015), anemia (P = 0.017), and vomiting (P = 0.024) compared to two cycles of IC.

Conclusions

The number of IC cycles (two or three) did not seem to affect the survival outcome of LANPC patients in this retrospective analysis. However, three cycles of IC were associated with a higher incidence of mild to moderate acute toxicities. Prospective studies in well-defined patient groups with a more uniform treatment program differing only in the number of IC cycles are warranted.

Introduction

Nasopharyngeal carcinoma (NPC) is a malignant tumor that originates in the nasopharynx and exhibits significant population and regional distribution characteristics, with a particularly high incidence in Southern China [1]. According to GLOBOCAN 2022, there were 120,416 new NPC cases diagnosed globally, with about 51,000 of these cases reported in China [2, 3]. Currently, approximately 70% of patients are diagnosed with locoregionally advanced NPC (LANPC). The National Comprehensive Cancer Network and the Chinese Society of Clinical Oncology both recommend a combination of induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) as the standard treatment for LANPC [4, 5]. In the era of intensity-modulated radiotherapy (IMRT), the locoregional control rate of NPC has significantly improved. However, distant metastasis remains the primary cause of treatment failure, affecting approximately 20% of patients [6, 7].

Several studies have shown that IC is beneficial for treating LANPC, as it can eliminate distant micrometastases and reduce tumor volume at an early stage [8, 9]. Nevertheless, IC is also associated with treatment-related toxicity, with grade 3–4 toxicity rates ranging from 27.3 to 43.0% in patients receiving IC [10,11,12]. Although IC offers therapeutic advantages, the optimal number of IC cycles remains a topic of debate. Prospective studies have utilized different numbers of IC cycles, with some employing two cycles and others using three [12,13,14,15]. Considering the impact of treatment toxicity, the economic burden on patients, and other factors, it remains uncertain whether three cycles of IC are the most effective in maximizing patient survival. Additionally, the relationship between the number of IC cycles and the prognosis of LANPC patients has not been fully elucidated. In this study, we aimed to investigate the optimal number of IC cycles for LANPC patients, while also considering treatment-related toxicity. Our goal was to identify the most effective number of IC cycles that can improve survival outcomes without significantly increasing adverse effects.

Materials and methods

Patients

We conducted a retrospective analysis of patients diagnosed with NPC at the First Affiliated Hospital of Xiamen University from January 2015 to December 2021. The inclusion criteria were as follows: (1) age between 18 and 70 years; (2) histologically confirmed NPC; (3) staged as T1-4N2-3 or T4N0-1 according to the 8th edition of the AJCC/UICC staging system; (4) received either two or three cycles of IC in combination with CCRT; (5) Eastern Cooperative Oncology Group performance status of 0 or 1; (6) adequate hematological and organ function. Patients were excluded if they met any of the following criteria: (1) diagnosed with metastatic NPC at initial presentation; (2) had a history of other malignant tumors. The study was approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University (approval number. XMFHIIT-2025SL119), and informed consent was waived due to the retrospective nature of the study.

Variables

The analysis included the following variables: age, gender, smoking history, alcohol consumption, histological type, clinical stage, tumor (T) stage, nodal (N) stage, number of IC cycles, and pre-treatment Epstein-Barr virus DNA (EBV-DNA) levels. Pre-treatment EBV-DNA levels were measured in detail in our previous study, with a cut-off value of 430 IU/mL [16].

Treatment

In the present study, all patients were administered standardized therapeutic interventions utilizing regulatory-approved pharmacological agents in accordance with established clinical guidelines. At our institution, the IC regimens for LANPC comprised the following: the GP regimen (gemcitabine 1000 mg/m² on days 1 and 8, cisplatin 25 mg/m² on days 1–3), the TPF regimen (docetaxel 75 mg/m² or nab-paclitaxel 260 mg/m² on day 1, cisplatin 25 mg/m² on days 1–3, and 5-FU 600–750 mg/m² per day as a continuous 120-hour infusion or S1 capsules 40 mg/m² twice daily on days 1–14), or the TP regimen (docetaxel 75 mg/m² or nab-paclitaxel 260 mg/m² on day 1, cisplatin 25 mg/m² on days 1–3). Patients received either two or three cycles of IC before commencing CCRT. All patients underwent IMRT with the following dosing schedules: 70 Gy/32–33 fractions for primary nasopharyngeal tumors, 66–70 Gy/32–33 fractions for cervical metastatic lymph nodes, 62 Gy/32–33 fractions for high-risk clinical target volumes, and 56 Gy/32–33 fractions for low-risk clinical target volumes.

In line with the guidelines from the Chinese Society of Clinical Oncology and the American Society of Clinical Oncology, concurrent cisplatin is typically administered in combination with IMRT every week at a dosage of 40 mg/m² or once every three weeks (triweekly) at a dosage of 100 mg/m² (or at least 80 mg/m²) [17]. Notably, the findings from the NPC-0501 trial indicated that the optimal platinum dosage during the concurrent phase is 160 mg/m² [18]. This result adds a significant dimension to the existing knowledge regarding platinum dosing in the concurrent treatment of the relevant disease. Furthermore, a prior randomized phase 3 trial demonstrated that lobaplatin-based IC plus CCRT achieved non-inferior survival outcomes and was associated with fewer toxic effects compared to cisplatin-based therapy in patients with LANPC [19]. This evidence suggests that lobaplatin may be a viable alternative to cisplatin in the treatment of LANPC, offering a potentially more favorable safety and efficacy profile. Therefore, CCRT was delivered using platinum-based regimens in our study, specifically cisplatin (80 mg/m² administered on days 1–3, repeated every 21 days) or lobaplatin (30 mg/m² on day 1, repeated every 21 days), for a total of two treatment cycles.

In accordance with evidence from prior prospective clinical trials, adjuvant chemotherapy was not routinely recommended in our treatment protocol. However, for selected high-risk patients, adjuvant metronomic chemotherapy with oral S-1 or capecitabine administered over one year may be considered as a therapeutic option [8, 20, 21]. Notably, the administration of adjuvant immune checkpoint inhibitors was not recommended in this setting due to insufficient evidence from prospective clinical studies. Acute toxicities during IC were graded according to the Common Terminology Criteria for Adverse Events version 4.0.

Assessment of treatment response after induction chemotherapy

Treatment response following IC was assessed in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Quantitative tumor response analysis was conducted by two independent, board-certified radiation oncologists through comparative evaluation of pre- and post-treatment imaging studies, focusing on both primary nasopharyngeal lesions and metastatic cervical lymph nodes. Tumor response was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), with the overall response rate (ORR) defined as the combined percentage of patients achieving CR and PR.

Survival outcomes

Survival endpoints included locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS). LRFS was defined as the period from the diagnosis of NPC to the occurrence of local or regional recurrence or both. DMFS was defined as the interval from NPC diagnosis to distant recurrence. PFS was defined as the time from NPC diagnosis to disease progression or death from any cause. OS was defined as the duration from NPC diagnosis to death from any cause or the last follow-up.

Statistical analysis

Differences in baseline characteristics and acute toxicities between the two groups were assessed using the Chi-square test or Fisher’s exact test. Statistical analyses were performed using a paired samples t-test to assess differences between related means. To address potential confounding factors and minimize selection bias, propensity score matching (PSM) was implemented at a 2:1 ratio between the comparative treatment cohorts using the following variables: age, gender, histology, alcohol consumption, smoking history, clinical stage, T stage, N stage, EBV-DNA levels before treatment, and IC regimens. Survival analysis was performed using the Kaplan-Meier method, and comparisons were made using the log-rank test. Cox proportional hazards regression analyses were conducted to identify independent prognostic factors associated with survival outcomes. Variables with a P value < 0.10 in the univariate Cox regression model were incorporated into the multivariate Cox proportional analysis. All statistical analyses were performed using IBM SPSS version 26.0 (IBM Corp., Armonk, NY) and the R program (version 4.4.2) (Vienna, Austria), with a significance level of P < 0.05 indicating statistical significance.

Results

Patients characteristics

During the study period, 668 patients were diagnosed with T1-4N2-3 or T4N0-1 NPC. Among them, 123 patients did not receive IC, 25 patients received 1 cycle of IC, 23 patients received 4 cycles of IC, and 6 patients received 5 cycles of IC. A total of 491 patients who met the enrollment criteria were included in this study. Of these, 166 (33.8%) received two cycles of IC, and 325 (66.2%) received three cycles. The median interval between pathological confirmation of NPC and commencement of the initial IC cycle was 13 days (range, 0–35 days). Furthermore, adjuvant metronomic chemotherapy was administered to 28 patients in the cohort. The majority of patients were male (n = 368, 74.9%), had the WHO III subtype (n = 430, 87.6%), and received the TP regimen (n = 348, 70.9%). Comparative analysis revealed significant differences in treatment cycles, with the TP group demonstrating a lower proportion of patients completing three IC cycles (60.6%) compared to both GP (78.5%) and TPF (80.8%) groups (P < 0.001). During CCRT, 44 patients (9.0%) received lobaplatin-based CCRT and 447 patients (91.0%) received cisplatin-based CCRT. Patients with stage IVA disease (P < 0.001), advanced T stage (P = 0.011), and advanced N stage (P < 0.001) were more likely to receive three cycles of IC. No significant differences were observed in gender, age, smoking history, alcohol consumption, or histology between the two groups (Table 1). Treatment completion analysis revealed comparable rates of two-cycle CCRT completion between groups (93.4% vs. 91.1%, P = 0.379).

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All patients subsequently received IMRT combined with CCRT. The mean interval between the final IC cycle and IMRT initiation was 21.5 days (range, 21–30 days) for two-cycle recipients and 21.6 days (range: 21–35) for three-cycle recipients, with no statistically significant difference observed (P = 0.433).

To address potential confounding factors, PSM was performed at a 2:1 ratio, and 144 patients in the two-cycle cohort and 242 patients in the three-cycle cohort were matched (Table 2). No significant differences were observed in baseline characteristics between the two treatment groups after PSM.

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Treatment response to induction chemotherapy

Response evaluation demonstrated no significant differences in treatment response between patients receiving two versus three IC cycles, with CR rates of 7.8% vs. 7.4%, PR of 75.9% vs. 83.1%, SD of 15.1% vs. 8.6%, and PD of 1.2% vs. 0.9% (P = 0.169). However, a significantly higher ORR was observed in the three-cycle IC group compared to the two-cycle group (90.5% vs. 83.7%, P = 0.029).

Survival outcomes

The median follow-up period was 61.4 months (range, 2.6-114.2 months). The median follow-up period for patients receiving the GP regimen was 44.4 months (range, 10.2–103.0 months), whereas those treated with either TP or TPF regimens demonstrated a median follow-up period of 59.5 months (range, 2.6-114.2 months). Locoregional recurrence was observed in 46 patients (9.4%), with a median time to recurrence of 23.8 months (range, 7.6–85.7 months). Distant recurrence occurred in 86 patients (17.5%), with a median time to recurrence of 16.2 months (range, 3.0-98.4 months). Additionally, 82 patients (16.7%) died due to NPC or other causes. The 5-year LRFS, DMFS, PFS, and OS rates were 89.3%, 81.8%, 72.2%, and 82.3%, respectively.

Prognosis analysis

In the pre-PSM cohort, univariate Cox regression analysis was conducted. The results indicated that for LRFS, variables with a P-value less than 0.10 were histology (P = 0.093) and pre-treatment EBV-DNA levels (P = 0.003). Regarding DMFS, variables with a P-value less than 0.10 were age (P = 0.003), N stage (P = 0.008), and pre-treatment EBV-DNA levels (P = 0.010). In terms of PFS, the variables showing a P-value < 0.10 were gender (P = 0.055), age (P = 0.011), clinical stage (P = 0.027), T stage (P = 0.079), N stage (P = 0.030), and pre-treatment EBV-DNA levels (P = 0.003). For OS, variables with a P-value less than 0.10 were age (P = 0.009), smoking history (P = 0.002), clinical stage (P = 0.012), T stage (P = 0.002), N stage (P = 0.007), and pre-treatment EBV-DNA levels (P = 0.013) (Table 3). However, the analysis revealed that the number of IC cycles did not significantly impact survival outcomes. Specifically, patients who received three IC cycles demonstrated comparable outcomes to those receiving two cycles across multiple endpoints: LRFS (hazard ratio [HR] 0.910, 95% confidence interval [CI] 0.499–1.657, P = 0.757), DMFS (HR 0.759, 95% CI 0.493–1.169, P = 0.209), PFS (HR 0.904, 95% CI 0.635–1.286, P = 0.575), and OS (HR 0.882, 95% CI 0.565–1.376, P = 0.579).

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The 5-year survival analysis further supported these findings, with comparable rates observed between the two treatment groups: LRFS (88.6% vs. 89.9%, P = 0.757; Fig. 1A), DMFS (79.2% vs. 83.1%, P = 0.209; Fig. 1B), PFS (70.5% vs. 73.2%, P = 0.575; Fig. 1C), and OS (81.0% vs. 84.0%, P = 0.579; Fig. 1D). These results remained consistent in the post-PSM analysis (Fig. 2A-D).

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Additionally, several independent prognostic factors were identified using the multivariate Cox proportional analysis, including age, pre-treatment EBV-DNA levels, T stage, N stage, and smoking history, all of which significantly influenced survival outcomes.

We further investigated the PFS and OS between patients receiving two and three cycles of IC after stratifying by gender, age, histology, alcohol consumption, smoking history, clinical stage, T stage, N stage, and pre-treatment EBV-DNA levels. The results showed no significant differences in PFS (Fig. 3A) and OS (Fig. 3B) between the two-cycle and three-cycle IC groups across all subgroups.

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Stratified analysis of survival outcomes by induction chemotherapy regimens

A comprehensive stratified analysis was conducted to evaluate survival outcomes between two and three cycles of IC across different IC regimens in the pre-propensity score matching cohort. Survival curves were generated using the Kaplan-Meier method, with between-group comparisons performed through log-rank tests.

In the GP cohort (n = 65), no significant differences were observed between two and three IC cycles across all survival endpoints: LRFS (P = 0.119), DMFS (P = 0.410), PFS (P = 0.895), and OS (P = 0.747) (Supplementary Fig. 1).

Similarly, in the TP/TPF cohort (n = 426), comparable outcomes were noted between treatment groups for LRFS (P = 0.723), DMFS (P = 0.899), PFS (P = 0.503), and OS (P = 0.892) (Supplementary Fig. 2).

Acute toxicities during induction chemotherapy

Table 4 summarizes the acute toxicities during IC between the two- and three-cycle groups. No significant differences were observed in the incidence of Grade 3–4 acute toxicities between these groups. However, three cycles of IC significantly increased the incidence of Grade 1–2 leukopenia (P = 0.001), neutropenia (P = 0.015), anemia (P = 0.017), and vomiting (P = 0.024) compared to two cycles of IC.

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Discussion

IC has been increasingly utilized in the management of LANPC due to its potential to eliminate distant micrometastases and reduce tumor volume at an early stage. However, the optimal number of IC cycles remains undefined. This study aimed to investigate the optimal number of IC cycles in terms of survival outcomes and treatment-related toxicity for LANPC patients. Our study showed that three cycles of IC did not improve survival outcomes but increased acute toxicity compared to those receiving two cycles of IC.

Although the optimal number of IC cycles for LANPC remains unclear, the most commonly used regimens in clinical practice are two or three cycles. More chemotherapy cycles may not bring additional survival benefits [22, 23]. In clinical practice, the choice between two and three cycles often leans towards three cycles (66.7-71.1%) [8, 20]. In our study, 66.2% of patients received three cycles of IC. However, in another study, 71.2% of patients received two cycles of IC [24], which may be due to the different patient populations (64.8% with stage III disease). In our study, we further found that patients with stage IVA disease, advanced T stage, and advanced N stage were more likely to receive three cycles of IC. This is consistent with the findings of Ahmed et al. [24], who noted that three cycles of IC were more common in patients with advanced disease stages, aligning with the clinical practice of intensifying treatment for more advanced disease stages.

In the management of locally advanced nasopharyngeal carcinoma, the CR rate has been consistently shown to increase incrementally with each treatment cycle, reaching a plateau after the third cycle in patients receiving cisplatin and 5-fluorouracil (PF) regimen [25]. However, the PF regimen has been largely superseded in contemporary clinical practice due to its inferior survival outcomes compared to GP, TPF, or TP regimens [26]. Our study demonstrated a statistically significant difference in ORR, comprising both CR and PR, between patients receiving two versus three cycles of IC (83.7% vs. 90.5%, P = 0.029). This observation is consistent with the findings of Liang et al., who reported comparable results (88.6% vs. 92.0%, P < 0.01) while noting similar survival outcomes between the two treatment groups [26], a finding that aligns with our findings. The inherent radiosensitivity of NPC suggests that subsequent radiotherapy may yield comparable efficacy in patients who have achieved either CR or PR through IC. This hypothesis is further supported by prospective clinical trials investigating the three-cycle TPF regimen, which demonstrated that patients attaining CR or PR during IC experienced significantly improved survival outcomes compared to those with SD, while no significant survival difference was observed between CR and PR patients [27].

To date, no prospective studies have determined the impact of different numbers of IC cycles on survival outcomes. Several retrospective studies have explored the effects of different IC cycles on survival in LANPC patients. Wei et al. found that patients with N2-3 disease who received four cycles of IC had better outcomes compared to those who received two cycles. However, approximately 50% of patients in their study received cisplatin plus fluorouracil, and about 40% did not receive CCRT, which may have confounded the assessment of the impact of the number of IC cycles on survival [28]. Conversely, He et al. found that patients receiving four cycles of IC had significantly worse survival outcomes compared to those receiving two or three cycles [22]. Additionally, Jiang et al. found that for patients with N2-3 disease who achieved complete response or partial response after IC, three cycles of IC provided significantly better OS and PFS compared to two cycles. However, for patients with stable disease or progressive disease after IC, increasing the number of IC cycles did not improve survival outcomes [29]. This study, however, included only 32 patients who received two cycles and 58 who received three cycles, and the PFS in the two-cycle group was only around 50%, which may limit the accuracy of assessing the prognostic value of the number of IC cycles [29].

Several large-scale studies in the context of contemporary treatment paradigms have found that three cycles of IC did not provide survival benefits compared to two cycles and were associated with higher treatment toxicity [22,23,24, 30, 31]. An updated network meta-analysis has indicated that docetaxel-based and gemcitabine-based IC regimens positively impact survival in LANPC and should be considered the standard options [32]. In our study, patients primarily received IMRT-based CCRT after docetaxel-based and gemcitabine-based IC regimens, and we found that increasing the number of IC cycles did not improve survival rates. We conducted a stratified analysis to evaluate the impact of IC cycle number on PFS and OS across various subgroups, and the results showed that PFS and OS were similar between the two-cycle and three-cycle IC groups, regardless of patient characteristics or disease stage.

NPC is a chemosensitive tumor. Li et al. reported that the volume of the primary tumor and retropharyngeal lymph nodes continued to decrease after two cycles of IC but did not further decrease after the third cycle. In addition, 50% (27/54) of patients even experienced a slight increase in tumor volume, especially in those with T4 disease [33]. Moreover, a prolonged wait time between definitive diagnosis and the initial radiotherapy has negative prognostic effects on patients with LANPC receiving IC plus CCRT [34]. Liu et al. found that for patients with tumors that were insensitive to IC after two to three cycles, changing the IC regimen did not further improve survival rates, and it was essential to start subsequent CCRT as soon as possible [35]. Therefore, for patients receiving IC, it may be more important to accurately assess the response to IC and promptly adjust the treatment strategy. Two cycles of IC may be sufficient, and subsequent CCRT therapy should be pursued as soon as possible. With the increasing use of immunotherapy in LANPC [36,37,38], future studies should also investigate the impact of different numbers of induction chemoimmunotherapy cycles on complete response rates and long-term survival outcomes.

While the number of IC cycles did not influence survival outcomes, it did impact the incidence of acute toxicities. Specifically, three cycles of IC significantly increased the incidence of Grade 1–2 leukopenia, neutropenia, anemia, and vomiting compared to two cycles. However, there were no significant differences in the incidence of Grade 3–4 acute toxicities between the two groups. This finding is consistent with previous studies [22, 23]. This suggests that while three cycles of IC may be associated with more mild to moderate toxicities, the risk of severe adverse events remains similar to that of two cycles. The management of these toxicities is crucial for maintaining patient quality of life and adherence to treatment protocols. Therefore, two cycles of IC could minimize treatment-related complications without compromising survival benefits, thereby improving patient quality of life and treatment compliance.

The strength of our study lies in its large sample size and comprehensive analysis of both survival outcomes and treatment-related toxicity. Additionally, the stratified analysis provides insights into the impact of cycles of IC across various patient subgroups. However, our study has some limitations. First, it is a retrospective study, which may introduce selection bias and confounding factors. Second, these data were from a single center in an endemic area and may not be representative of the broader population and patients in non-endemic areas. Finally, the relatively short follow-up period for some patients might limit the detection of long-term differences in survival outcomes.

Conclusions

In conclusion, our study suggests that the number of IC cycles (two vs. three) does not significantly affect the survival outcomes of LANPC patients. However, three cycles of IC are associated with a higher incidence of mild to moderate acute toxicities. Therefore, two cycles of IC may be a more appropriate and clinically relevant choice for LANPC patients, balancing the potential benefits of treatment with the need to minimize adverse effects. Further research is warranted to explore the optimal cycles of IC in LANPC.

Data availability

The data supporting the findings of the article are available within the article.

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