Metronomic S-1 Adjuvant Chemotherapy Improves Survival in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma.
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Abstract
Purpose
This study aimed to investigate the efficacy and safety of using metronomic S-1 adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma (LANPC).Materials and methods
We retrospectively collected data on patients diagnosed with LANPC between January 2016 and December 2021. All patients were treated with induction chemotherapy and concurrent chemoradiotherapy with or without metronomic chemotherapy (MC). Toxicities during MC were recorded. The chi-square test, Kaplan-Meier methods, propensity score matching (PSM), and Cox proportional hazards model were used for statistical analyses.Results
A total of 474 patients were identified, including 64 (13.5%) and 410 (83.5%) patients with or without receiving MC, respectively. Patients who received metronomic S-1 had significantly better 3-year locoregional recurrence-free survival (LRFS) (100% vs. 90.9%, p=0.038), distant metastasis-free survival (DMFS) (98.5% vs. 84.1%, p=0.002), disease-free survival (DFS) (98.4% vs. 77.5%, p < 0.001), and overall survival (OS) (98.0% vs. 87.7%, p=0.008) compared to those without metronomic S-1. The multivariate prognostic analysis revealed that metronomic S-1 was identified as an independent prognostic factor associated with better DMFS (hazard ratio [HR], 0.074; p=0.010), DFS (HR, 0.103; p=0.002) and OS (HR, 0.127; p=0.042), but not in LRFS (p=0.071). Similar results were found using PSM. Common adverse events observed in the metronomic S-1 group included leukopenia, neutropenia, increased total bilirubin, anorexia, rash/desquamation, and hyperpigmentation. All patients with adverse events were grade 1-2.Conclusion
It is worth conducting a randomized controlled trial to assess the effect of metronomic S-1 on survival outcomes and toxicities of LANPC.Free full text
Metronomic S-1 Adjuvant Chemotherapy Improves Survival in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma
Abstract
Purpose
This study aimed to investigate the efficacy and safety of using metronomic S-1 adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma (LANPC).
Materials and Methods
We retrospectively collected data on patients diagnosed with LANPC between January 2016 and December 2021. All patients were treated with induction chemotherapy and concurrent chemoradiotherapy with or without metronomic chemotherapy (MC). Toxicities during MC were recorded. The chi-square test, Kaplan-Meier methods, propensity score matching (PSM), and Cox proportional hazards model were used for statistical analyses.
Results
A total of 474 patients were identified, including 64 (13.5%) and 410 (83.5%) patients with or without receiving MC, respectively. Patients who received metronomic S-1 had significantly better 3-year locoregional recurrence-free survival (LRFS) (100% vs. 90.9%, p=0.038), distant metastasis-free survival (DMFS) (98.5% vs. 84.1%, p=0.002), disease-free survival (DFS) (98.4% vs. 77.5%, p < 0.001), and overall survival (OS) (98.0% vs. 87.7%, p=0.008) compared to those without metronomic S-1. The multivariate prognostic analysis revealed that metronomic S-1 was identified as an independent prognostic factor associated with better DMFS (hazard ratio [HR], 0.074; p=0.010), DFS (HR, 0.103; p=0.002) and OS (HR, 0.127; p=0.042), but not in LRFS (p=0.071). Similar results were found using PSM. Common adverse events observed in the metronomic S-1 group included leukopenia, neutropenia, increased total bilirubin, anorexia, rash/desquamation, and hyperpigmentation. All patients with adverse events were grade 1-2.
Conclusion
It is worth conducting a randomized controlled trial to assess the effect of metronomic S-1 on survival outcomes and toxicities of LANPC.
Introduction
Nasopharyngeal carcinoma (NPC) is indeed a type of malignant tumor that originates from the epithelial cells lining the nasopharynx, with the highest incidence rates reported in Southern China and Southeast Asian countries [1]. NPC is characterized by its unique epidemiology, histopathology, and association with Epstein-Barr virus (EBV) infection, and approximately 95% of NPC patients are diagnosed with non-keratinizing pathological subtypes in endemic areas [2]. Approximately 70%-80% of patients were diagnosed with locoregionally advanced disease at NPC diagnosis (LANPC) [3]. Induction chemotherapy (IC) and concurrent chemoradiotherapy (CCRT) are commonly used as the main treatment strategies for LANPC, especially in those at a higher risk of disease failure [4,5]. Although CCRT can achieve complete clinical remission in more than 90% of patients, approximately 20%-30% experience subsequent disease failure due to minimal residual disease [6-9]. Therefore, adjuvant chemotherapy (AC) is often considered to improve tumor control. However, the addition of AC following CCRT has been a topic of controversy, possibly due to the high toxicity and poor tolerance associated with conventional adjuvant regimens using cisplatin and gemcitabine or cisplatin and fluorouracil [10,11]. Therefore, there is a need to explore suitable therapeutic options to improve survival for those with high-risk recurrence after definitive CCRT.
Metronomic chemotherapy (MC) is an emerging therapeutic approach that involves the administration of low-dose chemotherapy drugs at frequent intervals. This method allows for sustained and active plasma levels of the drugs, resulting in improved tolerability. MC shows promise as a novel treatment strategy for various types of tumors, including breast [12], colorectal [13], and lung cancers [14]. A previous phase 3 trial also showed that the addition of metronomic capecitabine to CCRT significantly improved failure-free survival in those with high-risk LANPC, with a manageable safety profile [15]. S-1, an oral fluoropyrimidine, is a widely used chemotherapy agent for the treatment of gastrointestinal malignancies. In those with advanced NPC or LANPC, S-1 maintenance therapy as a conventional treatment also has been found to improve survival outcomes of patients [16-20]. However, approximately 40% of patients were unable to complete the recommended treatment cycle or require dose adjustment. In the current Chinese Society of Clinical Oncology (CSCO) treatment guidelines for NPC, metronomic capecitabine is recommended as AC in high-risk LANPC [5]. However, we should note that in the metronomic capecitabine trial, there were also 26% of patients could not complete 1 year of capecitabine [15].
Regarding the previous studies on gastric and breast cancers, it is found that the AC with S-1 had better survival outcomes and less severe hand-foot syndrome compared to capecitabine [21-23]. Therefore, S-1 has emerged as a potential candidate for MC in LANPC. In this study, we aimed to investigate the efficacy and safety of using MC with S-1 in LANPC.
Materials and Methods
1. Patients
We retrospectively collected data on patients diagnosed with LANPC between January 2016 and December 2021. Eligibility criteria for this study included the following: histological confirmation of LANPC (stage III-IVa disease based on the eighth edition of the Union for International Cancer Control staging classification); received IC+CCRT; treated with or without MC; adequate hematological, renal, and hepatic function. Those with a history of cancer and those who still had residual tumors in the nasopharynx and/or neck during examination 1 month after CCRT were excluded. The ethics committees for the First Affiliated Hospital of Xiamen University approved this study.
2. Treatment
All patients initially received a minimum of two cycles of IC followed by platinum-based CCRT. TP (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2 on day 1, cisplatin 25 mg/m2 on days 1-3), TPF (docetaxel 75 mg/m2 or nab-paclitaxel 260 mg/m2 on day 1, cisplatin 25 mg/m2 on days 1-3, and S-1 capsules 40 mg/m2 twice a day on day 1-14 or 5-fluorouracil 600-750 mg/m2 per day as a continuous 120 hours infusion), or GP regimens (gemcitabine 1,000 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3) were used for IC in our institution.
All patients received definitive CCRT within 3 weeks after completing IC. Radiotherapy was administered using volumetric modulated arc therapy, and the target volumes were delineated based on the guidelines set by the CSCO for NPC. The primary target volumes included the gross tumor volume (GTV), high-risk clinical target volume (CTV1), and low-risk clinical target volume (CTV2). The prescribed radiation doses for GTV, CTV1, and CTV2 were 70.29 Gy, 62.04 Gy, and 56.10 Gy, respectively. The total dose was delivered in 33 fractions given five times per week. Cisplatin (80 mg/m2 on days 1-3) or lobaplatin (30 mg/m2 on day 1) were used for a total of two cycles during radiotherapy.
After confirming the absence of any remaining tumor in the locoregional area 1 month following CCRT, MC using S-1 was initiated within 2 weeks. The decision-making of the administration of MC was mainly according to physician-specific preference. S-1 was administered orally twice daily and the dosage of S-1 was 40 mg regardless of the body surface area (BSA) of patients, and uninterrupted for 1 year.
3. Adverse events assessment
Predefined and commonly observed adverse events associated with S-1 were monitored throughout the treatment. Adverse events were assessed and classified according to the Common Terminology Criteria for Adverse Events (CTCAE), ver. 3.0. In the S-1 group, blood tests and adverse events were evaluated every 2 weeks.
4. Follow-up
In this study, follow-up survival data were collected retrospectively by analyzing medical records. All patients underwent regular follow-up investigations, including magnetic resonance imaging, chest computed tomography scanning, and abdominal sonography every 3 months for at least 3 years, and then every 6 months up to 5 years. Immediate imaging studies were conducted for patients showing signs of disease progression. The primary endpoint of the study was disease-free survival (DFS), which was defined as the time from the date of diagnosis to the confirmation of locoregional recurrence (LRR) or distant metastasis (DM). Secondary endpoints included locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS), and safety. The duration of OS was defined as the time from the day of diagnosis to the date of death from any cause or the last known date when the patient was alive. LRFS referred to the time from diagnosis to the date of LRR, while DMFS referred to the time from diagnosis to the date of DM.
5. Statistical analysis
The chi-square test or Fisher’s exact test was employed to examine the differences between the two groups. Kaplan-Meier estimates were used to obtain survival curves, and the difference between the curves was confirmed using a log-rank test. A 1:1 propensity score matching (PSM) was used to minimize the effects of potential confounding factors. The Cox proportional hazards model was used to analyze independent prognostic factors associated with survival outcomes. All statistical analyses were conducted with R program (ver. 4.1.1, R Foundation for Statistical Computing, Vienna, Austria) or SPSS ver. 26.0 statistical software (IBM Corp., Armonk, NY). A p-value of < 0.05 was considered statistically significant.
Results
1. Patient baseline characteristic
A total of 474 patients were included in the analysis (Table 1). Of these patients, 13.5% (n=64) received metronomic S-1 and all had completed 1 year of MC. The median BSA was 1.66 m2 (range, 1.38 to 2.24 m2) in those with metronomic S-1 treatment, including 11 (17.2%) who had BSA 1.25-1.49 m2 and 53 (82.8%) who had BSA ≥ 1.5 m2. The median relative dose intensity (RDI) (the ratio of actual dose intensity to planned dose intensity) for metronomic S-1 was 100% (range, 88.4% to 100%). The majority of patients were male (n=340, 71.7%) and World Health Organization (WHO) III subtype (n=411, 86.7%). Regarding cancer staging, 216 (45.6%) and 258 (54.4%) patients had stage III and IV diseases, respectively. These were 395 patients who had available EBV-DNA levels before treatment, the median EBV-DNA level was 757 IU/mL. The cutoff point of EBV-DNA was 430 IU/mL according to our previous study [24]. There were 188 (47.6%) and 207 (52.4%) patients who had EBV-DNA < 430 IU/mL and ≥ 430 IU/mL, respectively. Patients with metronomic S-1 treatment were more likely to be younger age (p=0.005), WHO III subtype (p=0.029), and received gemcitabine-based IC (p < 0.001). A total of 50 pairs of patients were completely matched using PSM (Table 1).
Table 1.
Patient baseline characteristics before and after propensity score matching
| Variable | Before PSM | After PSM | ||||||
|---|---|---|---|---|---|---|---|---|
| No. | No S-1 | S-1 | p-value | No. | No S-1 | S-1 | p-value | |
| Age (yr) | ||||||||
| 226 | 185 (45.1) | 41 (64.1) | 0.005 | 62 | 31 | 31 | 1 | |
| 248 | 225 (54.9) | 23 (35.9) | 38 | 19 | 19 | |||
| Sex | ||||||||
| 340 | 298 (72.7) | 42 (65.6) | 0.244 | 62 | 31 | 31 | 1 | |
| 134 | 112 (27.3) | 22 (34.4) | 38 | 19 | 19 | |||
| Smoking history | ||||||||
| 253 | 215 (52.4) | 38 (59.4) | 0.301 | 60 | 30 | 30 | 1 | |
| 221 | 195 (47.6) | 26 (40.6) | 40 | 20 | 20 | |||
| Alcohol use | ||||||||
| 354 | 305 (74.4) | 49 (76.6) | 0.710 | 78 | 39 | 39 | 1 | |
| 120 | 105 (25.6) | 15 (23.4) | 22 | 11 | 11 | |||
| Histology | ||||||||
| 63 | 60 (14.6) | 3 (4.7) | 0.029 | 0 | 0 | 0 | 1 | |
| 411 | 350 (85.4) | 61 (95.3) | 100 | 50 | 50 | |||
| Clinical stage | ||||||||
| 216 | 190 (46.3) | 26 (40.6) | 0.393 | 53 | 30 (60.0) | 23 (46.0) | 0.161 | |
| 258 | 220 (53.7) | 38 (59.4) | 47 | 20 (40.0) | 27 (54.0) | |||
| T category | ||||||||
| 63 | 49 (12.0) | 14 (21.9) | 0.030 | 16 | 8 | 8 | 1 | |
| 411 | 361 (88.0) | 50 (78.1) | 84 | 42 | 42 | |||
| N category | ||||||||
| 164 | 144 (35.1) | 20 (31.3) | 0.545 | 30 | 15 | 15 | 1 | |
| 310 | 266 (64.9) | 44 (68.8) | 70 | 35 | 35 | |||
| EBV level (IU/mL) (n=395) | ||||||||
| 188 | 162 (48.6) | 26 (41.9) | 0.331 | 44 | 22 | 22 | 1 | |
| 207 | 171 (51.4) | 36 (58.1) | 56 | 28 | 28 | |||
| IC regimens | ||||||||
| 415 | 369 (90.0) | 46 (71.9) | < 0.001 | 86 | 43 | 43 | 1 | |
| 59 | 41 (10.0) | 18 (28.1) | 14 | 7 | 7 | |||
Values are presented as number (%). EBV, Epstein-Barr virus; IC, induction chemotherapy; N, nodal; PSM, propensity score matching; T, tumor; WHO, World Health Organization.
2. Survival outcomes
The median follow-up was 37.5 months (range, 5 to 90 months). A total of 90 patients had disease recurrence, 12 patients had LRR alone, 25 patients had LRR+DM, and 53 patients had DM alone. The median time for LRR and DM was 22.8 and 14.6 months, respectively. The 3-year LRFS, DMFS, DFS, and OS were 92.2%, 86.2%, 80.5%, and 89.1%, respectively.
Patients who received metronomic S-1 had significantly better survival outcomes than those without metronomic S-1. The 3-year LRFS, DMFS, DFS, and OS between those with and without metronomic S-1 was 100% (95% confidence interval [CI], 100% to 100%) vs. 90.9% (95% CI, 87.8% to 94.1%) (p=0.039) (Fig. 1A), 98.5% (95% CI, 95.3% to 100%) vs. 84.1% (95% CI, 80.4% to 88.1%) (p=0.002) (Fig. 1B), 98.4% (95% CI, 95.3% to 100%) vs. 77.5% (95% CI, 73.2% to 82.1%) (p < 0.001) (Fig. 1C), and 98.0% (95% CI, 94.2% to 100%) vs. 87.7% (95% CI, 84.3% to 91.4%) (p=0.008) (Fig. 1D). Similar trends were found between those with and without metronomic S-1 treatment regarding DMFS (p=0.027), DFS (p=0.020), and OS (p=0.038) after PSM. However, no significant difference in LRFS was found between the two groups after PSM (p=0.100) (Fig. 2).
The locoregional recurrence-free survival (A), distant metastasis-free survival (B), disease-free survival (C), and overall survival (D) between those with and without metronomic S-1 treatment before propensity score matching.
The locoregional recurrence-free survival (A), distant metastasis-free survival (B), disease-free survival (C), and overall survival (D) between those with and without metronomic S-1 treatment after propensity score matching.
In patients who received metronomic S-1 treatment, similar LRFS (p=0.724) and DFS (p=0.150) were found between those with BSA 1.25-1.49 m2 and BSA ≥ 1.5 m2. However, the 3-year DMFS was 90.9% (95% CI, 75.4% to 100%) and 100% (95% CI, 100% to 100%) between those with BSA 1.25-1.49 m2 and BSA ≥ 1.5 m2 (p=0.031). In addition, the 3-year OS was 88.9% (95% CI, 70.6% to 100%) and 100% (95% CI, 100% to 100%) between those with BSA 1.25-1.49 m2 and BSA ≥ 1.5 m2 (p=0.033). There were similar LRFS (p=0.777), DMFS (p=0.700), DFS (p=0.633), and OS (p=0.768) between those with RDI < 100% and RDI=100%.
In those receiving metronomic S-1, one patient had a recurrence in retropharyngeal lymph nodes after 22 months of completing 1 year of metronomic S-1 treatment. The patient continued to receive metronomic S-1 treatment until now, and the recurrent lymph nodes in the retropharyngeal region have continued to complete response (Fig. 3). In addition, another patient had bone metastasis after 5 months of completing 1 year of metronomic S-1, and the patient died of disease progression 4 months after bone metastasis.
Retropharyngeal lymph node recurrence in a patient receiving metronomic S-1 treatment (A, retropharyngeal lymph node enlargement before induction chemotherapy; B, complete response to retropharyngeal lymph node after 3 months of concurrent chemoradiotherapy; C, retropharyngeal lymph node recurrence after 22 months of completing 1 year of S-1 treatment; D, complete response to retropharyngeal lymph node recurrence after reusing of metronomic S-1 treatment) (orange arrow).
3. Prognostic analysis
In the Cox proportional hazards model analysis (Table 2), it was determined that metronomic S-1 was an independent prognostic factor associated with better DMFS (hazard ratio [HR], 0.074; 95% CI, 0.010 to 0.536; p=0.010), DFS (HR, 0.103; 95% CI, 0.025 to 0.421; p=0.002) and OS (HR, 0.127; 95% CI, 0.017 to 0.926; p=0.042). However, metronomic S-1 was not associated with LRFS using multivariate prognostic analysis (HR, 0.160; 95% CI, 0.022 to 1.168; p=0.071). Age, histology, smoking history, and EBV-DNA levels were also identified as independent prognostic factors associated with survival outcomes. Similar results were obtained using PSM (Table 3).
Table 2.
Multivariate prognostic analysis of independent prognostic factors associated with survival outcomes before propensity score matching
| Variable | LRFS | DMFS | DFS | OS | ||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
| Age (yr) | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 0.797 (0.412-1.543) | 0.501 | 1.741 (1.039-2.920) | 0.035 | 1.260 (0.821-1.932) | 0.290 | 1.660 (0.955-2.886) | 0.072 | |
| Sex | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 1.016 (0.438-2.354) | 0.971 | 0.706 (0.354-1.410) | 0.324 | 0.774 (0.435-1.375) | 0.381 | 0.591 (0.247-1.417) | 0.239 | |
| Smoking history | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 0.830 (0.359-1.921) | 0.663 | 0.965 (0.512-1.819) | 0.913 | 0.907 (0.535-1.540) | 0.718 | 2.374 (1.355-4.162) | 0.003 | |
| Alcohol use | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 1.014 (0.431-2.383) | 0.975 | 1.213 (0.662-2.222) | 0.532 | 1.248 (0.751-2.074) | 0.393 | 0.648 (0.346-1.213) | 0.175 | |
| Histology | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 0.543 (0.240-1.229) | 0.143 | 0.723 (0.378-1.382) | 0.326 | 0.540 (0.325-0.897) | 0.017 | 0.907 (0.460-1.787) | 0.777 | |
| T category | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 1.972 (0.584-6.659) | 0.274 | 1.199 (0.595-2.416) | 0.611 | 1.285 (0.683-2.416) | 0.437 | 2.031 (0.841-4.906) | 0.115 | |
| N category | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 1.283 (0.593-2.776) | 0.526 | 1.827 (0.938-3.561) | 0.077 | 1.448 (0.866-2.422) | 0.158 | 1.644 (0.860-3.145) | 0.133 | |
| EBV-DNA level (IU/mL) | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 2.055 (0.922-4.579) | 0.078 | 5.702 (2.785-11.675) | < 0.001 | 3.392 (2.014-5.712) | < 0.001 | 3.423 (1.680-6.972) | < 0.001 | |
| Metronomic S-1 | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 0.160 (0.022-1.168) | 0.071 | 0.074 (0.010-0.536) | 0.010 | 0.105 (0.026-0.430) | 0.002 | 0.122 (0.017-0.891) | 0.038 | |
| IC regimens | ||||||||
| 1 | 1 | 1 | 1 | |||||
| 1.399 (0.324-6.040) | 0.653 | 0.666 (0.297-1.494) | 0.324 | 0.850 (0.404-1.791) | 0.670 | 1.199 (0.282-5.098) | 0.806 | |
CI, confidence interval; DFS, disease-free survival; DMFS, distant metastasis-free survival; EBV, Epstein-Barr virus; HR, hazard ratio; IC, induction chemotherapy; LRFS, locoregional recurrence-free survival; N, nodal; OS, overall survival; T, tumor; WHO, World Health Organization.
Table 3.
Multivariate prognostic analysis of the impact of metronomic S-1 on survival outcomes after propensity score matching
| Variable | HR | 95% CI | p-value |
|---|---|---|---|
| LRFS | |||
| 0.175 | 0.027-1.155 | 0.070 | |
| DMFS | |||
| 0.058 | 0.004-0.934 | 0.045 | |
| DFS | |||
| 0.112 | 0.017-0.734 | 0.022 | |
| OS | |||
| 0.057 | 0.005-0.703 | 0.025 |
CI, confidence interval; DFS, disease-free survival; DMFS, distant metastasis-free survival; HR, hazard ratio; LRFS, locoregional recurrence-free survival; OS, overall survival.
4. Adverse events and dose adjustment
Leukopenia (n=16, 25.0%), neutropenia (n=11, 17.2%), total bilirubin increased (n=15, 23.4%), anorexia (n=17, 26.5%), rash/desquamation (n=10, 15.7%), and hyperpigmentation (n=14, 21.9%) were the most common adverse events in the 64 patients receiving metronomic S-1 (Table 4). However, all patients with adverse events were grade 1-2 and none patients had grade 3 or above adverse events. Moreover, 9.4% (n=6) and 1.6% (n=1) of patients had grade 1 and 2 hand-foot syndrome, respectively. There were eight patients (12.5%) who had dose adjustments and returned to their original dose after symptomatic relief. The median days for dose adjustments were 33.5 days (range, 22 to 85 days). The dosage of S-1 was decreased by one level in two patients and by two levels in another six patients.
Table 4.
Adverse events during metronomic S-1 chemotherapy
| Adverse event | Grade 1 | Grade 2 | Grade 3 | Grade 4 |
|---|---|---|---|---|
| Leukopenia | 13 (20.3) | 3 (4.7) | 0 | 0 |
| Neutropenia | 9 (14.1) | 2 (3.1) | 0 | 0 |
| Thrombocytopenia | 3 (4.7) | 0 | 0 | 0 |
| Anemia | 5 (7.8) | 1 (1.6) | 0 | 0 |
| Total bilirubin increased | 10 (15.6) | 5 (7.8) | 0 | 0 |
| Aspartate aminotransferase increased | 2 (3.1) | 1 (1.6) | 0 | 0 |
| Creatinine increased | 0 | 0 | 0 | 0 |
| Nausea | 6 (9.4) | 0 | 0 | 0 |
| Vomiting | 0 | 0 | 0 | 0 |
| Anorexia | 15 (23.4) | 2 (3.1) | 0 | 0 |
| Fatigue | 5 (7.8) | 0 | 0 | 0 |
| Rash/Desquamation | 9 (14.1) | 1 (1.6) | 0 | 0 |
| Hyperpigmentation | 12 (18.8) | 2 (3.1) | 0 | 0 |
| Diarrhea | 3 (4.7) | 1 (1.6) | 0 | 0 |
| Mucositis/Stomatitis | 2 (3.1) | 2 (3.1) | 0 | 0 |
| Hand-foot syndrome | 6 (9.4) | 1 (1.6) | 0 | 0 |
Values are presented as number (%).
Discussion
MC is a novel approach in the treatment of LANPC that has shown promising results in improving patient survival with a manageable safety profile. This therapy involves the continuous administration of low-dose oral chemotherapy over an extended period. In this study, we explored whether metronomic S-1 is also a potential candidate treatment option for LANPC. Our study adds to the current knowledge regarding MC using S-1 and suggests that it is worth conducting a randomized controlled trial to assess the effect of metronomic S-1 on survival outcomes and toxicities of LANPC.
The effect of MC has been confirmed in several tumors, including breast [12], colorectal [13], and lung cancers [14]. A recent study conducted by Huang et al. [25] investigated the use of conventional oral chemotherapy for a minimum duration of 6 months in patients with NPC who showed persistent detection of EBV-DNA during follow-up. The chemotherapy agents included capecitabine, S-1, tegafur, or a combination of tegafur and uracil. The study findings revealed that oral chemotherapy significantly prolongs DFS. However, it is worth noting that despite this treatment, 88.6% of patients experienced disease recurrence, and 60.8% of patients succumbed to the disease in the oral chemotherapy group. These results imply that the currently available conventional oral treatment regimens are still insufficient in effectively controlling tumor growth. Therefore, it is necessary to explore more aggressive treatment options for high-risk NPC patients. Several retrospective and prospective studies have explored the value of MC in NPC. The study by Twu et al. [26] using MC with tegafur and uracil for 1 year (2 capsules twice daily) in patients with residual EBV-DNA after radiotherapy, and the study found that MC could decrease distant failure and improve OS but not in LRR. The 5-year OS was 71.6% and 28.7% in those with and without MC, respectively. However, only 2.5% of patients received IC+CCRT in the above study. In the metronomic capecitabine trial, 77% of patients received IC and all patients received CCRT [15]. A previous study also showed metronomic capecitabine is a cost-effective strategy for LANPC [27]. In the current National Comprehensive Cancer Network (NCCN) guidelines, there is no recommended therapy for MC in NPC [28]. However, in the CSCO guidelines, it is recommended that metronomic capecitabine be used for high-risk LANPC [5]. Several studies in other types of cancers have found that AC with S-1 has better outcomes and lower toxicity than capecitabine [21,23]. In those with head and neck cancers, AC with S-1 also significantly improves OS compared to tegafur and uracil [29]. Based on the above results, S-1 may also be a suitable regimen of MC for LANPC.
In head and neck cancers, several studies have shown that the administration of conventional chemotherapy or MC with S-1 was associated with better survival outcomes [30,31]. In patients with advanced NPC or LANPC, S-1 maintenance therapy as a conventional treatment also has been found to improve survival outcomes of patients [16-20]. However, there were approximately 40% of patients were unable to complete the recommended treatment cycle or required dose adjustment [16-20]. In our study, all patients completed 1 year of metronomic S-1, and only 12.5% of patients had dose adjustment. Our study showed that low-dose MC has good tolerance. Moreover, the 3-year DMFS (98.5% vs. 84.1%), DFS (98.4% vs. 77.5%), and OS (98.0% vs. 87.7%) were significantly improved by using MC with S-1. To the best of our knowledge, this study represented the first investigation into the efficacy and safety of MC with S-1 in LANPC, and we found promising survival outcomes and manageable safety profiles in this population. Our study added the current evidence of MC in LANPC and added a new regime in this setting.
In the metronomic capecitabine trial, it was found that 17% of patients had grade 3-4 adverse reactions, of which 9% were hand-foot syndrome and 6% were leukopenia or neutropenia [15]. In addition, only 74% of patients completed 1 year of capecitabine. The using of AC with S-1 in NPC or head and neck cancers also showed a treatment completion rate was approximately 60% [16-20,31]. In those with head and neck cancers, Furusaka et al. [31] found that survival was significantly better in those with consecutive daily low-dose S-1 therapy, and only limited patients had dose adjustment or discontinued (17.3% of patients with dose reduction or discontinuation for 2 years, and most of them were due to disease recurrence or secondary cancers). In contrast to conventional chemotherapy, which involves administering drugs at a maximum tolerated dose, low-dose MC involves the frequent and regular administration of chemotherapeutic agents at significantly lower and less toxic doses over extended periods. This approach has been shown to have superior tolerability. There is still no study that assessed the clinical efficacy and adverse reactions between S-1 and capecitabine in NPC. However, several previous studies in other cancers have shown that AC with S-1 had less severe hand-foot syndrome compared to capecitabine-based AC [21-23]. In our study, no patients had grade 3-4 adverse reactions and only 12.5% of patients had dose adjustment. Moreover, only 11.0% of patients had grade 1 or 2 hand-foot syndrome. Therefore, metronomic S-1 had a manageable safety profile in LANPC.
The underlying mechanisms through which MC with S-1 exerts its effects on NPC could be attributed to several potential factors [32]. Firstly, S-1 is a 5-fluorouracil prodrug that can effectively inhibit the growth and division of tumor cells. Secondly, MC has been shown to exert anti-angiogenic effects in human cancers. S-1 has been discovered to inhibit the production of vascular endothelial growth factor, which is a crucial mediator of angiogenesis, thereby restricting the blood supply to the tumor and impeding its growth. Furthermore, MC with S-1 has been associated with immunomodulatory effects, which can enhance the overall antitumor immune response and contribute to eliminating cancer cells. Moreover, the continuous low-dose administration of S-1 leads to cumulative cytotoxic effects on tumor cells. Finally, MC appears to facilitate better inhibition of cancer stem cells compared with conventional chemotherapy and prevents the development of drug resistance.
Severe limitations should be acknowledged in this study. Firstly, it is important to acknowledge the inherent bias present in retrospective studies and the toxicities of MC tend to be underestimated in retrospective studies. Secondly, our study had a small sample size, emphasizing the need for a large prospective study to validate the effectiveness of metronomic S-1 in LANPC. Third, the underlying mechanisms of metronomic S-1 were not investigated in this study. In addition, the dosage of S-1 was not dependent on the BSA but was 40 mg twice a day among all patients. However, our results indicated that patients with higher BSA did not exhibit inferior survival outcomes compared to those with lower BSA. Finally, all the analyses in this study only apply to patients in the epidemic areas of NPC in China, and they cannot be considered representative of the entire NPC population, especially in non-endemic areas such as the United States. These may be the main reasons why MC is recommended in the CSCO guidelines but not in the NCCN guidelines.
In conclusion, our study suggests that it is worth conducting a randomized controlled trial to assess the effect of metronomic S-1 on survival outcomes and toxicities of LANPC. Additional studies are necessary to further validate the underlying mechanisms of metronomic S-1 in patients with LANPC.
Footnotes
Ethical Statement
This study was approved by the Institutional Review Boards of the First Affiliated Hospital of Xiamen University and informed consent was obtained from the study participants before study commencement (No. 3502Z20224ZD1005).
Author Contributions
Conceived and designed the analysis: Yu YF, Zhou R, Wu SG.
Collected the data: Yu YF, Wu P, Zhou R, Wu SG.
Contributed data or analysis tools: Yu YF, Wu P, Zhou R, Wu SG.
Performed the analysis: Wu P, Zhou R, Wu SG.
Wrote the paper: Yu YF, Wu P.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
References
Articles from Cancer Research and Treatment : Official Journal of Korean Cancer Association are provided here courtesy of Korean Cancer Association
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