Maintenance chemotherapy using S-1 following definitive chemoradiotherapy in patients with N3 nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is an endemic malignancy in South China that is highly sensitive to both radiotherapy (RT) and chemotherapy [1]. Due to its being asymptomatic in early stages and prone to lymph node metastasis,about 70% of NPC presents as local advanced disease or regional lymph node metastasis, and definitive concurrent chemoradiotherapy (CRT) is recommended as the standard of care [1]. The overall survival (OS) rate of advanced NPC patients treated with CRT is high, up to 80% at 5-years [2]. However, the 8-year OS rate decreases steeply to about 50% when patients were originally diagnosed with N3 NPC (N3-NPC); defined as cervical lymph nodes larger than 6 cm and/or extension below the caudal border of the cricoid cartilage (regardless of laterality) and are considered to have the highest metastatic risk [3].

Despite of the fact that several high level studies had verified that compared to concurrent chemoradiotherapy (CCRT) alone, adjuvant chemotherapy (AC) following CCRT (CCRT-AC), which is hypothesized to eradicate micrometastases, had not achieved survival benefits in advanced NPC [1]; although it had been thought to benefit survival of N3-NPC patients [4, 5]. However, intensive AC should be conducted cautiously due to potential patient intolerance to chemotherapy that can result from the acute toxicity of CCRT [6]. Thus, CCRT that followed neoadjuvant chemotherapy (NAC-CCRT) rather than CCRT-AC was thought to be a more feasible and effective strategy of treatment [7]. However, even treated with NAC combined with concurrent chemotherapy (CC), distant metastasis (DM) continuous to be the main cause of treatment failure [7]. Therefore, developing novel chemotherapy strategies to decrease DM is the foremost management objective to improve survival of N3-NPC patients.

Maintenance chemotherapy (MC), one of the chemotherapy strategies that includes continuation and switch maintenance, aims to prolong the duration of the response and maintain a quality of life that generally uses a well-tolerated, single-agent regimen of chemotherapy as continued therapy [8]. MC was originated for hematologic malignancies and applied subsequently for several metastatic solid tumors, such as lung and colorectal cancer [8‐10]. MC has been reported to achieve a satisfactory high response rate and superior survival in NPC patients with distant metastasis (DM) as well [11, 12]. However, its efficacy in a curative setting has rarely been reported. To the best of our knowledge, the efficacy of MC after definitive CRT in N3-NPC patients, who were prone to develop DM and hypothesized to benefit from MC, has not been reported.

The drug S-1 is a novel oral fluoropyrimidine derivative consisting of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo), mixed at the molar ratio of 1:0.4:1. It is designed to enhance the clinical utility of an oral fluoropyrimidineand is associated with low gastrointestinal toxicity [13]. Several researches have demonstrated that S-1 alone or in combination with other chemotherapy drugs yielded an excellent survival benefit in NPC patients as first or second line of chemotherapy [5, 14, 15]. Furthermore, S-1 is considered an appropriate regimen drug for MC owing to its convenience for outpatient oral administration, tolerable toxicity, favorable antitumor activity and improved survival [16, 17]. Based on these reports, we have recommend that N3-NPC patients proceed to maintenance chemotherapy using S-1 (MC-S1) following definitive CRT using intensity modulated radiation therapy (IMRT) technology in our center since 2014. This study reviews our experience with MC-S1 following CRT in N3-NPC patients.

Hong et al. had reported that MC with weekly 5-fluorouracil, leucovorin was effective and had minimal side-effects for treating metastatic NPC [11]. However, the efficacy of MC in patients treated with definitive treatment has rarely been reported. There have been several reports that argued that AC following definitive CRT could not improve the survival of NPC patients [21], questioning the effectiveness of MC in NPC following definitive RT. Fortunately, the results of the present polit study are quite encouraging albeit its small sample size and retrospective non-randomized nature. Compared with non-MC patients, MC-S1 achieved superior survival benefits for both OS and DMFS. This result suggests that MC-S1 might have a greater role in treating N3-NPC patients and deserves further clinical study.

Besides efficacy, the toxicity and tolerability are important factors in selecting a regimen for making MC decision. In the present study, a total of 366 cycles of MC were delivered to 21 patients with a median of 24 cycles (3–34 cycles). Besides skin hyperpigmentation, hematological toxicities were the most common in response to MC. The most sever toxicity were grade 2 leukopenia which were preventable with granulocyte colony stimulating factor treatment. Only three patients were required to reduce the dose of MC and were unwilling to continue with their therapy due to the grade 2 leukopenia. The gastrointestinal toxicities and stomatitis are other commonly reported toxicities of MC with S-1 [5]. However, as demonstrated in this study, only one patient (4.5%) encountered grade II gastrointestinal toxicities and no nephrotoxicity was observed. All these mild toxicities indicated that the S-1 was an appropriate and tolerable regimen for MC.

Currently, the best dose intensity and duration of MC-S1 for N3-NPC is not determined. Although we were unable to analyze the impact of various MC cycles on prognosis due to the limited number of patients enrolled in this study, a retrospective study of MC-S1 reported by Misato Hirai [22] for advanced squamous cell carcinoma of the head and neck (SCCHN) may serve as a reference. In that study, the clinical records of 89 patients with SCCHN who underwent adjuvant chemotherapy with S-1 were investigated. They found that S-1 administration for periods of 24 months or longer showed significantly lower hazard ratios (HRs) than administration for 0–12 months. Furthermore, our previous studies had found that most (73%) of metastasis occurred within 2-years after RT with the probability of metastasis after 2-years less than 25% [23]. Therefore, if we could control metastasis within the first 2-years after CRT by means of MC, there is about a 70% probability of DMFS with improved OS. Based on these conclusions, we believe that at least one year and at best a 2-year duration of MC-S1 may be an effective MC to decrease the patient’s DMFS. However, one notable finding of the current study was that both patients who had ≤4 cycles of MC developed distant metastasis a short time after MC suspension, whereas all 19 patients who received > 5 cycles of MC had disease free survival. The results suggest that at least 5 cycles of MC with S-1 were needed to achieve a survival improvement by MC. Certainly, in addition to the minimum required cycles of MC, the maximum number of cycles of MC are also of concern to clinicians. Unfortunately, because MC is usually adopted as a palliative treatment for patients with advanced cancer, the appropriate maximum number of cycles of MC has not been established, even in cancers like lung and rectal with skilled application of MC. In this study, as of the last follow-up date, no significant difference of DMFS were observed among the 19 patients with > 5 cycles, although they had various numbers of MC cycles. It seemed as if five cycles of MC were appropriate, however, because of the limitation of the number of enrolled cases, especially patients who accepted five cycles of MC, we will require more research.

Several clinical studies had been conducted on the different strategies of dosing schedules and intensity of chemotherapy using S-1, including four consecutive weeks every 6 weeks (regimen4–6) [5, 24] 2–3 weeks [14] and 2–4 weeks [16]. Up to the present, few studies have been conducted to optimize the treatment schedule for S-1. The 2–4 week [16] regimen had been reported to have mild toxicity and been chosen for the present study considering the poor compliance of adjuvant chemotherapy after radiotherapy for NPC patients [6]. The current MC regimen had resulted in superior survival benefit and mild toxicity and seemed to be a good selection for N3 NPC patients.

There are certain limitations to the present study, such as the retrospective design, disunified chemotherapy regimens, the unbalanced number of NAC cycles between the two groups, the small sample enrolled and the short surveillance time. Due to these limitations, the results of our investigation must be interpreted with caution.

MC-S1 in N3-NPC following IMRT achieved superior survival to the non-MC group. The toxicities of MC were mild and tolerable. The retrospective nature of the current study serves as a limitation; thus, further clinical trials are required to evaluate the efficacy of MC-S1 in N3-NPC patients.