Efficacy and feasibility of ambulatory treatment-based monthly nedaplatin plus S-1 in definitive or salvage concurrent chemoradiotherapy for early, advanced, and relapsed esophageal cancer

A combination of radiation therapy (RT) with chemotherapy for esophageal cancer in randomized trials has been used to try to improve local control and survival, and cisplatin (CDDP) and 5-FU seem to be the key drugs in these treatment protocols [17‐19]. NDP is a platinum derivative that was developed with the aim of reducing renal toxicity while maintaining the effectiveness of CDDP. In an in vivo study, a combination of NDP and 5-FU has been shown to be as effective as a combination of CDDP and 5-FU. In a clinical study, combination chemotherapy using NDP and 5-FU has been reported to be a safe and effective method for treating advanced esophageal cancer. Based on these facts, when the patient’s renal or cardiac function was bad, we had given NDP in place of CDDP since 2000 (i.e. NDP plus 5-FU regimen which is different from NDP plus S1 of this study), because NDP has less renal toxicity than CDDP and because the vigorous hydration needed to safely protect against cisplatin-related nephrotoxicity might affect cardiac function. Radiation combined with NDP and 5-FU was a safe and effective method for treating esophageal cancer. In our previous study [4], a combination of NDP plus 5-FU was comparable to that of CDDP plus 5-FU in survival, loco-regional and distant control, clinical response, and both acute and late toxicity, despite the NDP group had significantly more stage IVB patients (more than 50 %) than did the CDDP group. This chemotherapy regimen was NDP/5-FU and not NDP/S1 as in the present cohort.

The current guidelines such as those of the European Society for Medical Oncology (ESMO) [20] and National Comprehensive Cancer Network (NCCN) (Version 3. 2015) regard carboplatin/paclitaxel as an alternative non-fluoropyrimidine regimen. In many countries, this treatment is considered a standard alternative treatment for concurrent CRT as described in the CROSS (Chemoradiotherapy for Oesophageal Cancer Followed by Surgery Study) trials [21]. Additionally, oral capecitabine can be used as an alternative to 5-FU according to NCCN guidelines. However, in Japan, carboplatin, paclitaxel, and oral capecitabine are currently not included by insurance adaptation in CRT for esophageal cancer with definitive intent. On the other hand, both S1 and NDP are within insurance coverage for esophageal cancer. The costs of NDP plus S1 in Japan are at least comparable to other drug regimens such as capecitabine plus CDDP or carboplatin plus paclitaxel. The carboplatin plus taxane regimen may be also useful as an alternative in terms of efficacy and toxicity in the definitive CRT, although this regimen has been tested mainly in the neoadjuvant setting [21].

Tanaka et al. [22] performed a phase I dose-escalation study on docetaxel, NDP, and S-1 chemotherapy without RT for advanced esophageal carcinoma with T3-4 tumors and/or M1 staging and esophageal carcinoma with cervical lymph node metastasis. There are no other clinical studies published on NDP treatment in combination with S-1.

Minsky et al. [23] reported the activity and toxicity of definitive CRT with 5-FU and CDDP in 218 patients with T1-4/N0-1 esophageal cancer. Their chemotherapy consisted of 5-FU at a dose of 1,000 mg/m²/day on days 1–4, 29–32, 57–60, and 85–88 plus CDDP at a dose of 75 mg/m² on days 1, 29, 57, and 85. In 109 patients with standard dose of 50.4 Gy in 28 fractions, acute grade 3–5 toxicity was seen in 77/109 patients (71 %) and late grade 3–4 toxicity was seen in 37/99 patients (37 %) [23]. In their study, the 2-year OS was 40 %, median survival time was 18.1 months, and loco-regional failure plus residual was 52 % [23]. Ishikura et al. [24] assessed the long-term toxicity after definitive CRT for 139 patients with esophageal squamous cell carcinoma. The CRT consisted of two cycles of CDDP 40 mg/m² on days 1 and 8, and continuous infusion of 5-FU 400 mg/m²/d on days 1 to 5 and 8 to 12, repeated every 5 weeks with concurrent radiotherapy of 60 Gy in 30 fractions. Of 78 patients with complete remission, two patients died as a result of acute myocardial infarction and grade 3–4 late toxicities occurred with pericarditis in 10.3 %, heart failure in 2.6 %, pleural effusion in 10.3 %, and radiation pneumonitis in 3.8 % of the patients [24]. These rates were almost equal to ours (Table 3), although these comparisons might not be valid because their inclusion criteria were different from ours.

The radiation doses to the fresh cases were different from those administered to recurrent tumors in our institution because we wanted to determine promptly whether there are residual tumors and salvage surgery for them should be adapted after definitive CRT, and we stopped it in the 50–50.4 Gy dose range. The limitations of this report were that this is a retrospective review and that the treatments were not relatively homogeneous in terms of including older patients and patients in both definitive and salvage settings.

Most importantly, NDP plus S-1 can be administered on an outpatient basis, whereas CDDP plus 5-FU, which was used as the standard drug combination in CRT, requires hospitalization of at least 4-5 days per cycle during 5-FU administration. In this retrospective research, 30 % of the patients were treated as inpatients, at least transiently. Twelve of these patients (13 %) were hospitalized up to 2 weeks and 10 patients (11 %) were hospitalized throughout RT. The majority of the admitted patients were admitted because their homes were too far away from the hospital, so it was difficult to commute, or because of severe symptoms of esophageal stenosis by the primary tumor.