Even though postoperative adjuvant chemotherapy was considered the standard of care for esophageal cancer patients in Japan, preoperative treatment still predominated in Western countries due to the invasiveness of esophageal cancer surgery and the attending high morbidity [14]. Therefore, the positive role of preoperative chemotherapy regarding survival in patients with esophageal cancer compared with surgery alone or postoperative chemotherapy remained controversial. Details regarding this controversy are described in the next subchapter. The sixth JEOG RCT was, therefore, initiated to determine the optimal perioperative timing of chemotherapy in patients with locally advanced ESCC, that is, before or after surgery. In this study (JCOG9907, 2000–2006), eligible patients with clinical stage II or III, excluding T4, SCC were randomly assigned to undergo surgery either followed (Post group) or preceded (Pre group) by chemotherapy (80 mg/m² cisplatin on day 1 plus 800 mg/m² 5-FU, continuous infusion (c.i.) over days 1–5 × 2 courses with a 3-week interval). Progression-free survival, the primary endpoint, did not reach the discontinuation boundary, but OS in the Pre group (164 patients) was superior to that in the Post group (166 patients) (p = 0.01). Updated analyses showed that the 5-year OS was 43 % in the Post group and 55 % in the Pre group (hazard ratio, 0.73; 95 % confidence interval, 0.54–0.99; p = 0.04) [15] (Fig. 11.5a, b). Though renal dysfunction after surgery in the Pre group was slightly higher than that in the Post group, preoperative chemotherapy did not increase the risk of complications or hospital mortality after surgery [16]. There are three possible reasons for the better preoperative chemotherapy results. First, downstaging was achieved in some patients by preoperative chemotherapy. While the proportion of the patients with clinical stage II disease was similar in the two groups, the proportion with pathologic stage II or lower was greater in the Pre group. Second, complete resection (R0) was slightly more frequent in the Pre group than the Post group. Third, the rate of completion of the protocol treatment was much better in the Pre group than the Post group. Treatment according to the protocol with two courses of chemotherapy and R0 resection was done in 85.4 % of the Pre group patients but only in 75.0 % of patients in the Post group.

Based on these results, preoperative chemotherapy with cisplatin plus 5-FU came to be regarded as the standard of care for patients with stage II/III SCC, and this treatment modality was described as the new standard of care in the latest revision of the Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus. Thus, the optimal perioperative timing of surgical adjuvant therapy once again became before surgery.

The results of subgroup analyses in JCOG9907 showed that preoperative chemotherapy was more effective in clinical stage II or T1-2 cases than in stage III or T3, namely in relatively early stage patients. Furthermore, the lower rate of isolated loco-regional recurrence of 31 % among tumor recurrence cases in the postoperative chemotherapy group and of 25 % in the preoperative chemotherapy group may result from our meticulous surgical procedure. The results of our study suggest that preoperative chemotherapy using cisplatin and 5-FU is a good treatment strategy, if sufficient local tumor control is achieved by aggressive surgical procedures, while if local tumor control is insufficient, more aggressive adjuvant therapy such as preoperative chemoradiotherapy with an aim of local tumor control or more intensive preoperative chemotherapy with an aim of systemic disease control may be a preferable treatment modality. Docetaxel is one of the most promising drugs for esophageal cancer and the recently reported exploratory trial of preoperative chemotherapy with docetaxel plus CF (DCF) for locally advanced ESCC showed a good response rate (61.5 %) with no treatment-related deaths [17]. The clinical question of which is better, preoperative chemotherapy or preoperative chemoradiotherapy, still needs to be clarified.

Based on these background features, the JEOG has launched a three-arm randomized controlled trial JCOG1109 to confirm the superiority of DCF and the superiority of chemoradiotherapy with CF (CF-RT) in overall survival over CF as preoperative therapy for locally advanced ESCC [18]. Patients in arm A receive two courses of preoperative CF (80 mg/m² cisplatin on day 1 plus 800 mg/m² 5-FU, c.i. on days 1–5) repeated every 3 weeks. Patients in arm B receive three courses of preoperative DCF (70 mg/m² docetaxel on day 1 plus 70 mg/m² cisplatin on day 1 plus 750 mg/m² 5-FU, c.i. on days 1–5) repeated every 3 weeks. Patients in arm C receive preoperative chemoradiotherapy (41.4 Gy/23 fractions) with two courses of CF (75 mg/m² cisplatin on day 1 plus 5-FU 1,000 mg/m² 5-FU, c.i. on days 1–4) repeated every 4 weeks (Fig. 11.6).

Table 11.1 presents a comprehensive overview of the literature-based evidence on adjuvant and neoadjuvant therapies for ESCC out of Japan and from Japan.