Neoadjuvant treatment strategy for locally advanced thoracic esophageal cancer

Abstract Multimodal treatment combining surgery with chemotherapy and/or radiotherapy is necessary to improve the chances of survival in patients with locally advanced thoracic esophageal cancer. Based on the results of the Japan Clinical Oncology Group 9907 (JCOG9907) trial, neoadjuvant chemotherapy, two courses of cisplatin and 5‐fluorouracil (5‐FU), followed by esophagectomy with D2 lymphadenectomy is the recommended treatment in Japan. Alternatively, neoadjuvant chemoradiotherapy (NACRT) typified by carboplatin and paclitaxel plus concurrent radiotherapy with 41.4 Gy (Chemoradiotherapy for Esophageal Cancer followed by Surgery Study [CROSS]) has shown promising outcomes in some Western countries. Currently, several clinical trials are being conducted within and outside of Japan to confirm the best neoadjuvant treatment regimen. For instance, a three‐arm phase III randomized controlled trial (JCOG1109) is ongoing in Japan. The three arms comprise a doublet regimen (two courses of cisplatin 80 mg/m2 day 1 and 5‐FU 800 mg/m2 days 1‐5; repeated every 3 weeks) versus a triplet regimen (three courses of docetaxel, 70 mg/m2 day 1; cisplatin 70 mg/m2 day 1; and 5‐FU 750 mg/m2 days 1‐5; repeated every 3 weeks) versus a chemoradiotherapy (CRT) regimen (radiotherapy of 41.4 Gy/23 fractions with two courses of cisplatin 75 mg/m2 day 1 and 5‐FU 1000 mg/m2 days 1‐4; repeated every 4 weeks). Development of a multimodal strategy for neoadjuvant therapy is expected to receive the continuous focus of research in the hope of achieving better outcomes from treatment of patients with advanced thoracic esophageal cancer.

TA B L E 1 Randomized controlled studies of multimodal therapy for locally advanced thoracic esophageal cancer

| Neoadjuvant chemotherapy using 5-FU and cisplatin followed by surgery (JCOG9907)
Furthermore, to evaluate the optimal perioperative timing of adjuvant chemotherapy (before or after surgery), the JCOG9907 trial was conducted. 5 In this trial, patients with clinical stage II/III SCC of the thoracic esophagus, according to the Japanese Classification of Esophageal Cancer, were randomly assigned to the group (n = 164) with two courses of cisplatin (80 mg/m 2 , day 1) and 5-FU (800 mg/m 2 , days 1-5) NAC followed by surgery or to the group with an identical regimen of postoperative chemotherapy (n = 166). The 5-year OS in the NAC group was significantly superior to that of the postoperative chemotherapy group (55% vs 42%, respectively) (hazard ratio [HR] 0.73, P = 0.04).
Meanwhile, chemoradiotherapy (CRT) with a radiation dose of >50 Gy was another option for definitive therapy for thoracic esophageal cancer. In Japan, the single-arm phase II trial JCOG9906 with concurrent use of irradiation, totaling 60 Gy, cisplatin and 5-FU, showed a 5-year survival rate of 37%. 16 No RCT in Japan compared NAC followed by surgery with definitive CRT; therefore, from the results of JCOG trials 9907/9906 and several observational studies, NAC followed by esophagectomy with D2 lymphadenectomy is presently recommended in the Japanese guidelines. Thus, the first choice for physiologically fit patients with locally advanced SCC of the thoracic esophagus is NAC using cis-

| Definitive CRT followed by salvage treatment (JCOG0909)
In patients (27%), respectively. 17 Although the sample size in the singlearm phase II study was small, these results suggest that definitive CRT could be a promising option as an initial treatment for patients with a strong preference for sparing the esophagus.

| CURRENT WORLDWIDE TRENDS
It is essential to pay attention to the histopathological differences in esophageal cancer between patients from East Asia, including Japan,

| Perioperative chemotherapy
In the 1990s, unlike the Japanese clinical trials, the superiority of surgery plus perioperative chemotherapy using 5-FU and cisplatin was not week cycles of epirubicin, cisplatin, and FU or capecitabine), conducted in Germany, and the phase II part of this trial showed higher proportions of patients achieving pathological complete regression and fewer adverse events in the FLOT group. 15 In the phase III part,

3-year OS in the FLOT group was significantly superior to that in
the anthracycline-based triplet chemotherapy group (57% vs 48%, respectively; HR 0.75, P = 0.004).

| FUTURE PER S PEC TIVE S: WHAT IS THE OP TIMAL NEOADJ U VANT THER APY -NAC OR NACRT ?
According to the results of JCOG9907, the preoperative setting offers the advantage of dose intensity in chemotherapy in comparison with that in the postoperative setting. Based on the subgroup analysis in the JCOG9907 trial, only a small benefit was noted in OS between the preoperative and postoperative groups, particularly in patients with stage III esophageal cancer. A more aggressive regimen than with cisplatin and 5-FU is required for advanced esophageal cancer treatment. Addition of taxan to platinum and FU triplet regimen has been developed for treating head and neck cancer or gastric cancer. In esophageal cancer, a combination of docetaxel, cisplatin, and 5-FU in the form of NAC has shown promising results in several phase II studies. [22][23][24][25] Although hematological toxicity, especially neutropenia, was common in 80% of all cases during NAC with the triplet regimen, pathological complete response rate of 7%-13% after NAC with the triplet regimen was relatively higher than that after NAC with the doublet regimen of 5-FU and cisplatin.
Therefore, the triplet regimen may deliver a strong antitumor effect and potentially improve long-term outcomes. However, as previously indicated, NACRT typified by the CROSS trial has revived interest as a promising treatment. It is thus notable that in the CROSS trial, a positive effect of CRT was remarkable in patients with SCC.
There is only one RCT with a relatively large sample size comparing NAC with NACRT followed by surgery for esophageal or esophagogastric cancer (NeoRes trial). 26 In this trial, three cycles of cisplatin and FU were given in both arms, whereas 40 Gy of concomitant radiotherapy was included in the NACRT arm. Higher histological complete response was achieved in 28% of cases after NACRT versus in 9% of cases after NAC (P = 0.001). However, the 3-year OS was similar between both arms (49% in chemotherapy arm vs 47% in CRT arm, P = 0.77). Presently, no specific evidence has been obtained from the comparison between perioperative chemotherapy versus NACRT.
In practice, NAC with 5-FU and cisplatin has been the standard of care for patients with locally advanced esophageal cancer in Japan.
In cases with multiple lymph node metastases spreading three fields from the neck to the abdomen or enlarged lymph node metastasis, it may be more appropriate to select NAC with a triplet regimen such as the combination of docetaxel, cisplatin, and 5-FU than with NACRT because the irradiation field would then be extremely wide in the NACRT setting. However, for borderline resectable cases suspected of adjacent organ invasion, NACRT may be considered with an emphasis on local disease control.
Presently, in Japan, a three-arm phase III RCT (JCOG1109) is ongoing to confirm the best neoadjuvant treatment regimen for SCC ( Figure 1).  29 The optimal adjuvant strategy for esophageal and EGJ cancer is expected to be derived from these RCT.
In addition, promising results relating to anti-programmed cell death protein 1 antibody for treatment-refractory advanced esophageal cancer have been reported in a phase II trial. 30 Immune checkpoint inhibitors and molecular targeting drugs are also expected to function as an option for adjuvant therapy along with chemotherapeutic drugs for esophageal cancer.
In Europe, a new organ-sparing approach called active surveillance has been proposed based on the high pathological complete response rate (49% for SCC and 23% for AC) after NACRT of the CROSS trial.
In this organ-sparing strategy, patients with clinical complete response after NACRT undergo frequent diagnostic evaluations, including endoscopy, with fine-needle aspiration of suspected lymph nodes and 18 F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/ computed tomography (CT). An esophagectomy is carried out only in patients with a proven or high suspicion of locoregional regrowth.
The effectiveness of this active surveillance as compared to standard surgery has been assessed in the Surgery As Needed approach in Oesophageal cancer patients (SANO) trial. 31 As reported from the JCOG0909 trial, in Japan, CRT followed by salvage surgery can provide a promising therapeutic strategy. In the future, comparison of NACRT plus planned surgery with the esophagus-sparing treatment approach may be necessary not only for survival benefit but also for quality of life.
In conclusion, developmental research in a multimodal strategy for neoadjuvant therapy is expected to be continued in the hope of achieving better outcomes for treatment of patients with locally advanced thoracic esophageal cancer.