A phase-II/III randomized controlled trial of adjuvant radiotherapy or concurrent chemoradiotherapy after surgery versus surgery alone in patients with stage-IIB/III esophageal squamous cell carcinoma

The number of cases of esophageal cancer per year in China is ~ 480,000 [1]. Locoregional recurrence occurs in 23.8–58.0% of people after radical resection of thoracic esophageal squamous cell carcinoma (TESCC) [2‐6]. Moreover, spread to mediastinal lymph nodes and bilateral supraclavicular lymph nodes can occur [7, 8].

Postoperative radiotherapy (PORT) was applied first to treatment of esophageal cancer in 1969 [9]. Whether PORT can improve the overall survival (OS) for esophageal cancer is controversial [10‐14]. Three main issues have arisen from perspective studies. First, identifying patients who may benefit from PORT is difficult because studies conducted so far have involved small study cohorts. Second, obtaining consistent results is challenging because radiation fields and radiation doses differ between studies. Third, Fox and colleagues [11] showed severe toxicity related to PORT, which might be associated with a high dose per fraction.

Several large retrospective studies have shown that PORT or concurrent postoperative chemoradiotherapy (POCRT) after radical esophagectomy for esophageal carcinoma with positive lymph-node metastases and stage-III disease can increase OS [15‐23]. However, the rate of distant metastasis increases after PORT. However, a prospective randomized controlled trial (RCT) to ascertain if POCRT can decrease the rate of hematogenous metastasis has not been conducted.

A prospective phase-I clinical trial to compare the effect between POCRT or PORT after esophagectomy has been completed at our institution. Thus, a phase-II/III RCT in these patients is warranted to explore the safety and efficacy of adjuvant treatment.

National Comprehensive Cancer Network guidelines (2016–2019) recommend observation for pathologic T1-4aN0-1 M0 esophageal squamous cell carcinomas. However, 5-year OS decreases from 60.0 to 18.0% with increasing stage from IIA to III (p < 0.001) after surgery. Postoperative recurrence rates also vary with the number of lymph-node metastases (16, 44, 69 and 93% according to 0, 1–2, 3–7 and > 8, respectively p < 0.001) [24]. Also, recurrence in regional lymph nodes is predominant. The median time of recurrence is about 10.0–17.0 months [5, 6, 8, 25, 26]. Hence, PORT is indispensable for patients receiving SA. However, only a few small-sample-size studies on PORT by conventional radiotherapy methods have been carried out, and have shown that PORT does not improve OS. Besides, the irradiation field and PORT dose for esophageal cancer after surgery are controversial [10, 12, 13, 27‐29]. The main reasons are that studies enrolled patients with different: pathologic tumor stages; status of lymph-node metastases; sites of esophageal cancer. This led to different recurrence patterns. Thus, obtaining consistent results without subgroup analyses is challenging. Therefore, a stratified study to identify patients who may benefit from adjuvant treatment is warranted urgently.

Xiao and colleagues [13, 30] reported that PORT can reduce the recurrence rate at radiotherapy sites and improve OS in patients with pathologic stage-III and lymph node-positive esophageal carcinomas. Although OS did not differ significantly between the SA group and PORT for stage-IIA or lymph node-negative cases, 3- year OS increased by approximately 8.0–10.0%. Therefore, according to the recurrence rate and failure patterns of esophageal cancer after surgery, Xiao and coworkers designed different irradiation fields according to different locations of esophageal carcinoma and different lymph-node status.

With the development of radiotherapy methods, three dimensional-conformal radiation therapy and IMRT have been used widely. A prospective study on postoperative irradiation fields employed from 2004 to 2009 in our institution was launched to analyze tumor recurrence patterns after surgery. Results showed that, for pathologic lymph node-positive or stage-III patients, postoperative IMRT could further improve OS (p < 0.05) and reduce the recurrence rate in mediastinal lymph nodes from 34.6 to 13.4% (p < 0.001) and in supraclavicular lymph nodes from 13.3 to 6.1% (p = 0.015). There was no significant difference in recurrence in abdominal lymph nodes between the two groups (9.8 and 7.8%, respectively, p = 0.510). The rate of hematogenous metastasis in the PORT group (30.7%) was higher than that in the SA group (21.0%, p = 0.020) [20]. That study provided an important basis for POCRT of esophageal squamous cell carcinoma.

POCRT for esophageal adenocarcinomas or adenocarcinomas at the esophagogastric junction can improve OS in pT3–4 or lymph node-positive patients [27, 31‐33]. However, few retrospective studies have shown that POCRT can improve OS in patients with lymph node-positive or stage-III TESCC [21‐23]. Therefore, a prospective study on the irradiation field, irradiation dose, and dose of chemotherapy for POCRT is needed.

A phase-I study has been carried out to determine the optimal irradiation field and optimal dose for patients with positive lymph nodes and stage-III TESCC combined with concurrent chemotherapy in our institution. The irradiation field is contoured from the first thoracic vertebral body to the celiac axis at 54 Gy or 60 Gy. Concurrent five weekly cycles of chemotherapy are expected. Although grade-5 toxicity did not occur, escalation of the chemotherapy dose failed due to dose-limiting toxicity at the beginning of treatment. This might be one of the reasons why it is difficult to carry out a study of concurrent POCRT. Hence, the irradiation dose and irradiation field must be adjusted rationally. Due to the difficult anatomy and surgical field, recent studies have shown that supraclavicular and mediastinal lymph nodes are the most common recurrence regions after surgery [5, 34‐36]. These regions are always included in the irradiation region for PORT. Therefore, considering the low recurrence rate in abdominal lymph nodes (2.1–10.4%) [5, 37‐40], a phase-I study by rational reduction of the irradiation field (omitting the abdominal lymphatic drainage area) was carried out again. It showed that IMRT with small-target, concurrent five weekly cycles of chemotherapy were safe and efficacious in patients with positive lymph nodes and stage-III disease after surgery. Only one patient had recurrence in abdominal lymph nodes after reducing the irradiation area, and the recurrence site was below the abdominal lymphatic drainage area [41]. Then, a phase-II study was conducted using this scheme and 65 patients enrolled (unpublished). As many as 69.2% of patients (45/65 patients) did not complete the full dose of CRT due to refusal or intolerance. Therefore, on the basis of the phase-I/II study, a phase-II/III prospective RCT must be carried out to validate safety and efficacy by further reducing the irradiation dose to 50.4 Gy and reducing the irradiation field appropriately to guarantee completion of concurrent CRT. Primarily, this RCT will determine whether POCRT can further improve local control and decrease hematogenous metastasis compared with PORT, and whether it can continue to improve OS compared with SA.