**Background:** This document is part 2 of the 2022 edition of the Esophageal Cancer Practice Guidelines edited by the Japan Esophageal Society. It provides comprehensive, evidence-based recommendations for the management of esophageal cancer, covering endoscopic surveillance, surgical treatment for various anatomical subsites, perioperative management, chemotherapy/radiotherapy, follow-up, and palliative care. The guidelines reflect recent landmark clinical trials, particularly from the Japan Clinical Oncology Group (JCOG), and aim to standardize treatment across Japanese institutions while acknowledging areas where evidence remains limited.
**Methods:** The guidelines were developed by a committee of experts from the Japan Esophageal Society. Recommendations are based on a systematic review of the literature, with particular emphasis on large-scale randomized controlled trials and prospective studies. Key evidence sources include JCOG studies (JCOG9907, JCOG1109, JCOG0909, JCOG0502, JCOG0508, JCOG9516, JCOG0303), the CROSS trial, the Checkmate-577 study, the MIRO trial, the TIME trial, and the RTOG9405/INT0123 study. The guidelines also incorporate results from a nationwide survey of follow-up practices conducted by the Society in 2020.
**Key Results:**
- **Preoperative chemotherapy:** The JCOG1109 study demonstrated that preoperative DCF therapy significantly improved survival compared to conventional CF therapy (3-year overall survival: 72.1% vs. 62.6%; HR 0.68 [95% CI 0.50–0.92]). Preoperative chemoradiotherapy showed a 3-year survival of 68.3% but did not significantly outperform CF therapy (HR 0.84 [95% CI 0.63–1.12]).
- **Postoperative nivolumab:** The Checkmate-577 study showed that in patients who received preoperative chemoradiotherapy and did not achieve pCR, 1-year nivolumab significantly prolonged disease-free survival vs. placebo (median DFS 23.0 vs. 11.0 months; HR 0.69 [95% CI 0.56–0.86]).
- **Chemoradiotherapy for cStage I:** The JCOG0502 study reported a complete response rate of 87.3% and 5-year overall survival of 85.5% with chemoradiotherapy, not inferior to surgery.
- **Chemoradiotherapy for cStage II/III:** The JCOG0909 study showed a complete response rate of 59%, 3-year overall survival of 74.2% [90% CI 65.9–80.8], and 5-year overall survival of 64.5% [95% CI 53.9–73.3] with definitive chemoradiotherapy followed by salvage treatment as needed.
- **Surgical outcomes:** The MIRO trial showed significantly lower postoperative respiratory complications with laparoscopic surgery vs. laparotomy, with 3-year overall survival tending higher (67% vs. 55%). The TIME trial reported significantly lower postoperative pneumonia with thoracoscopic surgery vs. thoracotomy (12% vs. 34%).
- **Endoscopic surveillance:** After complete response to definitive chemoradiotherapy, endoscopy should be performed 1 month after response documentation, every 2–3 months for 1 year, then every 4–6 months.
- **Radiotherapy alone:** 5-year overall survival rates were 41.8%, 18.5%, 9.3%, and 13.9% for cStage 0-I, II, III, and IV, respectively.
- **Recurrence:** Postoperative recurrence occurs in approximately 40–60% of cases, with 80–90% occurring within 2 years.
**Clinical Implications:** These guidelines establish preoperative DCF therapy as the new standard for resectable advanced esophageal squamous cell carcinoma in Japan, replacing CF therapy. Postoperative nivolumab is recommended for patients who received preoperative chemoradiotherapy and did not achieve pCR, though caution is advised since the evidence primarily comes from a study where 70% of subjects had adenocarcinoma and most were from overseas, while the Japanese standard is preoperative chemotherapy without radiation. The guidelines support definitive chemoradiotherapy as a valid alternative to surgery for cStage I disease and as a treatment option for cStage II/III patients who do not wish surgery. For cervical esophageal cancer, treatment selection should prioritize quality of life, particularly larynx preservation. The guidelines highlight the importance of salvage treatments for residual/recurrent disease after chemoradiotherapy, with salvage esophagectomy achieving R0 resection in 85% of cases in the JCOG0909 study. The document also emphasizes the need for standardized follow-up protocols, regular QOL assessment, and multidisciplinary palliative care from the time of diagnosis.