Table 1 Patient inclusion and exclusion criteria

Inclusion Criteria

 Inclusion Criteria (for the primary locally advanced ESCC part)

1. Patients with histologically confirmed primary esophageal squamous cell carcinoma, adenosquamous carcinoma, or basaloid-squamous carcinoma.

2. Patients with primary lesion located in the thoracic esophagus based on the UICC TNM 7th edition classification, patients with invasion to cervical esophagus and/or abdominal esophagus are eligible when definitive CRT is eligible, patients with secondary lesions that are curable by endoscopic resection are eligible.

3. Patients diagnosed as having an unresectable tumor by a pre-CRT CT scan as described below. Patients with esophageal perforation, esophagotracheal fistula, esophagomediastinal fistula, bleeding from arterial invasion, or respiratory stenosis are ineligible.

i. The depth of the primary tumor is diagnosed as T4b (tumor invades other adjacent structures such as aorta, vertebral body, or trachea) according to the UICC TNM 7th edition and Japanese Classification of Esophageal Cancer The 11th Edition.

ii. Regional lymph nodes and/or supraclavicular lymph node have invaded adjacent structures other than esophagus.

4. Patients without distant metastases other than supraclavicular lymph node by pre-CRT CT scan.

5. Patients without prior esophageal cancer treatment except for endoscopic resection before CRT.

6. Patients for whom the CRT described below has been performed and for whom the protocol treatment can be started within 42 days after CRT completion.

i. Chemotherapy started at CDDP 70 mg/m² on day 1, 5-FU 700 mg/m² on days 1–4 and 2 times every 4 weeks. Second cycle dose reductions were allowed according to the toxicities.

ii. 60 Gy/30 fractions of radiotherapy performed without exceeding dose limitations to at-risk organs.

7. Patients without esophageal perforation, esophagotracheal fistula, esophagomediastinal fistula, bleeding from arterial invasion, or respiratory stenosis when CRT is completed.

 Inclusion Criteria (for the postoperative locoregionally recurrent ESCC part)

1. Patients with histologically confirmed esophageal squamous cell carcinoma, adenosquamous carcinoma, or basaloid-squamous carcinoma on surgical specimens.

2. Patients with local (mediastinum, anastomosis) or regional (regional lymph node) recurrences after curative surgery, whose recurrences are considered treated with definitive CRT.

3. Patients without distant metastases except those in supraclavicular lymph nodes by pre-CRT CT scan.

4. Patients treated with neoadjuvant chemotherapy 24 months or more before start-up of any definitive CRT.

5. Patients for whom the CRT described below has been performed and those for whom the protocol treatment can be started within 42 days after CRT completion.

i. Chemotherapy started at CDDP 70 mg/m² on day 1, 5-FU 700 mg/m² on days 1–4 and 2 times every 4 weeks. Second cycle dose reductions were allowed according to the toxicities.

ii. 60 Gy/30 fractions of radiotherapy performed without exceeding dose limitations to at-risk organs.

6. Patients without esophageal perforation, esophagotracheal fistula, esophagomediastinal fistula, bleeding from arterial invasion, or respiratory stenosis when CRT is completed.

 Inclusion Criteria (common to both study parts)

1. Patients 20 years or older.

2. Patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1.

3. Patients with the following organ functions within 14 days of registration:

i. Neutrophil count ≥1200/mm³

ii. Platelet count ≥75,000/mm³

iii. Hemoglobin ≥8.0 g/dL

iv. Serum albumin ≥2.5 g/dL

v. T-Bil ≤1.5 x ULN, in the case of Gilbert’s syndrome T-Bil ≤2.5 x ULN

vi. ALT and AST < 100 IU/L

vii. Serum creatinine ≤1.5 mg/dL or calculated or measured values of creatinine clearance ≥45 mL/min

viii. SpO2 ≥ 95% (room air)

4. Women of childbearing potential with a negative urine pregnancy test within 14 days of registration.

5. Patients who agree to take appropriate precautions to avoid pregnancy from the time of the informed consent to 5 months after the final administration of the investigational drugs.

6. Patients with life expectancy longer than 3 months.

7. Patients who sign written informed consent.

 Exclusion Criteria

1. Patients with active multiple primary cancers (synchronous multiple primary cancers and multiple cancers with a progression-free period of ≤3 years from the time of enrollment), carcinoma in situ or intramucosal carcinoma curable by local resection are not included in the definition of active multiple primary cancers.

2. Patients with active infection for which systemic treatments are needed.

3. Patients with past or concurrent inflammatory bowel disease.

4. Patients with past or concurrent pneumonitis or interstitial lung disease (ILD).

5. Patients with concurrent autoimmune disease or with past chronic or recurrent autoimmune disease.

6. Patients requiring treatment with systemic corticosteroids or immunosuppressants.

7. Patients with past or concurrent thyroid dysfunction (hyperthyroidism or hypothyroidism).

8. Patients with a history or finding of a cardiovascular risk:

i. Patients with a left ventricular ejection fraction below 50%

ii. Patients with clinically significant, poorly controlled arrhythmia

iii. Patients with acute coronary syndrome, coronary angioplasty, or stent placement within 6 months before enrollment

iv. Patients with class II or more severe congestive heart failure

v. Patients with treatment-resistant hypertension

vi. Patients wearing an implantable cardioverter defibrillator or permanent pacemaker

9. Patients with poorly controlled diabetes mellitus.

10. Patients positive for HIV antibody, HBs antigen or HCV antibody.

11. Pregnant or lactating patients.

12. Patients with a significant unstable mental disease or other medical disease that may interfere with their safety, obtaining informed consent, or compliance with the procedures for the clinical study.

13. Patients with a history of treatment with atezolizumab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody, or anti-CTLA-4 antibody or a history of any other antibody therapies or drug therapies intended to regulate T cells.

14. Patients who are not willing to or who cannot comply with the procedures specified in the protocol.

15. Patients unsuitable for the study due to complicated disorders affecting the assessment of toxicity according to the investigator’s judgment.