Neoadjuvant immunochemotherapy and chemoradiotherapy before surgery for advanced esophageal squamous cell carcinoma

Total Neoadjuvant Therapy With Induction Immunochemotherapy and Chemoradiotherapy Followed by Surgery for Locally Advanced Esophageal Squamous Cell Carcinoma

This study tests whether giving the immune drug tislelizumab with chemotherapy before and then combining chemoradiotherapy, followed by surgery, helps people with locally advanced esophageal squamous cell carcinoma.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: National Taiwan University Hospital (Academic / other)
• Drugs / interventions: chemotherapy, nivolumab
• Locations: 1 site (Taipei)
• Trial ID: NCT06764355 on ClinicalTrials.gov

What this trial studies

Participants receive induction immunochemotherapy (tislelizumab plus cisplatin-based doublet chemotherapy) followed by concurrent chemoradiotherapy and then surgical resection as a total neoadjuvant therapy approach. The plan aims to downstage the tumor, improve systemic control, and increase pathological complete response rates prior to surgery. Eligible patients are adults with intrathoracic locally advanced ESCC (specified TNM stages), limited tumor length, good performance status, and adequate organ function. The primary outcomes focus on tumor response and pathological complete response, with survival and recurrence monitored over follow-up.

Who should consider this trial

Good fit: Adults aged 18–75 with pathologically confirmed intrathoracic locally advanced esophageal squamous cell carcinoma (per AJCC 8th edition criteria), tumor length and extent within protocol limits, ECOG 0–1, and adequate blood and liver function are ideal candidates.

Not a fit: Patients with distant metastatic disease, tracheobronchial invasion or tracheoesophageal fistula, tumors extending more than 2 cm into the stomach, poor performance status, or inadequate organ function are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could increase complete tumor responses before surgery and reduce the risk of recurrence and metastasis.

How similar studies have performed: Prior studies have shown improved outcomes with adjuvant anti‑PD‑1 therapy after neoadjuvant chemoradiotherapy and anti‑PD‑1 plus chemotherapy has produced high response rates in late‑stage ESCC, but applying a total neoadjuvant immunochemotherapy then chemoradiotherapy sequence is relatively novel.

Eligibility criteria

Inclusion Criteria:

1. Pathologically proven squamous cell carcinoma of the intrathoracic esophagus.
2. Locally advanced disease, which is defined by the TNM system of the American Joint Committee on Cancer (AJCC) Cancer Staging System (8th edition), fulfilling one of the following criteria as determined by staging procedures (including but not limited to endoscopic ultrasound, computed tomography, bronchoscopy or positron emission tomography):

   1. cT3/4a, N0, M0;
   2. cT1-4a, N1-3, M0.
3. Tumor length longitudinal ≤ 10cm and radial ≤ 5cm.
4. The tumor must not extend more than 2cm into the stomach.
5. No invasion of the tracheobronchial tree or presence of tracheoesophageal fistula.
6. Age ≥ 18 and ≤ 75 years old.
7. Performance status ECOG 0\~1.
8. Adequate bone marrow reserves, defined as:

   1. white blood cells (WBC) ≥ 3,000/µl or neutrophil count (ANC) ≥ 1,500/µl;
   2. platelets ≥ 100,000/µl.
9. Adequate liver function reserves, defined as:

   1. hepatic transaminases ≤ 2.5 x upper limit of normal (ULN);
   2. serum total bilirubin ≤ 2.0 x upper limit of normal (ULN).
10. Adequate renal function: Creatinine ≤1.5 x upper normal limit or estimated creatinine clearance ≥ 50 ml/min (estimated by Cockcroft-Gault formulation)
11. Written informed consent.
12. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be mandatory.
13. Female subjects of childbearing potential must be willing to use an adequate method of contraception as outlined in Section - Contraception, for the course of the study through 120 days after the last dose of study medication.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
14. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section - Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

1. Adenocarcinoma
2. Previous thoracic irradiation
3. Previous systemic chemotherapy
4. Has received prior therapy with an anti-PD-1 or anti-PD-L1
5. Synchronous diagnosis of squamous cell carcinoma in the aerodigestive tract, other than esophageal cancer.
6. Prior malignancy, except for the following:

   1. adequately treated basal cell or squamous cell skin cancer;
   2. in-situ cervical cancer;
   3. a "cured" malignancy more than 5 years prior to enrollment.
7. Significant co-morbid disease, which prohibits the conduction of immunochemotherapy, concurrent CRT, or radical surgery, such as active systemic infection, symptomatic cardiac or pulmonary disease, or psychiatric disorders.
8. Documented myocardial infarction within the 6 months preceding registration (pretreatment ECG evidence of infarct only will not exclude patients). Patients with a history of significant ventricular arrhythmia requiring medication. Patients with a history of 2nd or 3rd degree heart block.
9. Pre-existing motor or sensory neurotoxicity greater than grade 1.
10. Patients with prior allergic reactions to drug containing Cremophor, such as teniposide or cyclosporine.
11. Weight loss \> 15%.
12. Dementia or altered mental status that would prohibit the understanding and completion of informed consent.
13. Estimated life expectancy less than 3 months.
14. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
15. Has a known history of active TB (Bacillus Tuberculosis)
16. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
17. Has known history of, or any evidence of active, non-infectious pneumonitis, interstitial lung disease or pulmonary fibrosis.
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
20. Patients with untreated chronic HBV or chronic HBV carriers whose HBV DNA is ≥500 IU/mL, or patients with active HCV. Patients who are inactive carriers or with treated and stable hepatitis B (detectable B surface antigen and HBV DNA \<500 IU/mL); patients with non-reactive HCV can be enrolled. Patients with chronic HBV infection need to be treated with anti-HBV agents while receiving immunochemotherapy and chemoradiotherapy according to the local and institutional guidelines.
21. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines are live attenuated vaccines, and are not allowed.
22. Has received organ transplantation.
23. Has declined esophagectomy.

Where this trial is running

Taipei

• National Taiwan University Hospital — Taipei, Taiwan (Recruiting)

Study contacts

• Study coordinator: Chih-Hung Hsu, M.D., PhD

Conditions ESCC; Total Neoadjuvant Treatment; Pathological Complete Response