Radiotherapy in Patients With Metastatic Esophageal Cancer Responding to PD-1 Inhibitor Plus Chemotherapy

Study Overview
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Brief Summary
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The treatment efficacy for stage IVb esophageal cancer has been improved through chemotherapy combined with immunotherapy recently. On this basis, the investigators intend to conduct a prospective, multicenter phase II clinical trial to assess whether radiotherapy could further improve the survival of patients with metastatic esophageal cancer responding to PD-1 Inhibitor plus chemotherapy. Accompanied tissue samples, blood samples and urine samples will be analyzed by molecular biological detection (Including Whole Exome Sequencing and proteomics) to explore potential biomarkers for predicting outcomes, efficacy and toxicity.

Detailed Description
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Esophageal cancer (EC) is one of the most common carcinomas with high morbidity and mortality worldwide. More than 30% of the patients were stage IV when diagnosed. Fluoropyrimidine plus platinum-based chemotherapy is recommended as first-line treatment for patients with metastatic EC for approximately four decades, however, only minimal improvement has been reached in overall survival (OS). Recently, immune checkpoint inhibitors have shown effective antitumor activity in patients with unresectable, advanced or metastatic EC. Several randomized trials have demonstrated the PD-1 inhibitor could further improve the OS in patients with advanced esophageal squamous cell carcinoma (ESCC) on the basis of chemotherapy. Chemotherapy combined with immunotherapy has become one of the the standard treatment modality for metastatic EC. As reported, for the patients with metastatic lung cancer or EC, locoregional radiotherapy could improve survival, especially in those who responding to systemic therapy. However, high-level evidence is still needed to assess whether these patients can benefit from local radiotherapy. The efficacy of immunotherapy combined with chemotherapy is obviously better than that of chemotherapy alone. On this basis, locoregional radiotherapy may help those patients with metastatic EC responding to systemic therapy improve local control, relieve the local symptoms, and even improve survival. Therefore, the investigators intend to conduct a prospective, multicenter phase II trial to assess the efficiency and safety of radiotherapy with chemotherapy and immunotherapy for patients with metastatic EC. Accompanied tissue samples, blood samples and urine samples will be analyzed by molecular biological detection to explore potential biomarkers for predicting outcomes, efficacy and toxicity.

Official Title
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Radiotherapy in Patients With Metastatic Esophageal Cancer Responding to PD-1 Inhibitor Plus Chemotherapy: a Patient Preference Multicenter Randomized Phase II Trial

Conditions
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Esophageal Neoplasm Metastatic, Esophageal Cancer Stage IVb

Intervention / Treatment
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* Drug: TP (Paclitaxel with cisplatin or carboplatin) or PF (Fluoropyrimidine with cisplatin or carboplatin) regimen depended on investigator's choice.
* Biological: PD-1 inhibitor
* Radiation: Consolidation Radiation
* Radiation: Salvage Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. ≥18 years, any gender 2. Histologically or cytologically confirmed squamous cell carcinoma of esophageal cancer. The initial clinical stage is IVb (2018 AJCC Cancer Staging Manual, 8th Edition) or recurrent patients with recurrence after radical treatment (radical treatment includes surgery and radiotherapy, but the recurrence site cannot be located in the previous radiotherapy field). 3. ECOG performance status <= 1. Patients aged 65 years and over need to complete G8 screening or Comprehensive Geriatric Assessment, and the final evaluation is good; 4.There was no significant abnormality in laboratory routine indicators such as blood routine and liver and kidney function; 5.No prior history of thoracic radiation; 6.Expected survival is more than 12 weeks; 7.Informed consent provided; 8.With response to 2-4 cycles of the first-line chemotherapy combined with immunotherapy. Exclusion Criteria: 1.Patients with other cancer history except hypopharyngeal carcinoma in situ, non-malignant skin cancer and cervical carcinoma in situ. 2.Received surgery (except ostomy), chemotherapy or other anti-tumor treatment before enrollment； 3. Active infection currently exists . The following conditions occurred within 6 months before randomization: myocardial infarction, cerebrovascular accident, or received gastrointestinal, neurological, cardiopulmonary surgery; 4. History of allergy to chemotherapy drugs or autoimmune disease; 5. Participate in other clinical trials at present or within 4 weeks before enrollment; 6.There are factors such as high risk of fistula that radiotherapy cannot be safely carried out as assessed by the radiation oncologist.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Consolidation radiotherapy<br>This treatment group will be receive radiotherapy on the basis of standard first-line treatment, after all planned cycles of chemotherapy combined with PD-1 inhibitor completed. | Drug: TP (Paclitaxel with cisplatin or carboplatin) or PF (Fluoropyrimidine with cisplatin or carboplatin) regimen depended on investigator's choice.<br>* A maximum of six cycles was recommended for chemotherapy. Fluoropyrimidine (fluorouracil or capecitabine) with carboplatin or cisplatin; Paclitaxel (or Albumin-bound paclitaxel) with carboplatin or cisplatin.<br>* Other names: Chemotherapy;Biological: PD-1 inhibitor<br>* Nivolumab or Pebolizumab or Tislelizumab or Serplulimab or Toripalimab or Sintilimab or Camrelizumab<br>* Other names: Immunotherapy;Radiation: Consolidation Radiation<br>* IMRT/VMAT technique. Patients receive radiotherapy once daily, 5 days a week for an average of 5 weeks. Radiotherapy is delivered to achieve a dosage of 49.22Gy/23f or 50Gy/25f to PGTV for lymphnode metastasis only patients and 40.66Gy/19f or 40Gy/20f for organ metastasis patients. Radiation treatment is planned after chemotherapy completed.<br>* Other names: Planned Radiotherapy;|
| Experimental: Salvage radiotherapy<br>This treatment group will be receive salvage radiotherapy on the basis of standard first-line treatment, when disease progressed and salvage radiotherapy is recommended by multidisciplinary team. | Drug: TP (Paclitaxel with cisplatin or carboplatin) or PF (Fluoropyrimidine with cisplatin or carboplatin) regimen depended on investigator's choice.<br>* A maximum of six cycles was recommended for chemotherapy. Fluoropyrimidine (fluorouracil or capecitabine) with carboplatin or cisplatin; Paclitaxel (or Albumin-bound paclitaxel) with carboplatin or cisplatin.<br>* Other names: Chemotherapy;Biological: PD-1 inhibitor<br>* Nivolumab or Pebolizumab or Tislelizumab or Serplulimab or Toripalimab or Sintilimab or Camrelizumab<br>* Other names: Immunotherapy;Radiation: Salvage Radiation<br>* IMRT/VMAT technique. Patients receive radiotherapy once daily, 5 days a week for an average of 5 weeks. Radiotherapy is delivered to achieve a dosage of 49.22Gy/23f or 50Gy/25f to PGTV for lymphnode metastasis only patients and 40.66Gy/19f or 40Gy/20f for organ metastasis patients. Radiation treatment is planned after disease progression when recommended by multidisciplinary team.<br>* Other names: Radiotherapy when needed;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFFICACY:1-year overall survival probability | Overall survival was defined as the time from first dose to death due to any cause. Participants without documented death at the time of the final analysis were censored at the date of the last follow-up. OS is reported for all participants of the Intent-To-Treat (ITT) population. The Kaplan-Meier method was used to calculated the 1-year survival probability. | 12 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EFFICACY: Median progression-free survival (PFS) | Median progression-free survival (PFS), was defined as the time from first dose to the first documented progressive disease (PD) per RECIST 1.1 as assessed by the investigator, or death due to any cause, whichever occurred first. | 12 month | 
| SAFETY: Acute toxicity rate | Acute toxicity Rate, was defined as the frequency of toxicities related to the treatment, which arises within one month after administration, according to National Cancer Institute Common Terminology Criteria for Adverse Event,Version 5.0 (CTC AE5.0). | One month within the end of one specific treatment | 
| SAFETY: Late toxicity rate | Late toxicity rate, was defined as the frequency of toxicities related to the treatment, which arises after one month after administration, according to National Cancer Institute Common Terminology Criteria for Adverse Event,Version 5.0 (CTC AE5.0). | One month after the end of one specific treatment. | 
| QUALITY OF LIFE: Change From Baseline in the EORTC QLQ-C30 Subscale Scores in Participants | The score of the participants evaluated by The EORTC core quality of life questionnaire (QLQ-C30). All of the scales and single-item measures range in score from 0 to100.A high scale score represents a higher response level. Thus a high score for a functional scale represents a high/healthy level of functioning. | 24 month | 
| QUALITY OF LIFE: Change From Baseline in the EORTC QLQ-OES18 Subscale Scores in Participants | The score of the participants evaluated by The EORTC Quality of Life Questionnaire - Oesophageal Cancer Module (EORTC QLQ-OES18). All of the scales and single-item measures range in score from 0 to100.A high scale score represents a higher response level. Thus a high score for a functional scale represents a high/healthy level of functioning. | 24 month |