Neoadjuvant Therapy for Esophageal Cancer and Cardiopulmonary Physiology

Study Overview
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Brief Summary
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Although recent global trends indicate reduced postoperative mortality after esophagectomy, major morbidity, in particular pulmonary, remains high, with considerable health and economic costs. In a recent modern international collaborative series of 2704 patients from high-volume centers, with an approximate equal mix of open and minimally invasive approaches, respiratory complications were evident in 28% of patients, pneumonia in 15%, and respiratory failure in 7%.1 In other series, respiratory failure is reported in up to 15% of patients and is the most common cause of mortality. Prediction of risk and prevention of respiratory morbidity is therefore of considerable importance, and in this context baseline assessment of respiratory physiology compliments clinical assessment, history and enhanced recovery pathways representing key elements of current patient management. In this study, which will include all prospective patients with locally advanced esophageal cancer treated at a National Center, pulmonary function will be systematically measured before and after neoadjuvant therapy. The investigators seek to evaluate the incidence of radiation induced lung injury (RILI), as well as subclinical changes in pulmonary physiology that may be linked to postoperative complications, and quality-of-life in survivorship, and to compare cohorts who received radiation therapy or chemotherapy alone, preoperatively.

Official Title
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Neoadjuvant Therapy for Locally Advanced Esophageal Cancer: Impact on Cardiopulmonary Physiology, Short- and Long-term Morbidity

Conditions
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Esophageal Cancer, Radiation Pneumonitis, Pulmonary Fibrosis, Respiratory Failure, Pneumonia, Surgery, Chemotherapy Effect, Radiation Fibrosis, Radiation Toxicity, Adenocarcinoma, Squamous Cell Carcinoma

Intervention / Treatment
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* Procedure: Esophagectomy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced esophageal cancer undergoing multimodal therapy with curative intent at study centre during study period Pulmonary function assessed at a minimum of one preoperative timepoint Exclusion Criteria: Salvage, palliative or emergency surgery

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Neoadjuvant chemotherapy<br> | Procedure: Esophagectomy<br>* FEV1, FVC and DLCO will be assessed at baseline and one month post induction therapy. Radiation induced lung injury (RILI EORTC grade≥2), CCI, Clavien-Dindo, and pulmonary complications will be monitored. Changes in pulmonary function will be compared with cardiorespiratory symptoms and HR-QL among disease-free survivors.<br>|
| Neoadjuvant chemoradiation<br> | Procedure: Esophagectomy<br>* FEV1, FVC and DLCO will be assessed at baseline and one month post induction therapy. Radiation induced lung injury (RILI EORTC grade≥2), CCI, Clavien-Dindo, and pulmonary complications will be monitored. Changes in pulmonary function will be compared with cardiorespiratory symptoms and HR-QL among disease-free survivors.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FEV1 following administration of neoadjuvant chemotherapy versus chemoradiation | Changes in FEV1 (forced expiratory volume in one second, litres), both as a raw value, and as percentage of predicted values normalized for ethnicity, sex, age and height according to Global Lung Function Initiative algorithms will be determined. | 4-6 weeks post completion of neoadjuvant therapy | 
| Change in FVC following administration of neoadjuvant chemotherapy versus chemoradiation | Changes in FVC (forced vital capacity, litres), both as a raw value, and as percentage of predicted values normalized for ethnicity, sex, age and height according to Global Lung Function Initiative algorithms will be determined. | 4-6 weeks post completion of neoadjuvant therapy | 
| Change in DLCO following administration of neoadjuvant chemotherapy versus chemoradiation | Changes in DLCO (pulmonary diffusion capacity for carbon monoxide, mmol·min.-1.kPa. -1), both as a raw value, and as percentage of predicted values normalized for ethnicity, sex, age and height according to Global Lung Function Initiative algorithms will be determined. | 4-6 weeks post completion of neoadjuvant therapy | 
| Incidence of postoperative pulmonary morbidity as per Esophagectomy Complications Consensus Group (ECCG) definitions | Incidence of postoperative pulmonary morbidity, defined according to ECCG guidelines, will be compared after neoadjuvant chemotherapy versus chemoradiation. | Up to 90 days postoperatively | 
| Global health-related quality of life (HR-QL) score as assessed by Eastern Co-operative Oncology Group QLQ-C30 questionnaire | Global health HR-QL scores at one year postoperatively among disease-free patients will be compared between neoadjuvant chemotherapy and chemoradiation cohorts | One year postoperatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival | Disease-free survival will be compared between neoadjuvant chemotherapy and chemoradiation groups using Kaplan-Meier methods, as well as multivariable Cox proportional hazards regression models adjusting for known prognostic factors. | To date of study completion or date of disease recurrence, whichever occurs first, with a minimum of one year follow-up for all surviving patients | 
| Overall survival | Disease-free survival will be compared between neoadjuvant chemotherapy and chemoradiation groups using Kaplan-Meier methods, as well as multivariable Cox proportional hazards regression models adjusting for known prognostic factors. | To date of study completion or date of death, whichever occurs first, with a minimum of one year follow-up for all surviving patients |