Neoadjuvant Therapy for Esophageal Cancer and Cardiopulmonary Physiology

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

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.

Study Overview

• Status: Completed
• Conditions: Pneumonia; Adenocarcinoma; Respiratory Failure; Esophageal Cancer; Pulmonary Fibrosis; Surgery; Chemotherapy Effect; Radiation Toxicity; Squamous Cell Carcinoma; Radiation Pneumonitis; Radiation Fibrosis
• Intervention / Treatment: Procedure: Esophagectomy

• Study Type: Observational
• Enrollment (Actual): 384

Contacts and Locations

Study Locations

• Ireland
  • Dublin, Ireland, D4
    • Department of Surgery, St. James's Hospital
  • Dublin, Ireland, D8
    • Wellcome Trust-Health Research Board Clinical Research Facility, St. James's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Records for all patients with LAEC treated with multimodal therapy with curative intent between 2010 and 2016 will be assessed for inclusion. Patients undergoing emergent or palliative surgery, or salvage esophagectomy will be excluded. All eligible patients for whom pulmonary function testing was undertaken at our Centre at a minimum of one preoperative timepoint will be included for analysis of operative and/or oncologic outcome. Then, HR-QL among disease-free patients at least one year postoperatively will be assessed using validated questionnaires (EORTC QLQC30, OG25 and OES18).

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Neoadjuvant chemotherapy	Procedure: Esophagectomy; 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.
Neoadjuvant chemoradiation	Procedure: Esophagectomy; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: St. James's Hospital, Ireland

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2010
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: February 28, 2018
• First Submitted That Met QC Criteria: March 5, 2018
• First Posted (Actual): March 12, 2018

Study Record Updates

• Last Update Posted (Actual): March 12, 2018
• Last Update Submitted That Met QC Criteria: March 5, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Neoplasms; Respiration Disorders; Lung Diseases; Neoplasms by Site; Wounds and Injuries; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Lung Diseases, Interstitial; Lung Injury; Radiation Injuries; Fibrosis; Respiratory Insufficiency; Pneumonia; Pulmonary Fibrosis; Esophageal Neoplasms; Radiation Pneumonitis
• Other Study ID Numbers: SJHDOS201701

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No