Prehabilitation on Fitness, Surgical Outcomes and Mitochondria Functionality in Patients With Esophageal Cancer

The most often reported complications of patients with resectable esophageal malignancies are pulmonary (25\~57%), which may cause increased intensive care unit utilization, prolonged length of hospital stay, increased mortality and medical expense. Also, neoadjuvant chemotherapy has a deleterious effect on patients' cardiopulmonary capacity, strength and muscle mass. Prehabilitation includes preoperative exercise training and nutrition management. The reporting outcome regarding whether it improves surgical outcomes is inconsistent. One of the reasons is that pulmonary complication tends to occur in patients with low cardiopulmonary fitness, but all studies included patients with all level of fitness.

Most of the chemotherapy interferes with cell division to inhibit tumor growth but is also harmful to mitochondria functionality. For example, Cisplatin and Paclitaxel, commonly used in esophageal cancer, alter mitochondria function, caused by disruption of respiratory chain function and increased production of reactive oxygen species. However, it remains unclear their negative effects on the oxidative phosphorylation capacity of mitochondria (OXPHOS). Furthermore, whether prehabilitation reverses this negative effect is scarcely explored.

Patients will be inquired to participate and randomized into prehabilitation or control group. The latter will undergo conventional therapy only, while the former will receive additional prehabilitation program. The prehabilitation program encompasses supervised and home-based aerobic, resistance training (large and inspiratory muscle) and nutrition management. The supervised exercise training will be performed right before or after the radiotherapy. Outcome variables are fitness-related testing \[the 1st year\], quality of life and surgical outcomes \[the 2nd year\] and mitochondria functionality (OXPHOS, membrane potential, matrix oxidant burden) \[the 3rd year\]. Evaluation is performed 3 times at baseline, before surgery and 4 weeks after surgery.

Neoadjuvant chemotherapy has significantly improved patient outcomes. The majority of patients with resectable esophageal malignancies are considered for neoadjuvant treatment. However, esophagectomy and chemotherapy have disadvantages. Morbidity and mortality associated with esophagus resection remain high. The most often reported complications are pulmonary (25\~57%), which may cause increased intensive care unit utilization, prolonged length of hospital stay, increased mortality and medical expense.

Also, neoadjuvant chemotherapy has a deleterious effect on patients' cardiopulmonary capacity, strength and muscle mass. Prehabilitation includes preoperative exercise training and nutrition management. The reporting outcome regarding whether it improves surgical outcomes is inconsistent. One of the reasons is that pulmonary complication tends to occur in patients with low cardiopulmonary fitness, but all studies included patients with all level of fitness. In the current investigation, only those with low cardiopulmonary fitness will be enrolled.

Most of the chemotherapy interferes with cell division to inhibit tumor growth but is also harmful to mitochondria functionality. For example, Cisplatin and Paclitaxel, commonly used in esophageal cancer, alter mitochondria function, caused by disruption of respiratory chain function and increased production of reactive oxygen species. However, it remains unclear their negative effects on the oxidative phosphorylation capacity of mitochondria (OXPHOS). Furthermore, whether prehabilitation reverses this negative effect is scarcely explored.

This is a three-year prospective randomized trial. Patients who suffer from locally-advanced esophageal cancer and will receive neoadjuvant chemoradiotherapy and operation in Chang Gung Memorial Hospital at Linkou will be inquired to participate. A total of 160 patients will be recruited expectedly and randomized into prehabilitation or control group. The latter will undergo conventional therapy only, while the former will receive additional prehabilitation program. The prehabilitation program encompasses supervised and home-based aerobic, resistance training (large and inspiratory muscle) and nutrition management. The supervised exercise training will be performed right before or after the radiotherapy. Outcome variables are fitness-related testing (cardiopulmonary exercise testing, 6-minute walk distance, handgrip, and body composition, maximal inspiratory pressure and muscle oxidative capacity) \[the 1st year\], quality of life and surgical outcomes (length of stay in the hospital and intensive care unit, surgical complication, perioperative pulmonary complications and medical expense) \[the 2nd year\] and mitochondria functionality (OXPHOS, membrane potential, matrix oxidant burden) \[the 3rd year\]. Evaluation is performed 3 times at baseline, before surgery and 4 weeks after surgery.

The investigators hypothesize that prehabilitation increases functional reserve to improve surgical outcomes \[2nd year\] in a subpopulation of patients with esophageal cancer who receive neoadjuvant chemo-radiotherapy plus having low cardiopulmonary fitness. It also reverses fitness decline during neoadjuvant chemotherapy \[1st year\], partly through amelioration of mitochondria functionality \[3rd year\]. The goal of the investigation is to provide an applicable prehabilitation model and establish its efficacy at clinical, tissue and cellular levels.

Eligibility Criteria:
Inclusion Criteria:

* nonmetastatic esophageal cancer patients.
* V'O2 \< 21ml/min/kg
* abnormality on spirometry.

Exclusion Criteria:

* Resting heart rate greater than 100 beats per minute
* Atrial fibrillation or flutter
* Poor control of high blood pressure or diabetes
* Patients with peripheral arterial occlusive disease
* Patients with end-stage renal disease
* Patients receiving anticoagulant therapy
* Neurological instability