Internet-based perioperative exercise program in patients with Barrett’s carcinoma scheduled for esophagectomy [iPEP - study] a prospective randomized-controlled trial

Risk management in esophageal surgery has become an essential feature with regard to postoperative outcome [ 1]. Although perioperative mortality in esophageal cancer surgery could be steadily reduced in recent years, morbidity is still high, and affects 30–50% of patients – even in the current literature and large surgical centers [ 2]. Pulmonary complications following esophagectomy are the most common and cost-intensive adverse events, mostly due to prolonged intensive care unit stays. This is partly due to one-lung ventilation (OLV) during thoracotomy. During OLV, the operated lung remains completely atelectatic. The non-ventilated lung is known to be hypoperfused owing to hypoxic vasoconstriction, and when the bronchial block is ended, the ensuing immediate lung re-expansion along with tissue reperfusion generates oxygen-derived free radicals. The single-ventilated lung is subjected to a combination of hyperoxia, volutrauma, and hyperinflation. Esophageal complications are not only life-threatening and associated with a high mortality in the short-term postoperative course, but have also exerted a long-lasting negative effect on Health-Related Quality of Life (HRQL) in patients who survive 5 years after esophagectomy for cancer [ 3]. Advances in surgical techniques, such as minimally-invasive esophagectomy (MIE), have been proposed to reduce surgical risk and perioperative morbidity and mortality, thus improving surgical short- and long-term outcomes. However, to the best of our knowledge, there is only one fully published prospective randomized trial comparing minimally-invasive versus conventional / open surgery (“time trial” = “ traditional invasive vs. minimally-invasive esophagectomy”) [ 4]. In this study, a significantly reduced rate of pulmonary infections in patients receiving minimally-invasive treatment versus open surgery was reported [ 4]. This striking result after 2 weeks following surgery might be due to the reduced trauma of thoracoscopy compared to thoracotomy. In addition, oncologic parameters, such as clear resection margins, and the number of dissected lymph nodes, were comparable in both groups [ 4]. As impressively shown for colorectal surgery, “fast-track” (FT) rehabilitation or enhanced recovery after surgery (ERAS) programs in visceral surgery, comprising atraumatic surgical techniques, stress-reduction of the organism as a response to major surgery, and a decrease of postoperative organ dysfunction, leads to fewer perioperative complications, while reducing hospital costs and increasing patient turnover by shorter lengths of in-hospital stay [ 5, 6]. However, there are only few studies with limited case numbers regarding fast-track concepts in esophageal surgery [ 7– 12]. Although no routine use of minimally-invasive surgery and other advances of modern surgical techniques were applied, all studies revealed a very short ICU stay, early extubation, thoracic peridural anaesthesia, multimodal pain management, early enteral nutrition (usually via a jejunal catheter), enhanced postoperative mobilisation, and physio−/ ventilation therapy [ 7– 12]. Fast-tracking or enhanced recovery programs for esophagectomy are promising, but still far from reaching the results of e.g. colorectal or minor non-oncological surgery, owing to the higher invasiveness of the procedure with the associated increased general and surgical risk.

A recently published systematic review concluded that preoperative exercise therapy can be effective for reducing postoperative complication rates and lengths of hospital stay after cardiac and abdominal surgery [ 13]. Preoperative physical activities were lower in patients who developed postoperative pulmonary complications in a study by Feeney et al. [ 14]. Taking into account the importance of the physical condition, the preoperative physical activity level should be further examined [ 14]. A prospective observational study by Tatematsu et al. confirmed low-level physical activity – among others – as a significant risk factor for postoperative complications after esophagectomy [ 15].

One randomized controlled pilot study [ 16], two non-randomized controlled pilot studies [ 17, 18], one retrospective cohort study [ 19], and one study protocol [ 20] are available in the current literature with regard to preoperative inspiratory muscle training and postoperative pulmonary complications in patients undergoing esophagectomy. In all studies, preoperative inspiratory muscle training was feasible and effective as it resulted in a reduced postoperative pulmonary complication rate [ 16– 19]. Following these encouraging results, we designed an internet-based exercise program for patients scheduled for esophagectomy. The objective of this study is to investigate the pulmonary outcomes of physically preconditioned patients with Barrett’s cancer scheduled for esophagectomy who receive physical training during the phase of neoadjuvant therapy.

This is a prospective multicenter randomized-controlled trial organized by the Department of Sports Medicine, Disease Prevention and Rehabilitation of the Johannes Gutenberg-University of Mainz, Germany, and the Department of Visceral, Transplant, Thoracic and Vascular Surgery of the University Medical Center of Leipzig, Germany. Patients are randomly assigned to either undergo internet-based perioperative exercise program (iPEP) (intervention group) or treatment as usual (TAU) (control group). The randomization procedure is performed using an online random number generator, which is provided by the University of Geneva’s online service [ 21]. Randomization is stratified by center. The study is funded by the “Barrett-Initiative e.V.” ( http://​www.​barrett-initiative.​de/​). Inclusion (Table 1) and exclusion (Table 2) criteria are clearly defined. Primary staging, neoadjuvant treatment, preoperative nutrition as customized to the initial nutritional risk screening (NRS) [ 22], re-staging, preoperative peridural anesthesia, abdomino-thoracic esophagectomy with 2-field lymph node dissection and intrathoracic anastomosis, postoperative fluid management and nutrition, analgesia, physical therapy, mobilization and ventilation therapy following esophagectomy as well as rehabilitation are performed according to standard operating procedures (SOPs). At the beginning of the study, smokers are advised and supported to stop smoking by smoking cessation programs when needed. Smoking habits are recorded throughout the study.

Primary objective of the trial is to investigate the effect of the perioperative training on physical capacity.

Primary endpoint is the change in peak oxygen uptake (VO _2peak) prior to surgery as compared to baseline.

Secondary endpoints are

All respiratory parameters are assessed by a spirometer.

Further secondary endpoints encompass pneumonia within 12 weeks after surgery, anastomotic insufficiency within 12 weeks after surgery (according to Veeramootoo et al.) [ 23], duration of mechanical ventilation, re-intubation rate, length of intensive care unit stay, postoperative in-hospital stay, feasibility of the internet-based exercise program, quality of life as assessed with the EORTC (European Organization for Research and Treatment of Cancer), QoLQ-C30 questionnaire with the esophagus-specific module OES-18 [ 24], and social support of disease coping by means of the modified Berlin Social Support Scale [ 25].

In spite of significant advances in surgical techniques, postoperative intensive care and complication management, esophagectomy is still a high risk-procedure associated with considerable postoperative pulmonary morbidity and mortality. This often encounters for prolonged periods of reconvalescence and reduced quality of life, apart from socioeconomic disadvantages. In addition, postoperative pulmonary complications after esophagectomy are associated not only with worse short-, but also long-term outcomes [ 35]. Although morbidity and functional results following esophagectomy are known to be multifactorial, regular, structured physical activity and ventilation training before surgery seem to be the most relevant leverages to optimize results [ 13– 20]. As most patients with locally advanced, potentially resectable esophageal cancer undergo neoadjuvant treatment, this period offers the possibility for improving fitness, even in patients with no or only few previous physical activities. As shown by a recent metaanalysis, neither neoadjuvant chemotherapy nor radiochemotherapy for esophageal carcinoma increases the risk of postoperative morbidity or perioperative mortality compared with surgery alone [ 36]. There was also no clear difference between the two neoadjuvant treatment modalities with respect to postoperative morbidity [ 36]. Therefore, both modalities are allowed in our study. The “ Nutrition and Physical Activity Guidelines for Cancer Survivors” recommend a minimum of 150-min exercise per week, and strength training at least 2 days per week [ 37]. Because of the short intervention time and in order to achieve an optimum development of physical resources until surgery, a daily training is advised in our study. Participants should perform up to four units of endurance and up to 3 units of resistance training per week (approximately one hour per unit) in the last phase of training [ 38]. In addition, daily ventilation exercises are carried out with the “ Voldyne” device [ 39].

To our knowledge, this is the first prospective randomized controlled trial to assess an internet-based perioperative setting for patients scheduled for esophagectomy.

To ensure individual extensive care, the use of our online exercise program is easily accessible.

This novel concept might have several advantages: (i) the patients can perform exercises at home, (ii) individual, close and stepwise adaptation of the program is possible according to patient’s actual status, physical efficacy and symptoms / side effects of tumor presence or neoadjuvant therapy, (iii) there is only one supervisor / trainer for all centers of the study, strongly reducing the potential of bias due to different caregivers involved, (iv) social networking of all participants via different channels of communication will be possible in order to increase compliance and motivation to complete the program, and (v) an “open” area of the webpage offers information and news regarding Barrett’s carcinoma and respective measures / therapies, which can also be used by partners, relatives and friends of the individual. All these aspects supply the possibility to enable consequent and close care with the overall aim to reach a maximum of physical fitness and lung function before surgery. This also bears the potential for durable and healthy lifestyle changes and is enforced by the fact that patients can use the webpage even beyond their cancer treatment and study participation. Through active engagement with other patients the social factor is positively affected.

To avoid unwanted guests, we have constructed a private login area and the supervisor sets as administrator the accounts of the patients at study entry. Hence, a login without participation in the study is impossible.

The objective of our study is to evaluate for the first time the impact of an internet-based perioperative exercise program in patients with Barrett’s carcinoma scheduled for esophagectomy on respiratory parameters and pneumonia rates. Based on our concept, we hypothesize that the postoperative course of patients might be less complicated while functionally optimized. This multicenter study has started recruitment. Centers meeting the logistics of this study are welcome to participate and contact the address for correspondence (PS) for the detailed study protocol, Study Manual (SM) and Case Report Forms (CRFs).