Esophagogastric Cancer Surgery

Esophagogastric Cancer Surgery: Comparison

Please note this is a comparison between Version 1 by Augustinas Bausys and Version 3 by Rita Xu.

Esophagogastric cancer is among the most common malignancies worldwide. Surgery with or without neoadjuvant therapy is the only potentially curative treatment option. Although esophagogastric resections remain associated with major surgical trauma and significant postoperative morbidity. Prehabilitation has emerged as a novel strategy to improve clinical outcomes by optimizing physical and psychological status before major surgery through exercise and nutritional and psychological interventions.

esophageal cancer
gastric cancer
esophagectomy
gastrectomy

1. Introduction

Esophagogastric cancer (esophageal and gastric cancer; EGC) is among the most common malignancies worldwide, with over 1.6 million new cases and 1.2 million deaths annually ^[1][2][3][1,2,3]. Surgery is the main and only curative treatment option ^[4][5][4,5]. However, gastric and esophageal resections remain associated with high postoperative morbidity and mortality rates ^[4][5][6][4,5,6]. Current evidence indicates the benefits of neoadjuvant chemo(radio)therapy ^[7][8][9][7,8,9]. Preoperative cytotoxic treatment improves oncological outcomes, but impairs patients’ physical and nutritional status, promotes sarcopenia, and decreases physiological reserve, thus further increasing the surgery-related risk ^{[4][10][11][12]}[4,10,11,12]. Consequently, there is a need for novel strategies to improve EGC surgery outcomes.

Recently, prehabilitation has emerged as a way to prepare a patient for major surgery. As it is a relatively new concept in surgical oncology, definitions of prehabilitation still vary. They consistently state that it is a pre-emptive preparation of a patient to reduce risks and enhance recovery after a stressful event. Prehabilitation has significantly reduced postoperative morbidity in some high-risk patients undergoing major abdominal surgery [13]. Additionally, it reduces systemic inflammation [14], attenuates chemotherapy-induced toxicity [15], modulates several host- and tumor-related pathways during standard chemotherapy [15], and may even promote tumor regression following neoadjuvant therapy [16]. Current studies on prehabilitation are very heterogenous in a perioperative care pathway and measured outcomes. Moreover, some studies show controversial results, as prehabilitation has no benefit in frail patients undergoing minimally invasive colorectal cancer surgery [17]. Therefore, the role of prehabilitation in modern EGC surgery remains unclear.

2. The Current Concept of Prehabilitation in Esophagogastric Cancer Surgery

Current definitions of prehabilitation vary but consistently state that it is a pre-emptive preparation of a patient to reduce risks and enhance recovery after a stressful event. EGC surgery is an ideal example of a stressor because of extensive surgical trauma, physiological consequences of previous cytotoxic treatments, and psychological distress. These factors interact with the burden of cancer, which includes impaired nutritional and physiological reserves due to cachexia, malnutrition, and sarcopenia. The preoperative period constitutes a unique opportunity to prepare the patient for these challenges because most are highly motivated to change behavior for perioperative benefits ^[18][20]. Contemporary prehabilitation programs may include one (unimodal) or several (multimodal) interventions aiming to correct modifiable risk factors, promote a patient’s physical activity, optimize nutritional status, and intervene in psychological wellbeing. There is no consensus on the optimal design of a prehabilitation program; thus, different approaches have been investigated (Table 1).

Table 1. Characteristics of studies investigating prehabilitation for esophagogastric cancer surgery.

Author; Year	Design	Description and Number of Participants; (n)	Measured Outcomes	N–O Score	Jadad Score

Table 3. Outcomes of included studies evaluating prehabilitation for esophagogastric cancer surgery.

Author; Year	Prehabilitation Impact on Physical Status	Prehabilitation Impact on Postoperative Outcomes	Other Effects of Prehabilitation
Allen et al. ^[19]; 2021	Allen et al. [21]; 2021
Allen et al.	RCT	^[19]; 2021	Allen et al. [21]; 2021Esophagogastric cancer patients scheduled for surgery after neoadjuvant chemotherapy; (	n	= 54)	Prehabilitation attenuated peak VO2 decrease and skeletal muscle loss following neoadjuvant therapy. Additionally, HGS was better retained in the prehabilitation group, and patients in this group were more physically active by higher weekly step count.	Prehabilitation had no impact on the number and severity of complications, length of hospital stay, 30-day readmission rates, and 3-year cancer-related mortality.	Primary outcome:	Change in AT by CPET.	Secondary outcomes:	Change in peak VO2 by CPET; Sarcopenia measured by computed tomography; HGS; Health-related quality of life by EORTC QLQ-C30 questionnaire, Beck Anxiety Inventory, and Beck Depression score; Full adherence to the planned neoadjuvant chemotherapy and its toxicity; Weekly step count; Postoperative morbidity; 30-day hospital readmission rate; 3-year mortality rate.		N/A	3
Prehabilitation improved QoL by global health status after 2 cycles of neoadjuvant chemotherapy and at 2 weeks, 6 weeks, and 6 months postoperatively. Additionally, prehabilitation resulted in better BAI and DBI II scores preoperatively and 6 weeks and 6 months postoperatively.		A higher proportion of patients in the prehabilitation group received neoadjuvant chemotherapy at full dose.	Minnella et al. ^[20]; 2018	Minnella et al. [22]; 2018	RCT
Minnella et al. [17]; 2018	Esophagogastric cancer patients scheduled for surgery ± neoadjuvant treatment; (	n	= 68)	Prehabilitation improved functional capacity before and after surgery by increasing 6MWD.	Primary outcome:	Change in functional capacity over time by 6MWD.	Secondary outcomes:	Postoperative morbidity at 30 days; Length of hospital stay; 30-day hospital visits;	Prehabilitation had no impact on the number and severity of complications, length of hospital stay, emergency department visits, and readmission rates.	30-day readmission rates; 30-day death rates; Full adherence to the planned neoadjuvant chemotherapy; Compliance with prehabilitation program.		N/A	3
N/A	Valkenet et al. ^[21]; 2018	Valkenet et al. [23]; 2018	RCT
Valkenet et al. ^[31]; 2018	Valkenet et al. [18]; 2018	Esophageal cancer patients scheduled for surgery ± neoadjuvant treatment; (	n	= 270)	Primary outcome:	Postoperative pneumonia rate.	Secondary outcomes:	Respiratory muscle function: maximum inspiratory pressure and inspiratory muscle endurance; Pulmonary function: expiratory volume in 1 s and FVC; Postoperative complication rate;	Prehabilitation resulted in a higher increase in inspiratory muscle strength and endurance.	Duration of mechanical bowel ventilation; Length of hospital stay; Quality of life by EuroQol-5D and SF-12 questionnaires; Physical activity by SQUASH questionnaire; Fatigue by MFI-20 questionnaire.		N/A	3
Prehabilitation did not affect postoperative pneumonia and other postoperative complication rates.	Prehabilitation did not affect the quality of life, fatigue, and physical activity levels.	van Adrichem et al. ^[22]; 2014	van Adrichem et al. [24]; 2014	RCT	Esophageal cancer patients scheduled for surgery ± neoadjuvant CRT; (	n	= 45)	Primary outcome:	Postoperative pulmonary complications rate.	Secondary outcomes:	Length of stay; Stay in ICU; Number of reintubations; Maximal inspiratory pressure before and after training; Lung functions (FVC, FEV1, FEV1/FVC, and PIF); Feasibility by the number of IMT-related adverse events, compliance to training, and a self-estimated load of participation.		N/A	3
Xu et al. ^[23]; 2015
van Adrichem et al. ^[32]; 2014	van Adrichem et al. [19]; 2014	The increase in maximal inspiratory pressure was similar between the groups which received preoperative inspiratory muscle training.	The incidence of postoperative pulmonary complications, length of stay, and the number of reintubations were lower in the high-intensity inspiratory muscle training group.	N/A	Xu et al. [25]; 2015	Pilot study (RCT)
Xu et al. ^[22]; 2015	Xu et al. [	Esophageal cancer patients scheduled for neoadjuvant CRT and surgery; (	n	= 59)	24]; 2015	Primary outcomes:	Functional walking capacity by 6MWD and strength by HGS; Nutritional status by BW and fat-free lean mass by bioelectrical impedance.	Secondary outcome:	Treatment tolerance by interruptions in chemotherapy or radiotherapy; unplanned hospital admission; grade > 2 neutropenia; fever > 38.5 °C; intravenous nutritional support and wheelchair use.		N/A	Prehabilitation ameliorated decline in 6MWD and hand-grip strength.3
N/A	Prehabilitation ameliorated weight and lean muscle mass loss.		Additionally, patients in the prehabilitation group had a significantly lower need for intravenous nutritional support and wheelchair use.	Yamana et al. ^[24]; 2015	Yamana et al. [26]; 2015	RCT	Esophageal cancer patients scheduled for surgery ± neoadjuvant treatment; (	n
Yamana et al. ^[18]; 2015	Yamana et al. [20]; 2015	Prehabilitation did not affect respiratory function representing parameters (FVC, FEV1, FEV1%, and PEF). = 63)	Primary outcome:	Postoperative pulmonary complication rate.	Secondary outcomes:	Respiratory function by FVC, FEV1, FEV1%, and PEF.		N/A	3
Prehabilitation ameliorated the severity of postoperative complications (by lower Clavien–Dindo score) and postoperative pneumonia (by lower Utrecht Pneumonia Scoring System score).	N/A	Christensen et al. ^[25]; 2018	Christensen et al. [27]; 2018	Non-randomized control trial
Christensen et al. ^[23	Patients with GOJ adenocarcinoma scheduled for neoadjuvant treatment and surgery; (	n	= 50)	^]; 2018	Christensen et al. [25]; 2018	Primary outcome:	Frequency of serious adverse events (defined as events that prevented surgery).	Secondary outcomes:	Neoadjuvant treatment tolerability; Postoperative complication rate; Postoperative hospital stay; Patient-reported tolerability to neoadjuvant treatment by FACT-E questionnaire;	Prehabilitation resulted in improved fitness and muscle strength.	Response to treatment by infiltration of the resection margin and immunoscore, tumor regression grade by Mandard, and pathological tumor stage (pTNM).	Prehabilitation did not affect the postoperative complication rate.			8	N/A
Prehabilitation resulted in improved quality of life by FACT-E score.	Dettling et al. ^[26]; 2013	Dettling et al. [28]; 2013	Non-randomized controlled trial
Dettling et al. ^[24]; 2013	Dettling et al. [	Patients scheduled for esophagectomy ± neoadjuvant treatment; (	n	= 83)	26]; 2013	Primary outcomes:	Feasibility by the occurrence of adverse effects, patients’ satisfaction; Initial effectiveness by pre-operative improvement in respiratory function.	Secondary outcomes:	Postoperative pneumonia rate; Length of hospital stay; Duration of mechanical ventilation; Reintubation rate; Length of stay in the ICU;	Prehabilitation increased inspiratory muscle strength and endurance.	Postoperative morbidity rate.		8	N/A
Prehabilitation did not affect postoperative pneumonia and other complication rates.	N/A	Argudo et al. ^[27]; 2020	Argudo et al. [29]; 2020
Argudo et al. ^[	Pilot study (prospective interventional study)	^19]; 2020	Argudo et al. [Esophagogastric cancer patients scheduled for neoadjuvant treatment and surgery; (	n	= 40)		Feasibility by TELOS components; Tolerability; Exercise capacity by cardiopulmonary exercise testing; Pulmonary and muscle function; Peripheral muscle function; Health-related quality of life by EORTC QLQ-C30 questionnaire.		6	N/A
Piraux et al. ^[28]; 2020	Piraux et al. [30]; 2020	Pilot study (prospective interventional study)	Esophagogastric cancer patients scheduled for surgery ± neoadjuvant treatment; (	n	= 23)	Primary outcome	Feasibility (recruitment, retention and attendance rates, adverse events, and patient satisfaction).	Secondary outcomes	Functional exercise capacity by 6MWD; CRF by FACIT-F scale; Quality of life by FACT-G questionnaire; Anxiety and depression by HADS questionnaire.		6	N/A
Yamamoto et al. ^[29]; 2016	Yamamoto et al. [31]; 2016	Pilot study (prospective interventional study)	Gastric cancer patients aged ≥ 65 years with a diagnosis of sarcopenia scheduled for gastrectomy; (	n	= 22)		Nutritional intake (total number of calories and protein daily intake); Body composition (body mass, fat mass, lean body mass); Sarcopenia parameters (handgrip strength, gait speed, and skeletal muscle mass index).		6	N/A
Cho et al. ^[30]; 2014	Cho et al. [32]; 2014	Matched pair analysis	Patients with clinical stage I gastric cancer and metabolic syndrome scheduled for gastrectomy; (	n	= 72)	Primary outcome:	Postoperative complications rate.	Secondary outcomes:	The operative time; Intraoperative blood loss; Hospital stay; Visceral fat and body weight.		7	N/A

RCT: randomized controlled trial; CRT: chemoradiotherapy; N/A: not applicable; GOJ: gastroesophageal junction; AT: anaerobic threshold; CPET: cardiopulmonary exercise testing; 6MWD: six minute walking distance; HGS: hand-grip strength; BW: body weight; FVC: forced vital capacity; FEV1: forced expiratory volume in the first second; FEV1%: forced expiratory volume in the first second predicted; PEF: peak expiratory flow. Among them, there are 5 randomized control trials (RCTs) ^{[19][20][21][22][24]}[21,22,23,24,26], 4 pilot studies ^{[23][27][28][29]}[25,29,30,31], 2 non-randomized control trials ^[25][26][27,28], and 1 matched-pair analysis ^[30][32]. Despite the fact that all studies focused on prehabilitation for EGC surgery, they are heterogeneous in applied interventions and measured outcomes. Table 2 and Table 3 show the structure of prehabilitation programs and their impact on clinical outcomes.

Table 2. Structure of interventions in prehabilitation programs for esophagogastric cancer surgery.

Author; Year	Prehabilitation Group			Control Group
Author; Year	Type of Prehabilitation (Unimodal vs. Multimodal)	Timing of Prehabilitation	Interventions Used for Prehabilitation	Control Group
Allen et al. ^[19]; 2021	Allen et al. [21]; 2021	Multimodal	Prehabilitation was initiated for 15 preoperative weeks.		Exercise intervention: supervised aerobic, resistance, and flexibility training twice a week and home-based exercise training three times per week; Nutritional intervention: needs-based nutritional interventions with frequent, tailored dietetic input from specialist dieticians, increasing calorie and protein intake where appropriate depending on assessments and physical activity levels; Psychological intervention: six sessions of medical coaching, which included discussion of health status, strength recognition, resilience profiling and development, social and support systems, emotional management, and goal setting.			Standard of care
Minnella et al. [17]; 2018	Multimodal	Prehabilitation was initiated before the initial surgery or at the time of neoadjuvant therapy.		Exercise intervention: individualized, home-based exercise training program including aerobic and strengthening exercise; Nutritional intervention: metabolic requirement was adjusted to meet the increased nutritional demand. Food-based dietary advice was given, and a whey protein supplement was prescribed to guarantee a daily protein intake.			Standard of care
Valkenet et al. ^[31]; 2018	Valkenet et al. [18]; 2018	Unimodal	Prehabilitation was initiated for 2 weeks or longer. When neoadjuvant therapy was administered, prehabilitation started afterward.		Exercise intervention: inspiratory muscle training.			Standard of care
van Adrichem et al. ^[32]; 2014	van Adrichem et al. [19]; 2014	Unimodal	Prehabilitation was initiated for 3 weeks. When neoadjuvant therapy was administered, prehabilitation started afterward.		Exercise intervention: high-intensity inspiratory muscle training.			Exercise intervention: endurance inspiratory muscle training
Xu et al. ^[22]; 2015	Xu et al. [24]; 2015	Multimodal	Prehabilitation was initiated for 4–5 weeks during the neoadjuvant chemoradiotherapy.		Exercise intervention: nurse-supervised walking; Nutritional intervention: nutritional advice.			Standard of care
Yamana et al. ^[18]; 2015	Yamana et al. [20]; 2015	Unimodal	Prehabilitation was initiated for ≥7 days before the surgery.		Exercise intervention: respiratory muscle training; muscle strengthening exercises for the lower limbs and abdominal muscles; biking on an ergometer.			Standard of care
Christensen et al. ^[23]; 2018	Christensen et al. [25]; 2018	Unimodal	Prehabilitation was initiated at the time of neoadjuvant treatment.		Exercise intervention: supervised high-intensity aerobic and resistance exercise.			Standard of care
Dettling et al. ^[24]; 2013	Dettling et al. [26]; 2013	Unimodal	Prehabilitation was initiated for 2 weeks or longer.		Exercise intervention: inspiratory muscle training.			Standard of care
Argudo et al. ^[19]; 2020	Argudo et al. [21]; 2020	21Multimodal	]; 2020Prehabilitation was initiated after neoadjuvant chemotherapy for 5 weeks.		Prehabilitation improved exercise capacity in terms of VO2 peak and workload and distance improvement in the 6MWD and inspiratory and expiratory muscle strength.		N/A	Exercise intervention: high-intensity interval training on the ergometric bicycle; respiratory muscle training using a respiratory muscle trainer. Nutritional intervention: individualized nutritional therapy based on nutritional status and ability to fulfill caloric-protein requirements.	Prehabilitation resulted in the improvement of some domains of health-related quality of life (social and role functions).	N/A
Piraux et al. ^[20]; 2020	Piraux et al. [22]; 2020	Unimodal	Prehabilitation was initiated for 2–4 weeks before the surgery.
Piraux et al. ^[20]; 2020	Piraux et al. [22]; 2020	N/A		Exercise intervention: aerobic, resistance, and respiratory muscle training using an online tele-prehabilitation platform.			N/A
N/A	Prehabilitation improved fatigue, quality of life, physical well-being, emotional well-being, and anxiety.	Yamamoto et al. ^[21]; 2016	Yamamoto et al. [23]; 2016	Multimodal	Prehabilitation was initiated for 3 weeks, although the actual duration differed depending on the surgery date.
Yamamoto et al. ^[21]; 2016	Yamamoto et al. [23]; 2016		Exercise intervention: handgrip training, walking, and resistance training; Nutritional intervention: nutritional advice and 2.4 g daily oral supplementation with leucine metabolite b-hydroxy-b-methylbutyrate (HMB).			N/A	Prehabilitation significantly increased handgrip strength.
N/A	Prehabilitation improved nutritional uptake by increasing calorie and protein intake.	Cho et al. ^[25]; 2014	Cho et al. [27]; 2014	Unimodal	Prehabilitation was initiated for 4 weeks.		Exercise intervention: aerobic exercise, resistance training, and stretching.		Standard of care

CRT: chemoradiotherapy; N/A: not applicable.

Cho et al.
^[
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; 2014
Cho et al. [
27
]; 2014
N/A
Prehabilitation decreased hospital stay and the number of severe postoperative complications (anastomotic leakage, pancreatic fistula, intra-abdominal abscess, and other severe abdominal complications).	Prehabilitation significantly decreased BMI, bodyweight, abdominal circumference, and visceral fat.