PeRioperative Study of Exercise Training in Patients With Operable Cancer of the Gastroesophageal Junction
Condition: Gastro-esophageal Cancer
Study type: Interventional

Summary: 
      Background:

      For patients diagnosed with operable cancer of the gastro-esophageal junction (GEJ), the
      perioperative course of therapy is associated with severe deconditioning which includes
      weight loss and poor physical function, which are strong predictor of post-surgical
      complication and survival . A strong rationale exists to explore how to develop supportive
      interventions aimed at maintaining/improving muscle function (lean body mass and muscle
      strength) during the pre-surgical phase.

      This study explores the safety, feasibility and efficacy of structured pre- and
      post-operative exercise training in patient undergoing surgery for cancer of the
      gastro-esophageal junction.

      Subjects: Patients with histologically verified, resectable adenocarcinoma of the GEJ
      scheduled for treatment af Rigshospitalet, Copenhagen, Denmark.

      Methods: In a case-control design, patients will be allocated to either an exercise training
      intervention group, or a usual-care observational group, based on geographical location.
      Forty patients will be included in this case-control study and allocated by geographical
      region as follows; 20 training intervention-cases living in the greater Copenhagen area, and
      20 observational control subjects living outside the greater Copenhagen area.

      All patients will undergo a total of 5 assessments during the perioperative trajectory; twice
      prior to surgery (baseline and pre-surgery test), three post-surgery (2 week post- and 15
      weeks post-surgery, and at 1-year follow-up).

      Assessments include measures of body composition by DXA scan and bioelectrical impedance
      analysis: systemic inflammation in fasting blood sample; quality of life by self-report
      questionnaires; physical function by handgrip strength and sit-to-stand test.

      As optional procedures, we will collect biological tissue from tumor, muscle and fat biopsies
      and a 10 ml blood sample at baseline and pre-surgery test only. Also, we will collect blood
      samples before, during and after an acute exercise bout exercise in order to explore the
      acute systemic changes in exercise-regulated biomarkers.
    

Detailed description: 
      BACKGROUND AND RATIONALE Patients diagnosed with operable cancer in upper gastro-intestinal
      (GI) tract undergo serious therapeutic procedures including invasive surgery combined with
      chemo- or chemo-radio therapy before (neo-adjuvant) and/or after (adjuvant) surgery. Despite
      recent advances, especially in surgical techniques and patient care follow-up, the population
      is faced with one of the worst prognosis for patients with operable staged disease, with a
      5-year relative survival of 35-40%. The only possibility of long-term survival is positive
      surgical outcome, which includes the surgical principle of performing wide clearance,
      achieving a negative margin (R0 resection), and performing a radical lymphadenectomy. To this
      end, considerable efforts have been made in recent years optimizing the perioperative period
      in order to provide the patients and the surgeons with the best possible chances of achieving
      this surgical outcome.

      Adenocarcinoma of the gastro-esophageal junction (GEJ) has increased in incidence over the
      last quarter century. For patients presenting with localized disease, advances in standards
      of care have emerged in recent years which have improved disease management. Firstly,
      comprehensive staging with Computed Tomography (CT), endoscopic ultrasound, diagnostic
      laparoscopy and fluoro deoxy glucose position emission tomography (18FDG-PET) permits
      exclusion of patients for curative therapy who might previously have been scheduled for
      resection. Secondly, evidence supports that esophagectomy is performed in high-volume
      hospitals by high-volume surgeons. Finally, standard neoadjuvant and adjuvant therapies are
      performed in most centers for patients with localized esophageal adenocarcinoma which has
      improved both short- and long-term cancer outcomes.

      Prognostic role of Muscle Function in upper GI cancer For all upper GI cancers, including
      GEJ, the perioperative course of therapy is associated with severe deconditioning which
      includes weight loss and poor physical function. Over the last decade, strong observational
      evidence has emerged supporting that poor pre-surgical muscle function, defined as either low
      muscle mass/area (sarcopenia) or low functional strength, is a strong independent predictor
      of post-surgical outcomes including mortality, surgical complications and chemotherapy
      dose-reduction. Importantly, strong evidence across different malignancies has shown that the
      prognostic value of muscle function is independent from body mass, and may actually be
      under-reported due to sarcopenic obesity. Thus, current available therapeutic countermeasures
      in clinical practice, which exclusively involve nutritional interventions, may have limited
      potential for ameliorating the progressive muscle dysfunction during perioperative treatment
      for GEJ cancer.

      Exercise-Oncology and Upper GI cancer Epidemiological evidence across both heterogeneous and
      homogeneous groups of cancer patients have shown that low physical activity level after
      diagnosis is associated with poor disease-specific and overall survival. Despite a general
      emerging interest, limited attention has been dedicated to the exploration of safety,
      feasibility and efficacy of structured exercise interventions in patients with upper GI
      cancer. However, data from recent studies suggests an unmet potential of physical exercise in
      these patients, with particular emphasis on the pre-surgical period.

      STUDY OBJECTIVES Primary Objective

      • To explore safety and feasibility of structured exercise in the pre- and post-operative
      phases among patients undergoing treatment for operable GEJ cancer

      Secondary objectives:

        -  To explore the effect of perioperative exercise training on clinical (e.g. clindo-davien
           score, pneumonia, anastomotic leakage) physiological (e.g. muscle strength, physical
           function) and psycho-social (e.g. fatigue, emotional well-being, anxiety) endpoints
           relative to usual care.

        -  To explore the prognostic role of pathophysiological profile (physical function,
           pulmonary function, and body-composition) on post-surgical complications

      Explorative objectives:

        -  To explore molecular adaptations of metabolism and physiology in tumor, muscle and fat
           samples taken before and after neo-adjuvant chemotherapy in the pre-operative phase in
           (a sub-group of) patients allocated to exercise training or usual care

        -  To explore the acute response in immune cells, hormones and cytokines in blood samples
           taken before, during and after a single exercise session

        -  Collection of blood and tissue samples for storage in bio-bank for future research.

      STUDY DESIGN This prospective, regional-based case-controlled feasibility trial will include
      in a minimum of 40 patients, including 20 training intervention-cases who are residents in
      greater Copenhagen Area, and 20 usual care controls living outside the greater Copenhagen
      area.

      Recruitment: Patients will be recruited from the department of surgical gastroenterology,
      Rigshospitalet, following multidisciplinary medical conference. The responsible physicians
      will provide oral information and present patients with the written information of the study.

      Patients who are willing to participate will sign informed consent, before any study related
      procedures are performed. After signing informed consent, patients are scheduled for baseline
      assessment and will be allocated based on geographical location (home-town municipality), to
      one of two experimental arms:

      I) Patient residing OUTSIDE the Copenhagen area, will be allocated to a usual care
      observation group, which includes nurse-based follow up procedures and information on life
      style factors (diet, smoking cessation, alcohol, and physical activity).

      II) Patients residing WITHIN the Copenhagen area, will be allocated to usual care plus
      hospital-based aerobic and resistance training at Centre for Physical Activity Research,
      Rigshospitalet

      Procedures will involve assessment-measures conducted a total of 5 times during the study
      period: twice prior to surgery (baseline and pre-surgery test), twice post-surgery (3 week
      post- and 15 weeks post-surgery) and at 1-year follow-up.

      The following assessments will be performed:

        1. Body composition by Bioelectrical Impedance

        2. Fasting blood sample for analyses of plasma biochemistry (cholesterol, triglycerides,
           inflammatory markers, HbA1C)

        3. Health related Quality of Life questionnaires

        4. Physical function: Handgrip strength and sit-to-stand test.

        5. Forced Expiration Volume in 1 second (FEV1)

        6. Biological tissue sampling (OPTIONAL): tumor, muscle and fat biopsies and blood samples
           - only baseline and pre-surgery.

        7. Acute Exercise Response (OPTIONAL); blood samples taken before and after a single
           exercise session.

      ANALYTIC PLAN As a feasibility study, this trial is explorative in nature and performed
      primarily in order to determine whether it is appropriate to advance with a larger scaled
      randomized controlled trial.

      Primary aim

      Safety and feasibility of perioperative exercise training in patients with operable GEJ
      cancer

      In order to evaluate the safety and feasibility of the pre- and post-surgical exercise in
      patients with operable cancer of the gastro-esophageal junction, incidence of serious adverse
      events in both groups will be determined, and adherence to exercise, assessed by number of
      training sessions completed in the training group.

      Secondary aims

      Efficacy of perioperative exercise training to improve clinical, physiological and
      psycho-social outcomes in patients operable GEJ cancer.

      In order to determine whether exercise training has the capacity to improve study outcomes
      intragroup changes, and inter-group differences for study outcomes will be calculated. For
      this purpose a random effect analysis will be performed with repeated measures and study
      outcomes as dependent variables, with the covariates "group", "time" and their interaction as
      fixed effects, and a random effect of "patient", adjusted for baseline-score, chemotherapy
      regimen, and surgical procedure (conventional vs laparoscopic).

      Prognostic role of pathophysiological profile in patients with operable GEJ cancer

      In order to explore the prognostic role of the study assessment outcomes on key clinical
      endpoints: post-surgical complications, hospital stay duration and disease free and overall
      mortality risk over the first years after surgery, by a general linear regression models with
      clinical endpoints being the dependent variable, and study assessment outcomes as the
      independent variables adjusted for baseline-score, chemotherapy regimen, and surgical
      procedure (conventional vs laparoscopic). For each variable (physical function, pulmonary
      function, and body-composition), the predictive value of: I) the diagnostic level (prior to
      neo-adjuvant therapy), II) the pre-surgical level (after neo-adjuvant treatment) and III) the
      change score from diagnostic to pre-surgical level (during neo-adjuvant therapy) will be
      determined.

      Dropouts and Missing Observations Patients who wish to drop-out of the study during the
      intervention-periods will be offered to remain in the study with regard to test-assessments.
      Patients who drop out prior to 'visit 2' will be replaced. For between-group analyses, all
      drop-outs and missing observations will be handled by the "missing at random" principle.

      ETHICAL CONSIDERATIONS This study will be conducted in accordance with the regional ethical
      committee and the Declaration of Helsinki (1964) with its subsequent revisions. The protocol
      and any substantial amendments, the study patient information and consent form, as well as
      other relevant or requested material have been approved by the local ethics committee
      (Videnskabsetisk Komite) for the Capital Region of Denmark (Protocol number: H-15014904) and
      is reported to the Danish Data Protection Agency (Datatilsynet: RH-2016-33, I-Suite nr.:
      04396) through Rigshospitalet/Capital Region of Denmark (j.nr. 2012-58-0004).

      The project is expected to cause limited risks, side effects and discomfort. All procedures
      will be performed by experienced physicians, therapists and physiologists with relevant
      safety, and patients will not experience any kind of delays or complications related to
      treatment or control process due to participation in the project. Patients may at any time,
      and without justification, retract their consent.
    

Intervention name(s): Aerobic and Resistance Exercise Training
Intervention type(s): Behavioral
Intervention description(s): Supervised aerobic and resistance exercise program consisting of 2 weekly sessions of approximately 60 minutes. Patients will perform a test of maximum cardio-respiratory (Watt-max test) and muscle strength (1 repetition maximum [1-RM] test) capacity. Using the patient's individual capacity score (Watt-max and 1RM), a personalized exercise program will be prescribed. After a light warm-up, patients will perform 20-30 min of aerobic interval training of stationary bicycle. Resistance training comprises 4 exercises for the major muscle groups: chest press, leg press, lateral pull, and knee extension with 3-4 sets of 8 to 15 repetitions. Each session will be supervised by trained instructors to ensure proper technique, and progression in training load.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Exercise training; Surgical complications; Cancer prognosis; Muscle function; Body composition; Pulmonary function; Quality of life