Adherence to a Combined Exercise and Dietary Intervention in Patients With Gastrointestinal Cancer Undergoing Neo-adjuvant Therapy.
Phase: NA
Conditions: Adherence, Gastrointestinal Cancer
Sponsor: Hospital Beatriz Ângelo

 
 
Adherence to a Combined Exercise and Dietary Intervention in Patients With 
Gastrointestinal Cancer Undergoing Neo-adjuvant Therapy. 
 
Date-23-4-18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Velho S1, Moço S1, Capitão C1, Branco M1, Costa L2, Rodrigues S3, Abreu C4, Sousa P5, 
Agostinho L5, Cruz R5, Clemente S3, Borges A4 , Lopes F2, Godinho J2, Faria A2, Teixeira JA2, 
Passos Coelho JL2, Maio R6, Baracos VE7, Cravo M8 
1 Dietetics and Nutrition Department, Hospital Beatriz Ângelo, Loures, Portugal 
 2 Oncology Department, Hospital Beatriz Ângelo, Loures, Portugal 
3 Pneumology Department, Hospital Beatriz Ângelo, Loures, Portugal 
4 Physical Medicine and Rehabilitation Department, Hospital Beatriz Ângelo, Loures, Portugal  
5Radiology Department, Hospital Beatriz Ângelo, Loures, Portugal 
6 Surgery Department, Hospital Beatriz Ângelo, Loures, Portugal 
7 Oncology Department, University of Alberta, Canada 
8Gastroenterology Service, Hospital da Luz, Loures, Portugal 
 
Introduction  
A high prevalence of patients with upper gastrointestinal (GI) cancer undergoing neo-adjuvant 
chemotherapy (ChT) experience dose limiting toxicity which may lead to a worse outcome. 
Factors associated with tolerance to ChT remain unclear, but it has recently been shown that 
alterations of body composition may play an important role. Body composition alterations 
such as sarcopenia and especially sarcopenic obesity have been related to higher ChT toxicity 
(Prado, et al., 2007) (Palmela, et al., 2017), increased post-op complications (Peng, et al., 2011) 
(Lieffers, Bathe, Fassbender, Winget, & Baracos, 2012) (Jolekar, Nau, & Mezhir, 2015) and 
lower overall survival (Martin, et al., 2013) (Kazemi-Bajestania, Mazurakb, & Baracos, 2016) 
(Chu, et al., 2017). Although, negative consequences of sarcopenia in cancer patients have 
been recognized, strategies focusing on improving/modifying body composition and whether 
these are able to modulate clinical outcome are still open to debate.  
Dietary intake is a modifiable factor that seems to have an important role in skeletal muscle 
maintenance. It has been suggested that cancer patients may experience an anabolic 
resistance to protein stimuli, however protein synthesis is not completely blunted and may be 
responsive to an elevated protein intake. In fact, recent studies demonstrated that whey 
protein supplementation improved protein synthesis (Deutz, et al., 2011) and walking capacity 
(Gillis, et al., 2016)  in cancer patients. Besides protein intake, the role of fat intake remains to 
be established. Most studies have focused on the effect of polyunsaturated fat intake, namely 

n-3 polyunsaturated fatty acids which have demonstrated a beneficial effect in the treatment 
of age-related sarcopenia (Henderson, 2015) and cancer associated muscle wasting (Deutz, et 
al., 2011). However, in a study with cancer patients with advanced disease, fish oil was 
compared with olive oil as placebo and no difference was found (Bruera, et al.). It is also worth 
pointing out that dietary patterns may be more relevant than a single nutrient intake, and 
interestingly in a study conducted with older adults higher adhesion to Mediterranean diet 
(high intake of fruit, vegetables, olive oil, nuts, fish) was associated with a lower odds of 
sarcopenia (Hashemi, et al., 2015). 
Exercise has been recently associated with improved functional capacity and better patient 
reported outcomes (quality of life and psychological outcomes) in cancer patients (Jones and 
Alfano 2013, Manja Idorna 2016). Although, only few studies have been conducted, there is 
already some evidence that exercise may improve functional capacity in several settings 
namely breast cancer patients receiving chemotherapy/radiotherapy (Jones and Alfano 2013), 
pre-surgery lung cancer (Jones and Alfano 2013) and incurable advanced disease (Oldervoll, 
Loge et al. 2011). In addition, operated breast cancer patients receiving adjuvant 
chemotherapy assigned to supervised resistance training were more likely to complete 
treatment (Jones and Alfano 2013). Still, there is limited information regarding the effect of 
exercise on body composition and outcomes such as post-operative complications, 
chemotherapy (ChT) response and toxicity. 
 It has also been hypothesized that exercise may inhibit tumor growth directly. In a recent 
experimental study, tumor bearing mice randomized to wheel running, showed a 60% 
reduction in tumor incidence across five different tumor models (Pedersen, et al.). Also, NK cell 
infiltration was significantly increased in tumors from running mice. Mechanistic analysis 
showed that NK cells were mobilized by epinephrine released during exercise, which resulted 
in a selective mobilization of IL-6 sensitive NK cells into the tumor. Another consequence of 
this mobilization of NK and other T cells, is to eventually sensitize and prime it to 
immunotherapy (Pedersen B. K., 2011).  
Although an adequate dietary intake and exercise are suggested to improve body composition 
which may influence outcome, reported adherence to behavioral interventions has been 
showed to vary substantially. In a study that focused on evaluating the impact of exercise 
during and after treatments of recruited cancer patients from Radiation Oncology and 
Gynaecology department, adhesion to 3 and 6 month program of exercise was 93 and 91%, 
respectively (Grabenbauer, Grabenbauer, Lengenfelder, Grabenbauer, & Distel, 2016). Another 

study aiming to explore the feasibility of dietary intervention focusing on a low-fat and high 
fruit and vegetable intake combined with moderate exercise in breast cancer patients, also 
found a high adherence (75%). However, according to a meta-analysis aiming at assessing 
adherence of colorectal adenoma patients to behavioral interventions such as diet and 
physical activity, a wide range of adherence was reported, 8 to 86 % and 13 to 47 %, 
respectively (McCahon, et al., 2015). Furthermore, in a feasibility study of exercise and diet 
interventions in pancreatic and lung cancer patients a suboptimal adhesion was reported, for 
exercise (60%), but especially for nutritional supplements (48%) (Solheim, et al., 2017). 
Bearing in mind that adherence may be a limiting factor for randomized controlled trials 
investigating the effect of behavioral interventions, the purpose of our study is to conduct a 
study to investigate adherence of upper GI cancer patients to a combined exercise and dietary 
intervention.  
General Aims: 
 
To study the adherence of upper GI cancer pts to a Combined Exercise and Diet 
Intervention (CEDI) during neoadjuvant chemotherapy. 
Specific Aims: 
 
To determine the rate of completion of CEDI protocol. 
 
To analyze the proportion of participants which achieve ≥ 50% of dietary and exercise 
goals. 
 
To explore the effect of CEDI on ChT toxicity and post-op complications 
 
Study design:  
 
Open label randomized controlled trial  
Patient recruitment:  
Recruitment will be conducted at the Oncology center of Hospital Beatriz Ângelo and patient 
selection will be done during the weekly multidisciplinary meeting. Patients will be enrolled at 
diagnosis of upper GI cancer, namely esophagus, gastric and pancreatic, provided that they are 
eligible for neoadjuvant ChT and with age higher than 18 years and lower than 80 years.  
Sample size per group was calculated bearing in mind that according to data form the World 
Health Organization, 14% of Portuguese adults are compliant to moderate exercise, and in our 
study adherence will be set as a compliance higher than 50%.  Considering a power of 0.80 and 
an α set at 0.05, 25 patients will be needed per group. Stratified block randomization will be 

conducted to allocate 25 patients to standard care and 25 to CEDI. Stratification will be 
performed according to disease location. Randomization will be undertaken by a 
randomization list created by a web based randomization system.  
 
Methods: 
 Clinical data: 
Demographic data such as age, sex, education level, drinking and smoking habits, and clinical 
data as tumor site and histological type, ChT regimens, response and toxicity, will be retrieved 
from electronic records. Adverse effects will also be recorded, namely ChT toxicitiy graded 
according to NCI Common Toxicity Criteria, and post -operative complications with Clavien 
Dindo classification. 
 Patient Generated Subjective Global Assessment (PG-SGA) 
PG-SGA is known to be an accurate tool for the identification of malnourished cancer patients 
(Ottery F. , 1996) (Ottery F. , 1994). In our study, PG-SGA assessment will be conducted by an 
experienced dietitian and patients will be classified as well nourished (SGA A), moderately or 
suspected of being malnourished (SGA B) or severely malnourished (SGA C). 
 Anthropometric measures (AM): 
AM have been used consistently due to their non-invasive feature, portability, and low cost 
(Rosa G, 2008). AM such as weight and height will be obtained, and Body Mass Index will be 
calculated. All AM will be conducted according to previously established protocols (Rosa G, 
2008). 
 Body composition assessment 
Body composition analysis will be conducted with CT scan image analysis. This technique is 
feasible since it is part of the clinical workup CD and GI cancer patients. CT methodology is 
highly precise to quantify specific tissues and to predict whole-body composition (Mourtzakis, 
Prado, Lieffers, Reiman, McCargar, & Baracos, 2008). Images will be acquired by Radiologists at 
the 3rd lumbar vertebra (L3) and processed with a specific software which performs a 
automatic segmentation of tissue cross-sectional areas. Manual corrections will be conducted 
by Radiologists, as necessary. Segmentation of tissue cross-sectional areas will be conducted 
according to the following Hounsfield unit (UH) thresholds: –29 to 150 for skeletal muscle, –
190 to –30 for subcutaneous and intra-muscular adipose tissue and –50 to –150 for visceral 

adipose tissue. Cross-sectional skeletal muscle, visceral fat and subcutaneous fat will be 
recorded in cm2 and mean muscle radiation attenuation in HU. Skeletal Muscle Index (SMI-
cm2/height2) will also be calculated. Gender specific cut-offs for SMI will be used to define 
sarcopenia (Martin, et al., 2013). 
BIA will also be performed since it is an objective, easy, portable and non-invasive technique 
(Kyle, et al., 2004). Several studies have used this methodology, and in particular phase angle 
has been investigated as a potential nutritional indicator (Gupta, et al., 2008). BIA will be 
performed using a bioelectrical impedance analyzer with dual frequency (5 and 50 kHz-
Bodystat 1500 MDD, Bodystat Ltd, British Isles). BIA will be conducted with patients lying in a 
supine position with both hand and foot not touching the rest of the body. Measurements 
were taken on the right side of the body. Fat Free Mass, body fat, total body water, phase 
angle were recorded as well as raw data such as resistance and reactance.  
 Dietary Intake assessment 
Dietary intake will be assessed with a Food frequency questionnaire and 24 recalls using a 
modified USDA five-pass method at diagnosis and every visit until surgery. The Semi-
quantitative Food Frequency Questionnaire that will be used, was developed for the 
Portuguese population (Lopes, Aro, Azevedo, Ramos, & Barros, 2007) and is designed to 
evaluate usual dietary intake. This questionnaire includes 86 commonly-eaten food or drinks 
and participants were asked to estimate the amount and frequency of intake of each 
food/drink according to frequency and amount. Conversion of foodstuffs to nutrients will be 
conducted with software Food Processor Plus (ESHA Research, Salem, Oregon) which has been 
adapted to the Portuguese commonly-eaten food or drinks.  
 The 24h recall using a modified USDA five-pass method consists in 5 steps, the first is to list all 
foods consumed on the previous 24h. On the second step the interviewer asks about possible 
forgotten food items. In the third step the interviewer clarifies the time and occasion of the 
consumed foods. On the fourth step subject answers to standardized questions and clarifies 
portion size. In the last fifth step the interviewer seeks to obtain any additional information 
related to the foods consumed (Johnson & K, 2002).  Conversion of foodstuffs to nutrients will 
be conducted with Sanut software which has been developed for the Portuguese population. 
 Functional status assessment 
Performance Status will be assessed with Eastern Cooperative Oncology Group Performance 
Status scale (Oken, et al., 1982). According to these criteria patients are classified from grade 0 

(fully active) to grade 4 (bedridden). Prior to initiation of ChT and before surgery, data on 
oxygen-consumption, optimum aerobic heart rate and ECG-recordings as well as 6 min walk 
test will be conducted. Also, hand held dynamometer assessing grip strength will be obtained. . 
 Physical activity 
Physical activity will be assessed with the International Physical Activity questionnaire (Craig, 
Marshall, Sjostrom, Bauman, Booth, & Ainsworth, 2003). This questionnaire has been validated 
in several countries including Portugal, and is known to be a valid and reliable tool. Participants 
will be categorized has having a low, moderate or high physical activity according to the 
frequency, duration and intensity of physical activity on the previous seven days.  
 Patient Reported Outcome Measures(PROMs) 
Quality of life questionnaires from the European Organization for Research and Treatment of 
Cancer (EORTC), specifically gastric, esophagus and pancreas modules, which have already 
been validated for the Portuguese population, will be used to asses Patient Reported Outcome 
Measures at the end of Chemotherapy treatment.  
 Intervention arm-Combined Dietary and Exercise Intervention in the  
The intervention group will receive a supervised combined moderate aerobic and resistance 
training, once per week with duration of 40-60 min plus daily home exercise The exercise 
program will be planned by an exercise physiologist aiming at personalization of exercise 
according to patient’s age and functional capacity.  
Besides exercise, intervention group will receive a one-on-one nutritional counseling, by a 
Dietitian. In the first visit the dietary plan will be designed and oral nutritional supplements 
(Forticare®, Nutricia) will be recommended to meet 1.5g of protein/kg. Patients will be 
recommended to take one of the supplements after exercise. Also, in order to meet a calorie 
intake of 30kcal/kg, patients will be recommended to maintain a fat intake of 30% of total daily 
calories, where 20% will be supplied by olive oil. Written materials will be given to patients and 
caregivers, namely a dietary plan, standard menus, recipes, and standard portions information. 
Follow up visits will take place every time the patient is at the hospital to receive ChT . 
Patients will be recommended to maintain the dietary plan and exercise during the whole ChT 
treatment plan. However, due to possible symptoms after ChT, namely nausea and vomitings, 
patients will be asked to intensify compliance on the week preceding ChT when there is a 
higher probability that patients are symptom free.  Patients will be contacted twice a week by 
phone call or interview to provide motivation support and to assess if any diet or exercise 

adjustment is needed in order to maximize adherence. Also an adhesion record will be 
provided to the patient for monitoring of adhesion to protein, olive oil, water, supplements 
intake as well as home exercise. 
 Control arm- Standard care: 
Patients allocated to the control arm will receive standard care, in which patients will be 
referred to the dietitian only when the clinician feels there is a need for a dietary review. 
Whenever relevant, exercise will be recommended but without a personalized training 
program, which is our current practice.  
 Adherence Assessment 
The primary outcome will be intervention adherence, in which patients consenting to engage 
in the intervention protocol will be evaluated. As a secondary outcome, we will assess to what 
extent participants achieve their dietary and exercise goals. Participants will be considered as 
adherent if they have met ≥ 50% of their diet and exercise goals on the week preceding ChT. 
Also, follow up rates will be recorded, as well as comments on burden and acceptability of the 
intervention. Dropout rates and reasons for leaving the study will also be recorded. 
Contamination of the control arm will also be analyzed. Patients will be contacted every week 
by phone call or interview to assess adherence. 
Statistical analysis:  
Statistical analysis will be conducted for the primary and secondary outcome with an intention 
to treat and per protocol approach, respectively. Continuous variables will be described as 
mean, median and range, while categorical variables will be expressed as frequency and 
percentage. Differences in mean continuous variables will be analyzed by t-test or Mann 
Whitney U test as appropriate, according to variable´s adjustment to a normal distribution. 
Shapiro-Wilk test will be used to test normality. Pearson or Spearman correlation analysis will 
be performed as appropriate to assess the association between continuous variables. Chi 
square test of independence or Fisher exact test will be used to assess the association 
between categorical variables. 
Ethics: 
The study protocol has been approved by the Scientific and Ethics Committee of Hospital 
Beatriz Ângelo in Loures, Portugal. Informed consent will be obtained from every patient. 

Clinical data will be prospectively collected from electronic charts, however data will be coded 
in order to maintain anonymity. 
References: 
Bruera, E., Strasser, F., Palmer, J., Willey, J., Calder, K., Amyotte, G., et al. (s.d.). Effect of Fish 
Oil on Appetite and Other Symptoms in Patients With Advanced Cancer and 
Anorexia/Cachexia: A Double-Blind, Placebo-Controlled Study. Journal of Clinical 
Oncology, 21(1), 129-134. 
Chu, M. P., Lieffers, J., Ghosh, S., Belch, A., Chua, N. S., Fontaine, A., et al. (2017). Skeletal 
muscle density is an independent predictor of diffuse large B-cell lymphoma outcomes 
treated with rituximab-based chemoimmunotherapy. Journal of Cachexia, Sarcopenia 
and Muscle, 8(2), 298-304. 
Craig, C., Marshall, A., Sjostrom, M., Bauman, A., Booth, M., & Ainsworth, B. (2003). 
International physical activity questionnaire:12-country reliability and validity. Med Sci 
Sports Exerc, 35(8), 1381-95. 
Deutz, N., Safar, A., Schutzler, A., Memelink, R., Ferrando, F., Spencer, H., et al. (2011). Muscle 
protein synthesis in cancer patients can be stimulated with a specially formulated 
medical food. Clin Nutr, 30(6), 759–768. 
Gillis, C., Loiselle, S., Fiore, J., Awasthi, R., Wykes, L., Liberman, A., et al. (2016). Prehabilitation 
with Whey Protein Supplementation on Perioperative Functional Exercise Capacity in 
Patients Undergoing Colorectal Resection for Cancer: A Pilot Double-Blinded 
Randomized Placebo-Controlled Trial. J Acad Nutr Diet, 116(5), 802-12. 
Grabenbauer, A., Grabenbauer, A. J., Lengenfelder, R., Grabenbauer, G. G., & Distel, L. V. 
(2016). Feasibility of a 12-month-exercise intervention during and after radiation and 
chemotherapy in cancer patients: impact on quality of life, peak oxygen consumption, 
and body compositio. Radiation Oncology, 11(42). 
Gupta, D., Lis, C., Dahlk, S., King, J., Vashi, P., Grutsch, J., et al. (2008). The relationship 
between bioelectrical impedance phase angle and subjctive global assessment in 
advanced colorectal cancer. Nut J, 7(19), 2-6. 
Hashemi, R., Motlagh, A., Heshmat, R., Esmaillzadeh, A., Payab, M., Yousefinia, M., et al. 
(2015). Diet and its relationship to sarcopenia in community dwelling Iranian elderly: a 
cross sectional study. Nutrition, 31(1), 97-104. 
Henderson, G. (2015). Lipid-Based Therapeutic Strategies for Sarcopenic and Dystrophic 
Muscular Impairment. Cell Mol Biol 2015, 61(120), 2-10. 
Johnson, & K, R. (2002). Dietary Intake—How Do We Measure What People Are Really Eating? 
Obes Res, 10. 

Jolekar, S., Nau, P., & Mezhir, J. (2015). The Impact of Sarcopenia on Survival and 
Complications in Surgical Oncology: A Review of the Current Literature. J Surg Oncol, 
11, 503-509. 
Kazemi-Bajestania, S. M., Mazurakb, V. C., & Baracos, V. E. (2016). Computed Tomography-
defined Muscle and Fat Wasting are Associated with Cancer Clinical Outcomes. 
Seminars in Cell and Developmental Biology, 54, 2-10. 
Kyle, U., Bosaeus, I., De Lorenzo, A., Deurenberg, P., Elia, M., Gómez, J., et al. (2004). 
Bioelectrical impedance analysis-part II:utilization in clinical practice. Clin Nutr, 23, 
1430-1453. 
Lieffers, J., Bathe, O., Fassbender, K., Winget, M., & Baracos, V. (2012). Sarcopenia is 
associated with postoperative infection and delayed recovery from colorectal cancer 
resection surgery. British Journal of Cancer , 107, 931-93. 
Lopes, C. (2000). Reprodutibilidade e validação de um questionário semi-quantitativo de 
frequência alimentar. Obtido em 17 de 11 de 17, de https://repositorio-
aberto.up.pt/bitstream/10216/9938/3/2734_TD_01_P.pdf. 
Lopes, C. (2000). Reprodutibilidade e validação de um questionário semi-quantitativo de 
frequência alimentar. Alimentação e enfarte do miocardio: um estudo caso-controlo de 
base populacional. Universidade do Porto: Tese de Doutoramento. 
Lopes, C., Aro, A., Azevedo, A., Ramos, E., & Barros, H. (2007). Intake and adipose tissue 
composition of fatty acids and risk of myocardial infarction in a male Portuguese 
community sample. J Am Diet Assoc, 107, 276-286. 
Martin, L., Birdsell, L., Macdonald, N., Reiman, T., Thomas Clandinin, M., McCargar, L., et al. 
(2013). Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful 
prognostic factor, independent of body mass index. J Clin Oncol, 31, 1539-1547. 
McCahon, D., Daley, A. J., Jones, J., Haslop, R., Shajpal, A., Taylor, A., et al. (2015). Enhancing 
adherence in trials promoting change in diet and physical activity in individuals with a 
diagnosis of colorectal adenoma; a systematic review of behavioural intervention 
approaches. BMC Cancer, 15(05). 
Mourtzakis, M., Prado, C., Lieffers, J., Reiman, T., McCargar, L., & Baracos, V. (2008). A practical 
and precise approach to quantification of body composition in cancer patients useing 
computed tomography images acquired during routine care. Appl Physiol Nutr Metab, 
33, 997-1006. 
Oken, M., Creech, R., Tormey, D., Horton, J., Davis, T., McFadden, E., et al. (1982). Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol, 5, 649-
655. 
Ottery, F. (1994). Rethinking nutritional support of the cancer patient the new field of 
nutritional oncology. Sem. Oncol, 21, 770-778. 

Ottery, F. (1996). Definition of standardized nutritional assessment and interventional 
pathways in oncology. Nutrition, 12, S15– 19. 
Palmela, C., Velho, S., Agostinho, L., Branco, F., Santos, M., Santos, M., et al. (2017). Body 
Composition as a Prognostic Factor of Neoadjuvant Chemotherapy Toxicity and 
Outcome in Patients with Locally Advanced Gastric Cancer. J Gastric Cancer, 17(1), 74-
87. 
Pedersen, B. K. (2011). Exercise-induced myokines and their role in chronic diseases. Brain, 
Behavior and Immunity, 25, 811-16. 
Pedersen, L., Idorn, M., Olofsson, G., Lauenborg, B., Nookaew, I., Hansen, R., et al. (s.d.). 
Voluntary running supresses tumor growth through epinephrine-and IL6-dependent 
NK cel mobolization and redistribution. Cell Metab, 23, 554-562. 
Peng, P. D., Vledder, M. G., Tsai, S., Jong, M. C., Makary, M., Ng, J., et al. (2011). Sarcopenia 
negatively impacts short-term outcomes in patients undergoing hepatic resection for 
colorectal liver metastasis. HPB, 13, 439-446. 
Prado, C. M., Baracos, V. E., J, M. L., Mourtzakis, M., Mulder, K. E., Reiman, T., et al. (2007). 
Body Compositionas an Independent Determinantof 5 Fluorouracil Based 
Chemotherapy Toxicity. Clinical Cancer Research, 13(11), 3264-3268. 
Rosa G, P. A. (2008). Avaliação antropométrica. In R. G, Avaliação nutricional do paciente 
hospitalizado (pp. 29-62). Rio de Janeiro: Guanabara Koogan S.A. 
Solheim, T., Laird, B., Balstad, T., Sten, G., Bye, A., Johns, N., et al. (2017). A randomized phase 
II feasibility trial of a multimodal intervention for the management of cachexia in 
lungand pancreatic cancer. Journal of Cachexia, Sarcopenia and Muscle .