Loading

Archives of Palliative Care

Effects of Eight-Week Whey Protein Supplementation in Palliative Care Patients with Advanced Cancer: A DoubleBlind Randomized Controlled Pilot Trial

Research Article | Open Access Volume 5 | Issue 1 |

  • 1. Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
  • 2. The Nethersole School of Nursing, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
  • 3. Palliative Care Department, Shatin Hospital and Bradbury Hospice, Hong Kong, China
  • 4. Centre for Nutritional Studies, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
+ Show More - Show Less
Corresponding Authors
Suey S.Y. Yeung, Department of Medicine & Therapeutics, Prince of Wales Hospital, Shatin, N.T., Hong Kong; Tel: +852 3505 2190; Email: sueyyeung@cuhk.edu.hk
Abstract

Background: Evidence of the effect of whey protein (WP) supplementation in palliative cancer patients is limited. This study evaluated the effectiveness of an 8-week WP supplementation on quality of life (QOL) and predefined outcomes in Hong Kong Chinese palliative care patients with advanced cancer.

Methods: This was a randomized, double-blind placebo-controlled clinical trial. Palliative care patients with advanced cancer were randomized to receive one sachet of WP supplement at 36 g daily (intervention), or casein at 36 g daily (placebo) for 8 weeks. Outcome measures, including QOL, weight, body fat %, lean body mass, biceps and triceps circumferences, waist circumference, handgrip strength, 6-minute walking test, up & go test, Barthel Index, Karnofsky Performance Scale Index, London Handicap Scale, Elderly Mobility Scale and glutathione (GSH) level, were assessed at week 0, 4 and 8. The intention-to-treat or per-protocol principle was applied to examine the effects of the intervention on each outcome, with the use of linear mixed-effects model analysis.

Results: A total of 92 patients (mean age 60.9±13.7, male 54.3%) were randomized and completed the baseline assessment. There was no significant group difference in the changes of QOL, anthropometry, physical function or intracellular GSH level over time (all p for interaction >0.05), either by intention-to-treat or per-protocol analysis.

Conclusion: In Chinese palliative care patients with advanced cancer, there were no significant differences in the changes of QOL, anthropometry, physical function and intracellular GSH level over time between the group receiving an 8-week WP supplementation daily and casein supplementation daily.

Keywords

Cancer ,Glutathione , Palliative care,Quality of Life , Whey protein.

Citation

Yeung SSY, Ng K, Lo RSK, Woo J (2022) Effects of Eight-Week Whey Protein Supplementation in Palliative Care Patients with Advanced Cancer: A Double-Blind Randomized Controlled Pilot Trial. Arch Palliat Care 5(1): 1018.

ABBREVIATIONS

BIA: bioelectrical impedance analyzer, BMI: body mass index, CT: chemotherapy, EMS: Elderly Mobility Scale, GSH: glutathione, ITT: intention-to-treat, MQOL-HK: McGill Quality of Life Questionnaire for Hong Kong Chinese, PP: per protocol, TUG: Timed up & go, WP: whey protein, QOL: quality of life

INTRODUCTION

Cancer is a leading cause of death worldwide [1]. It is estimated that the deaths of 10-20% of cancer patients occur as a result of malnutrition rather than the malignancy of the disease itself [2]. Cancer patients are at high risk of malnutrition because of the disease and its treatment. Systemic inflammation is frequently activated in cancer patients [3]. This can vary in degree but is associated with poor performance status, weight loss, fat and muscle mass loss, development of fatigue and anorexia [4]. These adverse effects may result in an unfavorable prognosis, increased toxicity of anticancer treatments and ultimately reductions or interruptions of scheduled treatment and reduced quality of life [3, 5-7]. Given the potential nutritional deficits and metabolic derangements, it is essential to initiate nutritional care among cancer patients. Whey protein (WP) supplementation has a great potential to support cancer patients by stimulating muscle protein synthesis and providing substrates for the synthesis of the antioxidant glutathione (GSH) [8]. GSH could protect cells against free radicals, ionize radiation, reactive oxygen species and carcinogens [9, 10]. WP supplementation has been shown to improve lean mass in colorectal cancer patients undergoing chemotherapy (CT) [11], and increase the GSH level in cancer patients undergoing CT [12]. In contrast, no significant effect of WP supplementation on body weight, body composition, handgrip strength and walking distance was observed in non-small-cell lung cancer patients undergoing CT [13]. To the best of our knowledge, no trials examining the effect of WP supplementation in cancer patients receiving palliative care are available.

Since the goal of palliative care is to improve the quality of life (QOL) of patients and their families [14], this study aimed to evaluate the effectiveness of an 8-week WP supplementation on QOL (primary outcome) and other predefined outcomes (anthropometry, physical function and GSH level) in Hong Kong Chinese palliative care patients with advanced cancer.

MATERIALS AND METHODS

Patients selection

This pilot study was conducted between October 2002 to May 2004, with a temporary halt in recruiting cases during the severe acute respiratory syndrome (SARS) outbreak period in Hong Kong. Patients were recruited from the inpatient service of hospice and palliative care at the Shatin Hospital in Hong Kong. Inclusion criteria were i) aged ≥18 years old, ii) with advanced cancer receiving palliative care, and iii) not receiving any type of artificial nutrition (enteral or parenteral). Exclusion criteria were i) history of allergy to WP, ii) less than 8 weeks of expected life expectancy, and iii) cognitive impairment with Abbreviated Mental Test of <6 points [15].

Study design

This was a randomized, double-blind, placebo-controlled clinical trial. Randomization was done by blocks of 10. Sealed envelopes were prepared, with five labels of ‘A’ and five labels of ‘B’ in each envelope. After informed consent was given, patients were randomized into either placebo control or intervention groups. Patients drew a label out by himself or herself without looking into the envelope. The sachet labeled ‘A’ or ‘B’ was given to the patients accordingly. All the assessors (clinicians and laboratory technicians) and patients were blinded to whether the patient was in the placebo or intervention group. Assignment to the placebo or intervention group was disclosed only after the whole study was completed. Patients were assessed at weeks 0, 4 and 8 for outcome measurements.

Intervention and placebo group

Patients in the intervention group were given one sachet of ImuPower® per day (36 g whey protein daily) for 8 weeks. They were instructed to take the supplement with his/her usual drinks and with lukewarm water only. Patients in the placebo group were given one sachet of identical-looking packs of casein per day (36 g casein protein) for 8 weeks. They were given the same instruction on how to take the supplement and the same clinical management of his/her cancer as that of the intervention group.

Data collection

Demographic data including age, sex and type of cancer were collected at baseline. The primary outcome was QOL and secondary outcomes were anthropometry, physical function, and glutathione level.

Quality of life

The translated and modified version of the McGill Quality of Life Questionnaire for Hong Kong Chinese (MQOL-HK) was used to assess the quality of life (QOL) of patients with a lifethreatening illness [16]. The MQOL-HK has been validated crossculturally in Hong Kong and was shown to be acceptable, valid and reliable. Five essential domains were assessed: physical, psychological, existential well-being, support and sexuality. It contains 18 items and a single item rating the overall QOL. The response categories were based on a numerical scale from 0 to 10, with verbal anchors at the ends of the scale. For the final statistical analysis, all scores are transposed on a 0 to 10 scale, with 0 indicating the least and 10 the most desirable situation. The domain score was calculated as the mean of the individual item scores of that domain, whereas the total QOL score was calculated as the mean of all the domain scores.

Anthropometry Body

weight was measured using a standard weighing scale with patients wearing light clothing. Height was measured using a stadiometer or estimated from an arm-span. Body Mass Index (BMI) was calculated by body weight in kg divided by height in squared meter. Skinfold thickness of biceps and triceps were measured using a skinfold caliper to the nearest 0.1 cm. Waist circumference was measured to the nearest 0.1 cm using a measuring tape. Percent body fat and lean body mass (kg) were measured using a Bioelectrical Impedance Analyzer (BIA).

Physical function

The handgrip strength of each hand was measured using a handheld dynamometer. Submaximal level of functional capacity was assessed using the six minutes walking test. Patients were instructed to walk on a flat, hard surface in a period of six minutes at a speed suitable to their condition. They were allowed to stop or slow down if required and resume walking as soon as possible. The six minutes walking distance was calculated and expressed in meters. Timed up & go (TUG) test was used to assess patients’ mobility [17]. Patients were timed while they rise from an armchair, walk at a comfortable and safe pace to a line on the floor three metres away, turn and walk back to the chair and sit down again. The time to complete the TUG test was recorded as seconds. Walking aid was allowed if needed for six minutes walking test and TUG test. Activities of daily living (ADL) was assessed using the Barthel Index [18]. The ability to perform ten different tasks including bowels and bladder control, grooming, toilet use, feeding, transfer, mobility, dressing, stairs and bathing were rated. Total possible scores range from 0 to 20, with lower scores indicating increased difficulty in performing ADL. Karnofsky Performance Scale Index was used to measure the ability of cancer patients to perform ordinary tasks [19]. The Karnofsky score ranges from 0 to 100, with a higher score indicating the patient is better able to carry out daily activities. The London Handicap Scale (LHS) was used to assess the effect of chronic conditions on a patient’s functional ability [20]. Six dimensions of handicap were assessed: mobility, orientation, occupation, physical independence, social integration and economic self-sufficiency. On a scale of 0 (none) to 6 (extreme), patients selected one category per dimension indicating their perceived level of disadvantage. The total LHS score was calculated as the mean of all the dimension scores. For patients over 65 years old, the Elderly Mobility Scale (EMS) was used to assess their mobility, considering locomotion, balance and key position changes [21]. The EMS includes the assessment of the following tasks: lying to sitting, sitting to lying, sitting to standing, standing, gait, 6- metres timed walk and functional reach. Possible EMS score ranges from 0 (totally dependent) to 20 (independent mobility).

Glutathione level

Venous blood was taken for glutathione (GSH) assay using a standardized kinetic method [22]. Both whole blood and plasma GSH were measured (μmol/L), and the value of whole blood GSH minus plasma GSH was taken as intracellular GSH level for subsequent statistical analysis. Quality control samples were included in every batch of assays to monitor interassay variations.

Ethical consideration

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and was carried out according to the principles set out in the Declaration of Helsinki 1964 and all subsequent revisions, informed consent was obtained, and the relevant institutional review board had approved the study (CRE-2002.127). Written informed consent was obtained from all patients.

Statistical analysis

Characteristics of patients are presented as mean and Standard Deviation (SD) for continuous variables and as numbers and percentages (%) for categorical variables. Independent student’s t-test and chi-square test were used to examine the differences in characteristics between patients in the intervention group and patients in the placebo group.

Data were analyzed using the Intention-To-Treat (ITT) principle and as Per Protocol (PP). ITT was applied to examine the effects of the intervention on each outcome variable, including all available data from patients who consented to participate in the study. PP was defined as completing the 8-week intervention. Treatment, time, and interaction effects during the 8-week study period were examined with the use of linear mixedeffects model analysis with treatment, time and interactions as fixed effects and patients as random effects. Significant treatment and time interactions in the linear mixed model analysis indicate significant treatment effects. Changes between the baseline and week 4 and week 8 were analyzed accordingly. P values of <0.05 (two-tailed) were considered statistically significant. All data were analyzed using SPSS, version 26.0 (SPSS Inc, Chicago, IL, USA).

RESULTS

Patients’ characteristics

Figure 1 shows the number of patients at different study stages. A total of 122 patients were approached, however, 9 of them were excluded, while another 21 patients dropped out before completing the assessment at week 0. Out of the 92 patients (40 in the placebo group and 52 in the intervention group) who completed the assessment at week 0, 30 dropped out before the assessment at week 4 and another 22 dropped out before the assessment at week 8.

Figure 1 Study flow chart.

Figure 1 Study flow chart.

Table 1 shows the baseline characteristics of the patients. The mean age of the patients at study entry was 60.9 years old (SD 13.7) and the proportion of male patients was 54.3%. The top three primary cancer sites were lung (37.0%), breast (16.3%) and sarcoma (5.4%). Baseline characteristics of the two groups were similar, with no significant differences between the placebo group and the intervention group.

Table 1: Baseline characteristics between placebo group and intervention group.

  Placebo group (n= 40) Intervention group (n= 52) P-valuea
Age, years 63.4 (13.7) 58.9 (13.5) 0.116
Male, n (%) 21 (52.5) 29 (55.8) 0.834
Primary cancer site, n (%)     0.751
Breast 9 (22.5) 6 (11.5)  
Gynecology 1 (2.5) 3 (5.8)  
Colon 1 (2.5) 3 (5.8)  
Lung 12 (30.0) 22 (42.3)  
Lymphoma 1 (2.5) 3 (5.8)  
Multiple myeloma 0 2 (3.8)  
Nasopharyngeal cancer 2 (5.0) 2 (3.8)  
Oral 2 (5.0) 1 (1.9)  
Pancreas 1 (2.5) 1 (1.9)  
Prostate 2 (5.0) 1 (1.9)  
Sarcoma 3 (7.5) 2 (3.8)  
Stomach 1 (2.5) 2 (3.8)  
Others 5 (12.5) 4 (7.7)  
McGill Quality of Life, score      
Physical domain 6.4 (1.7) 6.3 (1.9) 0.771
Psychological domain 8.0 (2.2) 8.1 (1.9) 0.925
Existential domain 6.8 (2.0) 6.5 (1.7) 0.441
Support domain 8.1 (2.0) 7.8 (2.2) 0.524
Sexuality/intimacy 7.2 (3.9) 6.4 (4.1) 0.350
Single item (Overall) 6.3 (2.2) 6.3 (2.0) 0.935
Total quality of life 7.3 (1.5) 7.0 (1.3) 0.310
Weight, kg 53.8 (10.3) 53.9 (11.3) 0.970
Body mass index, kg/m2 20.9 (3.3) 20.9 (4.0) 0.902
Biceps skinfold, cm 11.0 (7.0) 11.1 (10.0) 0.962
Triceps skinfold, cm 13.8 (7.8) 12.5 (6.9) 0.394
Body fat, % 30.2 (7.5) 27.4 (8.9) 0.166
Waist circumference, cm 76.9 (17.4) 76.0 (20.1) 0.868
Lean muscle mass, kg 36.5 (7.3) 36.5 (7.3) 0.392
Right handgrip, kilopascal 16 (8) 17 (9) 0.949
Left handgrip, kilopascal 15 (7) 16 (9) 0.657
6 min walk test, metres 167 (87) 180 (115) 0.554
Up and go test, seconds 24 (24) 21 (25) 0.572
Barthel index, score 16 (3) 16 (3) 0.815
Karnofsky Performance Scale Index, score 63 (8) 63 (9) 0.697
London Handicap Scale, score
Mobility 3.9 (1.0) 3.7 (1.0) 0.231
Physical independence 3.5 (0.8) 3.4 (0.8) 0.820
Social integration 2.0 (0.8) 2.1 (0.8) 0.680
Occupation 3.6 (0.9) 3.7 (0.7) 3.7 (0.7)
Environmental orientation 1.7 (0.5) 1.9 (0.7) 0.276
Economic sufficiency 3.6 (1.0) 3.4 (1.0) 0.313
Total handicap 3.1 (0.5) 3.0 (0.5) 0.758
Elderly mobility scale 15 (5) 13 (7) 0.495
Intracellular GSH level, μmol 1013 (421) 997 (383) 0.855
Abbreviations: GSH, glutathione. Values are presented as mean (standard deviation) or otherwise as indicated. a P value by independent t test or chi-square where appropriate

Study outcomes

Figure 2 shows the changes in QOL scores from baseline to week 4 and week 8 in the placebo group and intervention group according to the ITT analysis. Patients in the intervention group showed a consistent improvement in all QOL measures from baseline to week 4. However the inter-group comparison showed no significant group differences in the changes of any domains of QOL scores, single item and total QOL scores (all P for interaction >0.05). There were also no significant group differences in the changes of body weight, BMI, body fat %, lean body mass, biceps and triceps circumferences, waist circumference, handgrip strength, 6-minute walking test, TUG test, Barthel Index, Karnofsky Performance Scale Index, London Handicap Scale, Elderly Mobility Scale and intracellular GSH level over time (all P for interaction >0.05) (Table 2). Similar results were observed for the PP analysis (data not shown).

 

Figure 2 Mean changes of QOL from baseline to week 4 and week 8 in placebo group (n=40) and intervention group (n=52): a) physical domain, b) psychological  domain, c) existential well-being, d) support domain, e) sexuality domain, f) single item, g) total score. Data are presented as mean ± 95% confidence interval. Mean  change was calculated as: week 4/week 8 value minus baseline value.

Figure 2 Mean changes of QOL from baseline to week 4 and week 8 in placebo group (n=40) and intervention group (n=52): a) physical domain, b) psychological domain, c) existential well-being, d) support domain, e) sexuality domain, f) single item, g) total score. Data are presented as mean ± 95% confidence interval. Mean change was calculated as: week 4/week 8 value minus baseline value.

Table 2: Comparison of the changes of anthropometry, physical function and glutathione level among the placebo group (n=40) and the intervention group (n=52).

  Mean (SD) Change after 4 weeks Change after 8 weeks
  Week 0 Week 4 Week 8 Mean changea (95% CI) P value of interactionb Mean changea (95% CI) P value of interactionb
Anthropometry Weight, kg              
Placebo 53.8(10.3) 54.0(12.0) 51.2(10.4) 0.12(-5.61,5.86) 0.459 -2.70(-9.62,4.23) 0.180
Intervention 53.9(11.3) 57.0(13.1) 57.4(13.0) 3.06(-2.27,8.39)   3.46 (-2.40,9.32)  
Body mass index, kg/m2              
Placebo 20.9 (3.3) 21.0 (3.8) 20.5 (3.6) 0.10(-1.81,2.01) 0.688 -0.41(-2.84,2.02) 0.472
Intervention 20.9 (4.0) 21.5 (4.4) 21.6 (4.7) 0.63(-1.15,2.41)   0.74 (-1.32,2.80)  
Biceps skinfold, cm
Placebo 11.0 (7.0) 0.7 (6.9) 9.1 (6.0) -0.31(-4.10,3.48) 0.803 -1.91(-6.15,2.33) 0.683
Intervention 11.1(10.0) 11.4 (7.3) 10.3 (6.4) 1.11 (-2.55,4.76)   -0.76(-4.36,2.83)  
Triceps skinfold, cm
Placebo 13.8 (7.8) 13.1 (7.9) 12.8 (7.1) -0.70(-4.37,2.97) 0.391 -0.92(-5.13,3.30) 0.547
Intervention 12.5 (6.9) 13.9 (7.7) 13.2 (7.5) 1.48 (-1.92,4.87)   0.77 (-2.87,4.42)  
Body fat, %              
Placebo 30.2 (7.5) 29.6 (7.2) 29.7 (8.9) -0.55(-5.24,4.15) 0.399 -0.52(-6.42,5.39) 0.498
Intervention 27.4 (8.9) 29.5 (8.5) 29.6 (8.6) 2.11 (-1.98,6.20)   2.16 (-3.09,7.41)  
Waist circumference, cm
Placebo 76.9(17.4) 79.9 (8.9) 77.6 (3.3) 2.99 (-7.45,13.4) 0.829 0.74 (-10.4,11.9) 0.478
Intervention 76.0(20.1) 80.5(13.1) 81.8(12.0) 4.48 (-4.35,13.3)   5.78 (-2.85,14.4)  
Lean body mass, kg
Placebo 36.5 (7.3) 37.1 (9.4) 34.2 (7.4) 0.56 (-4.60,5.72) 0.937 -2.30(-8.20,3.60) 0.349
Intervention 38.1 (8.2) 38.4 (9.5) 39.5 (9.8) 0.29 (-4.21,4.79)   1.40 (-3.84,6.65)  
Physical function              
Right handgrip, kilopascal              
Placebo 16 (8) 15 (8) 17 (8) -0.84(-5.04,3.37) 0.416 0.78 (-4.28,5.83) 0.750
Intervention 17 (9) 18 (9) 16 (9) 1.50 (-2.29,5.29)   -0.28(-4.56,3.99)  
Left handgrip, kilopascal
Placebo 15 (7) 15 (9) 16 (9) -0.86(-4.94,3.22) 0.941 0.25 (-4.42,4.92) 0.623
Intervention 16 (9) 15 (9) 15 (7) 15 (7)   -1.27(-5.22,2.69)  
6 min walking test, metres              
Placebo 167 (87) 189 (128) 236 (127) 22.5 (-33.8,78.8) 0.761 69.5 (-1.34, 140) 0.359
Intervention 180 (115) 214 (118) 206 (118) 34.5 (-19.6,88.6)   26.7 (-33.1,86.5)  
Up & go test, seconds
Placebo 24 (24) 21 (23) 15 (15) -3.48(-14.0,7.01) 0.620 -8.71(-19.1,1.64) 0.782
Intervention 21 (25) 15 (11) 16 (11) -7.05(-16.6,2.52)   -6.81(-15.7,2.06)  
Barthel Index, score              
Placebo 16 (3) 16 (4) 17 (4) 0.07 (-1.74,1.88) 0.989 0.96 (-1.45,3.38) 0.609
Intervention 16 (3) 16 (4) 16 (5) 0.09 (-1.58,1.75)   0.16 (-1.84,2.16)  
Karnofsky Performance Scale Index, score
Placebo 63 (8) 66 (11) 69 (13) 2.77 (-2.07,7.61) 0.960 6.63 (-0.67,13.9) 0.371
ntervention 63 (9) 66 (11) 66 (14) 2.60 (-1.85,7.05)   2.37 (-3.64,8.39)  
London Handicap Scale, score
Mobility
Placebo 3.9 (1.0) 3.6 (1.0) 3.4 (1.2) -0.30(-0.79,0.18) 0.990 -0.49(-1.10,0.13) 0.464
Intervention 3.7 (1.0) 3.4 (1.0) 3.5 (1.0) -0.30(-0.74,0.14)   -0.19(-0.70,0.31)  
Physical independence              
Placebo 3.5 (0.8) 3.4 (1.0) 3.3 (1.2) -0.05(-0.48,0.39) 0.790 -0.15(-0.80,0.50) 0.876
Intervention 3.4 (0.8) 3.5 (0.9) 3.2 (1.2) 0.03 (-0.37,0.43)   0.03 (-0.37,0.43)  
Socialintegration              
Placebo 2.0 (0.8) 2.1 (0.7) 2.1 (0.7) 0.08 (-0.29,0.45) 0.418 -0.09(-0.61,0.43) 0.229
Intervention 2.1 (0.8) 2.0 (0.7) 2.4 (0.9) -0.13(-0.46,0.21)   0.32 (-0.11,0.75)  
Occupation
Placebo 3.6 (0.9) 3.5 (1.0) 3.4 (1.1) -0.05(-0.46,0.36) 0.99 -0.13(-0.67,0.42) 0.846
Intervention 3.7 (0.7) 3.6 (0.8) 3.5 (0.9) 3.5 (0.9)   -0.20(-0.65,0.26)  
Environmental orientation
Placebo 1.7 (0.5) 2.0 (0.8) 2.3 (1.2) 0.28 (-0.06,0.62) 0.158 0.53 (0.04, 1.02) 0.266
Intervention 1.9 (0.7) 1.8 (0.7) 2.0 (0.6) -0.05(-0.36,0.26)   0.18 (-0.23,0.58)  
Economic sufficiency
Placebo 3.6 (1.0) 3.5 (1.1) 3.8 (1.0) -0.12(-0.62,0.39) 0.701 0.19 (-0.40,0.77) 0.725
Intervention 3.4 (1.0) 3.4 (1.1) 3.7 (1.0) 0.02 (-0.45,0.48)   0.32 (-0.17,0.81)  
Total handicap              
Placebo 3.0 (0.5) 3.0 (0.6) 3.0 (0.8) -0.03(-0.30,0.24) 0.789 -0.03(-0.43,0.38) 0.817
Intervention 3.0 (0.5) 2.9 (0.6) 3.0 (0.7) -0.08(-0.33,0.17)   0.04 (-0.30,0.37)  
Elderly mobility score
Placebo 15 (5) 14 (6) 14 (6) -0.84(-5.12,3.44) 0.495 1.44 (-3.35,6.23) 0.784
Intervention 13 (7) 15 (7) 16 (7) 1.20 (-2.90,5.29)   2.32 (-2.00,6.64)  
Intracellular GSH, μmol
Placebo 1013(421) 954 (286) 992 (412) -59.2 (-240, 121) 0.352 -21.2 (-224, 181) 0.773
Intervention 997 (383) 1054(415) 937 (267) 57.0 (-110, 224)   -60.6 (-241, 120)  
Abbreviations: SD, standard deviation; CI, confidence interval; GSH, glutathione a Mean change was calculated as the week 4/week 8 value minus the baseline value. b P value of interaction (time x treatment) was tested using linear mixed models.

 

DISCUSSION

This 8-week double-blind randomized controlled pilot study showed that in Chinese palliative care patients with advanced cancer, there were no significant differences in the changes of QOL, anthropometry, physical function and intracellular GSH level over time between the group that received WP supplementation and the group that received casein supplementation daily. WP is a rapidly digested, high-quality protein with excellent amino acid profiles, which makes them an important source for sustaining muscle protein anabolism and function, and providing substrates for the synthesis of GSH [8, 23]. However, we did not find a significant group difference in the change of any outcome variables over time. Our results were consistent with a pilot double-blind randomized controlled trial in patients with non-small-cell lung cancer undergoing CT, in which there was no significant effect of 12-week WP supplementation (20 g WP daily) on body weight, body composition, handgrip strength and walking distance [13]. In contrast, a previous study among cancer patients undergoing CT showed that GSH levels significantly improved at week 6 by 6.0% and at week 12 by 11.7% compared with the control after a daily supplementation of 40 g WP with zinc (2.64 mg) and selenium (0.76 mg) [12]. The enhanced immune function from zinc and selenium may improve cell-mediated immunity and antioxidant capacity, and therefore it may explain why the result was in contrast with our study of WP alone. In colorectal cancer patients undergoing CT, 13.5 g WP supplementation for six months improved lean mass compared with the placebo group [11]. The longer duration of the intervention may partly explain the different results compared with our 8-week intervention.

According to the current guidelines, oral nutritional supplementation plus individual nutritional counseling is recommended as the standard care for all cancer patients at nutritional risk [7]. In malnourished patients with different cancer types and receiving CT, personalized nutritional counseling with 40 g WP supplementation for three months resulted in improved body composition, body weight and muscle strength compared to nutritional counseling alone [24]. The lack of treatment effect in our study may emphasize the need for personalized nutritional counseling in addition to nutritional supplementation to educate patients, or provide strategies to support patient convenience/compliance [25]. However, similar to our study, QOL scores were not significantly different between the group receiving WP supplementation and the control group [12, 24]. It should be noted that QOL is a subjective construct which is influenced by various factors. It has been suggested that the stage of disease was the major determinant of patients’ QOL, followed by deterioration in nutritional status and dietary intake [26, 27]. This may explain why there was no treatment effect on QOL over time in our sample of palliative care patients with advanced cancer.

There are other reasons which may explain the lack of group difference in the changes of any outcomes in our study. First, the effectiveness of WP supplementation would depend on patients’ baseline nutritional status and habitual protein intake [28]. However, it is not known if there was any group difference in terms of baseline nutritional status and protein intake in our study. Literature has suggested that losses in lean body mass were ~40% lower in older adults in the highest quintile than those in the lowest quintile of energy-adjusted protein intake [29]. In patients with advanced cancer, malnutrition is often associated with chronic cancer-induced systemic inflammation resulting in anorexia, insulin resistance, anabolic resistance and muscle loss [30]. These metabolic derangements may interfere and limit the effect of WP supplementation in this subgroup of patients. Second, included patients may be at different phases of cachexia, namely pre-cachexia, cachexia and refractory cachexia. It has been suggested that cachexia cannot be treated with nutrition alone but rather a combination of physical exercise to counteract inactivity atrophy and catabolism, pharmacological agents affecting metabolism, and nutritional intervention to secure adequate energy intake [31, 32]. Therefore, the benefits of WP supplementation alone may be limited in extent due to the multifactorial etiology of cancer cachexia. In addition, the advanced stage of the disease and its catabolic effects may have counteracted the positive effect of the WP supplementation [33]. The insignificant effect of WP on our outcome measures may also be explained by a heterogeneous group of patients with different types of cancer and treatments in our study as compared with a homogeneous group of patients with similar types of cancer and treatments [11, 12].

To the best of our knowledge, the present study was the first trial examining the effect of WP supplementation in palliative care patients with advanced cancer. Several limitations should be acknowledged. First, the low statistical power due to the small sample size may reduce the chances of detecting the significant differences in outcome measures. However, the high drop-out rate as a result of progressive disease and clinical deterioration has been reported in other palliative oncology trials [34]. Second, the duration of the intervention was 8-week, which was relatively short compared with other studies. Third, we did not have strict inclusion criteria in terms of anorexia, cachexia, nutritional status, type of cancer and current therapy in this study as we wanted to test the effectiveness of WP supplementation in a broad population of palliative cancer patients. Therefore, a heterogeneous group of patients may be resulted and dilute the treatment effect [35]. Fourth, lean mass was measured using BIA which may lack the accuracy to detect small changes in body composition over time compared with computerized tomography [36].

 

CONCLUSION

In conclusion, the present study did not show an improvement in QOL, anthropometry, physical function and intracellular GSH level through an 8-week WP supplementation in Chinese palliative care patients with advanced cancer. It appears that current findings did not support the use of WP supplementation in advanced cancer patients. In light of the small sample size, larger trials with a more homogeneous population are warranted to clarify its effectiveness in this population.

ACKNOWLEDGEMENTS

The study was funded by Fortress Pharmaceutical Company Limited. The company provided the whey protein (ImuPower®) and casein placebo and supported funding for a research assistant. The sponsor had no role in subject recruitment, data collections, analysis or preparation of this article.

REFERENCES

1. Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. In: 2020.

2. Pressoir M, Desne S, Berchery D, Rossignol G ,Poiree B, Meslier M , et al. Prevalence, risk factors and clinical implications of malnutrition in French Comprehensive Cancer Centres. Br J Cancer. 2010; 102: 966- 971.

3. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014; 15:e493-503.

4. McMillan DC. The systemic inflammation-based Glasgow Prognostic Score: a decade of experience in patients with cancer. Cancer Treat Rev. 2013; 39: 534-540.

5. Gannavarapu BS, Lau SKM, Carter K, Cannon NA, Gao A, Ahn C, et al. Prevalence and Survival Impact of Pretreatment Cancer-Associated Weight Loss: A Tool for Guiding Early Palliative Care. J Oncol Pract. 2018; 14: e238-e250. 

6. Narducci F, Grande R, Mentuccia L, Trapasso T, Sperduti I, Magnolfi E, et al. Symptom improvement as prognostic factor for survival in cancer patients undergoing palliative care: a pilot study. Support Care Cancer. 2012; 20: 1221-1226.

7. Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, et al. ESPEN guidelines on nutrition in cancer patients. Clin Nutr. 2017; 36:11-48.

8. Teixeira FJ, Santos HO, Howell SL, Pimentel GD. Whey protein in cancer therapy: A narrative review. Pharmacol Res. 2019; 144: 245-256.

9. Bounous G. Whey protein concentrate (WPC) and glutathione modulation in cancer treatment. Anticancer Res. 2000; 20: 4785-4792.

10.Ortega AL, Mena S, Estrela JM. Glutathione in cancer cell death. Cancers (Basel). 2011; 3: 1285-1310.

11.Mazzuca F, Roberto M, Arrivi G, Sarfati E, Schipilliti FM, Crimini E, et al. Clinical Impact of Highly Purified, Whey Proteins in Patients Affected With Colorectal Cancer Undergoing Chemotherapy: Preliminary Results of a Placebo-Controlled Study. Integr Cancer Ther. 2019; 18: 1534735419866920.

12.Bumrungpert A, Pavadhgul P, Nunthanawanich P, Sirikanchanarod A, Adulbhan A, et al. Whey Protein Supplementation Improves Nutritional Status, Glutathione Levels, and Immune Function in Cancer Patients: A Randomized, Double-Blind Controlled Trial. J Med Food. 2018; 21: 612-616.

13.Laviano A, Calder PC, Schols A, Lonnqvist F, Bech M, Muscaritoli M et al. Safety and Tolerability of Targeted Medical Nutrition for Cachexia in Non-Small-Cell Lung Cancer: A Randomized, Double-Blind, Controlled Pilot Trial. Nutr Cancer. 2020; 72: 439-450.

14.World Health Organization. National cancer control programmes - Policies and managerial guidelines - WHO 2002. In: 2002.

15.Chu L, Pei C, Ho M, Chan P. Validation of the abbreviated mental test (Hong Kong version) in the elderly medical patient. Hong Kong Med J. 1995; 1: 207-11.

16.Lo RS, Woo J, Zhoc KC, Li CY, Yeo W, Johnson P, et al. Cross-cultural validation of the McGill Quality of Life questionnaire in Hong Kong Chinese. Palliat Med. 2001; 15: 387-397.

17.Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991; 39: 142-148.

18.Mahoney FI, Barthel DW. Functional evaluation: The Barthel Index: A simple index of independence useful in scoring improvement in the rehabilitation of the chronically ill. Md State Med J. 1965; 14: 61-65.

19.Karnofsky DA. The clinical evaluation of chemotherapeutic agents in cancer. Evaluation of chemotherapeutic agents. 1949: 191-205.

20.Harwood RH, Gompertz P, Ebrahim S. Handicap one year after a stroke: validity of a new scale. J Neurol Neurosurg Psychiatry.1994; 57: 825-829.

21.Smith R. Validation and Reliability of the Elderly Mobility Scale. Physiotherapy.1994; 80: 744-747.

22.Richie JP, Abraham P, Leutzinger Y. Long-term stability of blood glutathione and cysteine in humans. Clin Chem. 1996; 42: 1100-1105.

23.Devries MC, Phillips SM. Supplemental protein in support of muscle mass and health: advantage whey. J Food Sci. 2015; 80 Suppl 1:A8- A15.

24.Cereda E, Turri A, Klersy C, et al. Whey protein isolate supplementation improves body composition, muscle strength, and treatment tolerance in malnourished advanced cancer patients undergoing chemotherapy. Cancer Med. 2019; 8: 6923-6932.

25.de van der Schueren MAE, Laviano A, Blanchard H, Jourdan M, Arends J, Baracos V E , et al. Systematic review and meta-analysis of the evidence for oral nutritional intervention on nutritional and clinical outcomes during chemo(radio)therapy: current evidence and guidance for design of future trials. Ann Oncol. 2018; 29: 1141-1153.

26.Ravasco P, Monteiro-Grillo I, Vidal PM, Camilo ME. Cancer: disease and nutrition are key determinants of patients’ quality of life. Support Care Cancer. 2004; 12: 246-252.

27.de Oliveira LC, Abreu GT, Lima LC, Aredes MA, Wiegert EVM, et al. Quality of life and its relation with nutritional status in patients with incurable cancer in palliative care. Support Care Cancer. 2020; 28: 4971-4978.

28.Zanetti M, Gortan Cappellari G, Barazzoni R, Sanson G. The Impact of Protein Supplementation Targeted at Improving Muscle Mass on Strength in Cancer Patients: A Scoping Review. Nutrients. 2020; 12.

29.Houston DK, Nicklas BJ, Ding J, Harris TB, Tylavsky FA, Newman AB, et al. Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) Study. Am J Clin Nutr. 2008; 87: 150-155.

30.Arends J, Baracos V, Bertz H, Bozzetti F, Calder PC, Deutz NEP, et al. ESPEN expert group recommendations for action against cancerrelated malnutrition. Clin Nutr. 2017; 36:1187-1196.

31.Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011; 12: 489-495.

32.Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol. 2013; 10: 90-99.

33.Uster A, Ruehlin M, Mey S, Gisi D, Knols R, Imoberdorf R , et al. Effects of nutrition and physical exercise intervention in palliative cancer patients: A randomized controlled trial. Clin Nutr. 2018; 37:1202- 1209.

34.Hui D, Glitza I, Chisholm G, Yennu S, Bruera E, et al. Attrition rates, reasons, and predictive factors in supportive care and palliative oncology clinical trials. Cancer. 2013; 119: 1098-1105.

35.Balstad TR, Solheim TS, Strasser F, Kaasa S, Bye A, et al. Dietary treatment of weight loss in patients with advanced cancer and cachexia: a systematic literature review. Crit Rev Oncol Hematol. 2014; 91: 210-221.

36.Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE, et al. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab. 2008; 33: 997- 1006.

Yeung SSY, Ng K, Lo RSK, Woo J (2022) Effects of Eight-Week Whey Protein Supplementation in Palliative Care Patients with Advanced Cancer: A Double-Blind Randomized Controlled Pilot Trial. Arch Palliat Care 5(1): 1018.

Received : 16 Nov 2021
Accepted : 07 Dec 2021
Published : 11 Mar 2022
Journals
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X