A rapid review of nutrition and exercise approaches to managing unintentional weight loss, muscle loss, and malnutrition in cancer

Abstract

Purpose

This narrative review summarizes the evidence for nutrition, exercise, and multimodal interventions to maintain weight and muscle mass and prevent malnutrition from meta-analysis, systematic reviews, and randomized controlled trials published within the last 5 years, and in comparison to future research priority areas identified by international guidelines.

Recent findings

Dietary counseling with oral nutrition support (ONS), escalated to enteral nutrition if weight loss continues, is the gold standard treatment approach to maintaining weight and preventing malnutrition. Recent ONS trials with dietary counseling show promising findings for weight maintenance, extending the literature to include studies in chemoradiotherapy, however, change in body composition is rarely evaluated. Emerging trials have evaluated the impact of isolated nutrients, amino acids, and their derivatives (ie, β-hydroxy β-methylbutyrate) on muscle mass albeit with mixed effects. There is insufficient evidence evaluating the effect of exercise interventions on unintentional weight loss, muscle mass, and malnutrition, however, our knowledge of the impact of multimodal nutrition and exercise interventions is advancing. Prehabilitation interventions may attenuate weight and muscle loss after surgery, particularly for patients having gastrointestinal and colorectal surgery. Multimodal trials that commence during treatment show mixed effects on weight and muscle mass when measured.

Summary

This review highlights that the evidence for preventing unintentional weight loss and malnutrition from cancer treatment is strong within nutrition. Multimodal interventions are emerging as effective interventions to prevent unintentional weight loss. Promising interventions are demonstrating improvements in muscle mass, however further exploration through studies designed to determine the effect on muscle is required.

This narrative review summarizes the evidence for nutrition, exercise, and multimodal interventions to maintain weight and muscle mass and prevent malnutrition within the last 5 years.

Implications for practice summary.

Early and regular dietary counseling with or without oral nutrition support (ONS) remains the front-line approach to managing, treating, and preventing unintentional weight and muscle loss and malnutrition. There is emerging evidence of the cost-effectiveness of structured nutrition protocols to prove individualized nutrition support to hospitalized patients with cancer at risk of malnutrition. Exercise interventions are safe and can prevent muscle loss across the cancer treatment continuum. Given the breadth of evidence across multiple cancers and treatments multimodal rehabilitation should be included for hospitalized cancer patients at risk or with malnutrition. Prehabilitation trials are emerging but offer safe and effective interventions to offset weight and muscle loss post-surgery.

Introduction

Cancer-related malnutrition is common in people prior to, undergoing and recovering from cancer treatment, affecting approximately one in 3 people, albeit with a higher prevalence in people with cancers of the head and neck, lung, and gastrointestinal tract.^1,2 Global diagnostic criteria for malnutrition consider 3 phenotypic criteria, unintentional loss of weight, reduced muscle mass, and low body mass index (BMI) alongside 2 etiologic criteria, reduced food intake, and systemic inflammation.^3,4 At least 1 phenotypic and 1 etiologic criterion must be met for a diagnosis of malnutrition.^3,4 Malnutrition and its components, unintentional weight loss, and reduced muscle mass, are each independently associated with serious adverse outcomes in people with cancer including early mortality and reduced quality of life.^5-7 Importantly, reduced muscle mass can occur independently of malnutrition, with studies demonstrating only a 20% overlap between these conditions in people with cancer.^8,9 Furthermore, weight stability may mask underlying muscle loss, with an observational study in people with colorectal cancer found that 1 in 8 participants developed low muscle mass despite remaining weight stable.¹⁰ Therefore, a comprehensive nutritional assessment, that considers both recent unintentional weight loss and muscle mass, as well as food intake, symptoms, social factors, and functional status, is important to guide the initiation of appropriate intervention by a multidisciplinary team of health professionals. Validated tools such as the Patient-Generated Subjective Global Assessment (PG-SGA) may be used and supported by further measures of muscle mass suitable for use in clinical practice, such as calf or mid-upper arm circumference or bioelectrical impendence analysis.⁴

Nutrition and exercise are effective evidence-based treatments for cancer-related malnutrition and muscle loss, as recommended in guidelines from the European Society for Clinical Nutrition and Metabolism (ESPEN),^11,12 Clinical Oncology Society of Australia (COSA),¹³ and the American Society for Clinical Oncology (ASCO).¹⁴ Current recommendations for nutrition center around providing individualized dietary advice and oral nutrition supplements (ONS) to support adequate nutritional intake and improve quality of life, escalating to enteral (EN), or parental nutrition (PN) as required.^11,13 Recommendations for the use of special purpose nutrients vary, with omega-3 fatty acids recommended to improve appetite, muscle mass, and body weight, however, the evidence to support the use of amino acids and metabolites such as β-hydroxy β-methylbutyrate (HMB) is currently deemed insufficient.¹¹ Exercise is recognized within the ESPEN and COSA guidelines as necessary to support muscle mass, strength, and function, with resistance exercise required, in addition to aerobic exercise, to maintain muscle mass and strength.^11,13 However, the ASCO guidelines recommend aerobic and resistance exercise to mitigate the impact of treatment side effects albeit noting that studies testing the effect of exercise on body composition have been predominantly reported in people with breast or prostate cancer with variable effects.¹⁴

Several key areas of focus for future research are identified in the current guidelines. While evidence for the positive effect of individualized dietary counseling with or without ONS on improving dietary intake and quality of life is established, the ESPEN guidelines suggest further investigation of the effect on clinical outcomes such as treatment tolerance and survival is required.¹¹ Similarly, further research is to determine whether enteral nutrition, parenteral nutrition, or combinations affect clinical outcomes in those patients unable to achieve adequate food intake through dietary counseling and ONS.¹¹ With regard to special purpose nutrients, there is a call for large randomized trials (RCTs) to investigate HMB in weight loss patients and to examine whether omega-3 fatty acids may impact clinical outcomes such as survival when provided alongside cancer treatment.¹¹ The need to establish an effect on clinical outcomes is echoed in areas for future research in exercise, with a need to investigate the effect of exercise in people with malnutrition and muscle loss on clinical outcomes at all stages of treatment as well as examine the differential and combined effect of aerobic and resistance exercise.¹¹ Furthermore, there is a potential role for both nutrition and exercise interventions focused on maintaining muscle mass to support the maintenance of optimal chemotherapy treatment since the impact of low muscle mass on dose-limiting treatment toxicities is well established.¹⁴ The ASCO guidelines highlight a particular need for studies to examine the potential health economic benefit of nutrition and exercise interventions throughout cancer treatment from potential reductions in healthcare utilization.¹⁴ In this brief narrative review, we will summarize the progress made over the past 5 years in these areas with a focus on RCTs, systematic reviews, and meta-analyses. Interventions included nutrition, exercise, and multimodal interventions that measured change in body weight, body composition (muscle and fat mass), and malnutrition across any stage of the cancer continuum (pre-, during-, and post-treatment). Studies specifically in cachexia were included if participant criteria for inclusion in the study defined cachexia as unintentional weight loss.

Nutrition approaches to unintentional weight loss, muscle, and malnutrition

Dietary counseling and structured escalation of nutrition support

Interventions published in the past 5 years that examined the effect of providing individualized dietary counseling, including ONS, enteral, or parenteral support are summarized in Table 1. Nutrition interventions show mixed findings for maintaining or increasing weight during cancer treatment through dietary interventions specifically in head and neck,¹⁶ gastrointestinal,^18,19,23 colorectal,^15,22 and mixed cancers^17,20,21 where malnutrition risk is high. In addition, a limited number of trials have included measures of body composition, hindering our understanding of the best nutrition strategy to address muscle loss, and other clinical outcomes, such as severe treatment toxicity and completion. Overall, the evidence from systematic reviews is also mixed. A systematic review and meta-analysis of 6 RCTs reported improvement in energy intake but not body weight (WMD = 4.28 kg; P = .06) from dietary counseling in a mixed range of patients with cancer at risk or with malnutrition,⁴³ while others have shown improvements in nutritional status and unplanned admissions.⁴⁴ Heterogeneity in nutrition intervention design, consultation frequency, and timing (ie, pre-surgery, post-surgery, or during chemoradiotherapy) for a range of cancer diagnoses, likely explains the mixed findings on body weight from reviews. On the whole, the literature supports that dietary counseling improves nutritional status and body weight.^11,12 However, whether muscle mass along with body weight can be maintained through individualized dietary counseling across the cancer treatment continuum, requires further investigation.

Table 1.

Summary of nutrition, exercise, or multimodal RCTs effects on weight and body composition

Author (year), country	Participant characteristics (n, treatment type)	Cancer type	Intervention details for nutrition, exercise, and multimodal trials.	Comparator	Outcome measures (* denotes primary, if reported)	Results (body weight or composition only)
Nutrition alone
Burden et al15 (2017) UK	101, post-surgery	Colorectal	Dietary counseling with ONS Single dietary counseling at baseline aimed to increase energy and protein. ONS: (10.1 KJ, 0.096 g protein per 250 mL) commenced once the surgery date was confirmed. Pre-operative, 5 ONS provided, and post-operatively daily ONS was provided.	Dietary counseling Single dietary counseling post-operatively with ONS bottles of water.	Infection *, complications, length of stay in hospital, body weight	There was a significant difference in the percentage of weight lost between groups both pre-operatively (intervention 4.1% IQR 1.7–7.0 vs controls 6.7% IQR 2.6–10, P = .021) and post-operatively (intervention 7.4% IQR 4.3–10 vs controls 10.2% IQR 5.1–18.5, P = 0.016).
Cereda et al16 (2018) Italy	159, scheduled for radiotherapy	Head and neck	Dietary counseling with ONS Individualized weekly face-to-face dietary counseling with a dietitian commenced at the start of radiotherapy to meet energy requirements (Harris-Benedict derived), protein (1.2 g/kg−1), symptom management. ONS: Twice/day providing 500 kcal, 23 g protein, 1.9 g omega n−3.	Dietary counseling Dietary counseling as described above. ONS was provided if < 60% estimated requirements were not met.	Body weight *, dietary intake, muscle strength, quality of life, and treatment tolerance.	Significant between-group mean difference in body weight in favor of the ONS group (+ 1.6 kg, 95%CI 0.5-2.7, P = .006)
Cereda et al17 (2019) Italy	166, chemotherapy, diagnosed with malnutrition	Mixed, advanced cancer	Dietary counseling with whey protein ONS Individualized weekly-to-monthly face-to-face dietary counseling with a dietitian to meet energy requirements (Harris-Benedict-derived), protein (1.5 g/kg−1), symptom management. EN used if <60% requirements across 2 weeks after ONS trialed. ONS: Whey protein twice/day of 20 g protein (cysteine-rich, lactose-free) mixed in water or milk.	Dietary counseling Individualized weekly-to-monthly face-to-face dietary counseling with a dietitian to meet energy requirements (Harris-Benedict-derived), Protein (1.2 g/kg−1), symptom management. ONS twice/day providing 300-600 kcal, 20-40g protein, when < 60% estimated energy requirements across two consecutive weeks. EN used if <60% requirements across 2 weeks after ONS trialed.	Phase angle *, body weight, composition, hand grip strength, treatment toxicity	Significant between-group difference in body weight (MD 1.7, 95%CI 0.2, 3.1, P = .023) and fat-free mass (MD 0.46, 95%CI 0.02, 0.90, P = .041) at the end of the study (3-months).
Chen et al18 (2023) China	78, chemotherapy	Gastrointestinal	Dietary counseling with ONS Escalating decision-making on nutrition through (1) dietary counseling to meet energy (25-30 kcal/kg−1) and protein (1.2 g/kg−1), (2) counseling with ONS, (3) enteral nutrition, (4) partial enteral and parenteral nutrition, (5) full parenteral nutrition. Escalated each step based on failing to meet < 60% energy requirements in 3-5 days. Intervention commenced at chemotherapy and followed up weekly.	Usual care which included simple nutrition assessment and education.	PG-SGA *, body weight, hand grip strength, triceps skin fold, arm muscle circumference, calf circumference, quality of life.	Significant between-group difference in weight (MD 4.2 ± 1.9 kg vs −2.6 ± 1.7 kg).
Meng et al19 (2021) China	333, post-surgery and at risk of malnutrition	Gastric	Dietary counseling with ONS Fortnightly dietary counseling to increase energy and protein intake (unknown requirements). ONS: 100 kcal and 4.1g protein per 100 mL (goal of 500 mL).	Dietary counseling As described in the intervention arm. ONS provided if ≥5% weight loss is observed.	Weight, skeletal muscle index, sarcopenia, treatment tolerance, quality of life.	Significant between-group difference in weight loss (estimated −2.1 kg vs −4 kg) and skeletal muscle index at (estimated 40 cm2/m2 vs 38 cm2/m2) 3 months (post-program)
Molassiotis et al20 (2021) Australia & Hong Kong	74 patients and 54 family care givers, stage III-IV cancer with a life expectancy of ≥6 months and at risk of malnutrition.	Mixed	Family-centered nutrition intervention Three structured sessions with a dietitian over 4 weeks through telehealth with family/carers to individually meet energy and protein requirements (unknown) and considering symptom management. ONS may have been recommended.	Usual care nutrition advice and symptom management through palliative care team.	Feasibility *, quality of life, PG-SGA, eating-related distress, weight.	No significant differences between groups in weight
Patursson et al21 (2021) Svabosgøta	30, outpatient radiotherapy to the gastrointestinal and pelvic area	Mixed	Dietary counseling with ONS Individualized dietary counseling from a dietitian to meet nutritional requirements (unknown). ONS: 33.8 g protein, 2.2 g EPA, 1.1 g DHA, and 2500 kJ/day.	Usual care nutrition education provided by nurses	Body weight *, dietary intake, quality of life.	No significant difference between-group differences in weight
Tan et al22 (2021) China	212, post-surgery and at risk of malnutrition	Colorectal	Dietary counseling with ONS Fortnightly dietary counseling to increase energy and protein intake (unknown requirements). ONS: 100 kcal and 4.1g protein per 100 mL (goal of 500 mL).	Dietary counseling As described in the intervention arm. ONS provided if ≥5% weight loss is observed.	Body weight, skeletal muscle index, sarcopenia, treatment tolerance, quality of life.	No significant between-group differences in weight post-program, however significant increase in skeletal muscle index compared to the control group at 3-months (estimate mean 40 cm2/m2 vs 38 cm2/m2)
Zhu et al23 (2019) China	104, post-surgery	Gastrointestinal	Dietary counseling with ONS Dietary guidance from treating doctor (requirements unknown). ONS: 500 kcal, ~70 g protein per day for 90 days post discharge.	Dietary counseling The same dietary guidance from treating doctor.	Body weight *, biochemical markers, infection and complications, quality of life.	Significant between-group difference in weight at 60 days (1.34 ± 0.53 kg vs −1.01 ± 0.54 kg) and 90 days (1.35 ± 0.73 kg vs −1.59 ± 0.81 kg)
Exercise alone
Anandavadivelan et al24 (2022) Sweden	161, 1-year post-surgery	Esophageal	Exercise prescription: 12 weeks, home-based, weekly telephone calls. Education regarding PA and 5 UL and LL strength exercises with resistance bands and body weight, 10 repts × 2 sets. F: ×2/week. I: NR, progressed as acceptable to the patient. T: NR.	Education regarding PA guidelines for older people.	Muscle strength* (handgrip and 30secSTS) and muscle mass* (bio-impedance)	No significant between-group changes in muscle mass (intervention MD 0.14 (−1.34 to 1.61) kg and control group 0.33 (−0.83 to 1.48) kg, P = .84
Arrieta et al25 (2019) France	301, at commencement of curative treatment, aged ≥ 70 years	Lymphoma or carcinoma (36% breast)	Exercise prescription: Unsupervised, home-based. Phone calls ×2/month for 6 months and monthly from months 6-12. Aerobic, strength (UL and LL), flexibility, proprioception, and balance. F: ×2 days/week. I: low to high. RT—×10 reps, load added as tolerated) T: NR	Usual care booklet	Physical function (Short Physical Performance Battery)*, physical activity, cognition, hospitalization/institutionalization, falls, mortality at 12 months	Muscle mass not assessed.
Cheng et al26 (2021) China	120, during chemo +/- radiotherapy	Lung, gastric, or breast cancer	Exercise prescription (3-arm trial): Arm 1: Tai Chi 12 weeks F: ×3/week I: high-intensity (60% 1RM) T: 40 minutes/session Arm 2: Resistance exercise (6 exercises for UL and LL with weights or body weight) 12 weeks F: ×3/week I: low-intensity (30% 1RM) T: 10 sets × 3 minutes each exercise	Usual care	Muscle strength (1RM), weight, body composition (fat mass, lean body mass), fatigue, health-related quality of life, anxiety, depression, sleep quality and adverse events	Body weight increased in both resistance groups compared to the control group (P < 0.05). LM increased and FM decreased significantly in the high-intensity group compared to the low-intensity of Tai Chi groups (P < .05)
Grote et al27 (2018) Germany	20, during inpatient or outpatient RTx (65% combined chemoRTx), stage I-IV	HNC	Exercise prescription: Supervised during RTx (mean 16.6, range 13-25 sessions). Resistance (machine weights—leg press, lat pull-downs, and chest press), 8-12 reps × 3 sets. Progressed if RPE < 7 by increasing weight (UL 2.5 kg and LL 5kg). F: x 3/week. T: 30 minutes/session	Usual care (no muscle strengthening technique but could include IP physio)	Feasibility*, fatigue, health-related quality of life, physical performance (6MWT), muscle strength (elbow flexion, knee extension), body composition (BIA)	Baseline (T1), after 7 weeks of RTx (T1) and 8 weeks after RTx2 (T3). Fat mass—decreased by 20% UC and 30% IG (T1-T3), decreased by 2% UC and 16% IG (T2-T3), P = .545. Lean mass—decreased by 3% UC and increased by 1% IG (T1-T3), P = .267
Hacker et al28 (2017) USA	75, post allogeneic or autologous stem cell transplant	Hematological	Exercise prescription: AROM ×2/week during IP admission. Following discharge ×6 weeks of RT (11 exercises—UL, LL, abdominals with resistance bands and body weight). Progressed by increasing repetitions, then sets, then resistance. F: ×3/week (one-on-one supervised ×1-2/week, ×1-2 unsupervised at home). I: Borg 13 (moderate) T: NR	During IP admission—2 visits/week to discuss hospital experience. Following discharge 6-week health education program. F: ×1/week (one-on-one education).	Physical activity (objective* and patient-reported), fatigue, muscle mass (rectus femoris muscle ultrasound CSA), muscle strength (handgrip, arm curl test), functional ability (timed stair climb, TUG test, 15-ft walk time and 30 seconds CST), HRQoL	Pre-transplant to post-intervention measures. Non-significant between-group differences for muscle mass (P > .05)
Kamel et al29 (2020) Egypt	40, resectable and non-resectable, stage I-IV	Pancreatic	Exercise prescription: 12-weeks, supervised. Resistance (machine-based, 8 exercises for UL and LL). F: ×2 sessions/week. I: commenced 5 exercises, 20 reps × 1-2 sets 50%-60% 1RM, progressed week 5 to 8 exercises 8-12 reps × 3 sets 60%-80% 1RM. T: 60 minutes/session	No exercise, physio phone contact once/month about negative cancer therapy outcomes plus nutritional and psychosocial support	Mobility, muscle strength, and lean body mass	Pre–post intervention measures. Improvements in UL and LL lean mass (6.28-6.46 vs 6.31-6.23 kg and 16.31-16.58 vs 16.4-16.31 kg, respectively, favoring IG)
Lavigne et al30 (2020) Canada	22, completed RT +/- chemo (stage I-IV). Surgery (68%) and concomitant chemo (82%).	HNC	Exercise prescription: 12 weeks, supervised, novel strength training—eccentrically overloaded training (squats, intensity “to tolerance”) and NMES contractions (66 bilateral, 40 Hz, pulse duration 180, 5 s contraction, 10 s rest, 1.5 s ramp-up, 0.75 s ramp-down). F: ×3/week, 2 sets of 8 reps. I: NR T: NR.	Conventional strength exercises 5 exercises using body weight or dumbbells (squats, lunge, step up, knee extension) 2 sets of 8. intensity “to tolerance.”	Feasibility* (recruitment, completion, adherence, progression). HRQoL, fatigue, thigh muscle CSA ultrasound, neuromuscular function (isometric dynamometry and femoral nerve electrical stimulation), 30 seconds STS	Pre-post whole group: KE force increased by 22 (23)% P < .001, mass: 19% (23) increase in VL CSA P = .004, 17 (22)% increase in RF CSA P = .006)
Rosenberger et al31 Germany	25, TKI-based anti-tumor therapy	Mixed	Exercise prescription: 12-week, supervised, resistance training—8 machine-based exercises of major muscle groups (2 sets × 12 reps at 12RM). Progressed by weight increase. F: x2/week. I: NR T: 60 minutessss/session.	No intervention.	Feasibility*, fatigue, HRQoL, depression, muscle strength, cardiorespiratory fitness (CPET), anthropometric measures.	Pre–post-intervention measures. Unadjusted model significant change in body weight favoring IG 1.2 kg (−0.3 to 2.8) vs UC −0.9 kg (−2.6 to 0.7), P = .042 (adjusted for baseline P = .05)
Scott et al32 (2021) USA	90, < 1 or ≥ 10 years post definitive Rx completion (Stage I-IIIB or LS)	Lung	Exercise prescription: 16 weeks of individual, supervised sessions. 3 groups: AT (aerobic, interval training—stationary cycle ergometry), RT (resistance training with weights—14 UL and LL exercises, 6-18 reps × 3 sets), CT (aerobic and resistance combined). F: ×3/week. I: commenced 50%-60% 1RM and progressively increased to 75%-85% 1RM. T: 30-60 minutes/session.	Attention control—stretching exercises, 20-45 minutes/session.	Cardiorespiratory fitness*, maximal muscle strength, weight, percentage of lean and fat mass (DEXA or air displacement plethysmography), HRQoL, pain, sleep quality, and safety.	RT was associated with near-significant improvements in lean mass (1.6% (−0.2 to 3.4) P = .08) and reductions in fat mass (−1.6% (−3.4 to 0.2) P = .08) and no difference in weight (0.6 kg (−0.6 to 1.7) P = .33), compared with AC
Wiskemann et al33 Germany	65, resectable or non-resectable (stage I-IV). Surgery + adjuvant chemo (83%)	Pancreatic	Exercise prescription: 6 months. Two groups either: RT1 supervised (living < 20 km from study center) or RT2 home-based with weekly phone calls. UL and LL strength training with weights. F: ×2/week. I: RT1 60%-80% 1RM and RT2 14-16 Borg RPE. T: 60 minutes/session	Usual care, patient calls ×1/month regarding side effects and advised not to change exercise behavior.	Adherence, feasibility*, muscle strength, cardiorespiratory fitness, body weight	No significant changes in body weight from baseline (RT1 3.2 (3.7)%, RT2 −0.4 (6.2)%, control 0.8 (5.8)%.
Wochner et al34 Germany (Secondary analysis of Wiskemann 2019)					Body composition: CT scans (L3/4) fat area (total, visceral, subcutaneous, intramuscular) and visceral-subcutaneous fat ratio, muscle area, muscle density, and SMI. Overall survival.	Pre-post—no significant effects on body composition (P > .05). Loss of muscle mass was a predictor of poor OS (visceral fat ratio HR = 2.084, P = .014)
Yen et al35 Taiwan	84, during chemotherapy, stage NR	HNC	Exercise prescription: 8-week. Aerobic and resistance (10 UL and LL exercises with resistance band, 10 reps, 1-3 sets. F: ×3 + days/week. I: 60%-70% HR max; RT “somewhat heavy”-“heavy” RPE. T: 40-50 minutes/session.	NR	Body composition, functional exercise capacity (6MWT), pre and post 6MWT HR, BP, and rate-pressure product	Pre-post-intervention measures. Body weight (kg) significantly reduced in the control group (mean (SD) 59.1 (11.3) vs 58.1 (11.4)). BMI (kg/m2) significantly reduced in the control group (mean (SD) 22.3 (3.8) vs 21.9 (4)). Visceral fat was significantly reduced in the intervention group (mean (SD) 7.9 (4.7) vs 7.4 (4.5)). Skeletal muscle rate significantly increased in the intervention group (mean (SD) 32.1 (3.8) vs 33.6 (4.1)).
Multimodal interventions
Gillis et al36 (2019) Canada	76, pre- or post-colorectal surgery.	Colorectal	Prehab Duration 4 weeks prior to surgery to 8-weeks post-surgery. Exercise Aerobic and resistance training that is home-based. F: 3/7. I: NR T: 50 minutes per session. Plus weekly supervised group exercise. Nutrition Individualized dietary counseling from a dietitian (1.2 g/IBW/day) focused on symptom control, and optimizing body composition, plus whey protein supplement (nutritional breakdown not provided). Rehab Identical to above but baseline consultation occurred a few days prior to surgery, and the intervention started post-surgery. Other Anxiety-reduction consultation with a psychologist weekly.	NA	Body composition * 6MWT Feasibility (intervention compliance)	Significant increase in lean mass (change from baseline =+0.4 kg; 95% CI: 0.03-0.7 to kg, P = .031) and lost FM (change from baseline =−0.6 kg, 95%CI: −1.0 to −0.2 kg, P = .005) in the pre-surgery period. Baseline to 8 weeks shows no changes in lean mass. Rehabilitation group showed a reduction in lean mass (change baseline to 8 weeks: −1.1 kg, 95%CI: −2.3 to −0.02 kg, P = .045).
Hall et al.37 (2021) UK	45, diagnosed with incurable cancer with predicted survival > 3 months.	Mixed	Exercise Weekly consults with an exercise physiologist for home-based aerobic exercise (F: NR, D: 60 minutes/week, I: moderate, Borg scale 3-4) and resistance training of body weight exercises targeting major muscle groups. Nutrition Weekly consults with a dietitian for individualized counseling on food preferences to meet requirements plus ONS (330 kcal, 1 g EPA OR oral capsules of 2 g EPA).	NA	Feasibility*, quality of life, physical activity, and body weight.	Non-significant between-group differences in body mass post-program (median with IQR) Intervention +1 kg, (−2 to 2), control −3 kg (−2, 0).
Mikkelsen et al38 (2022) Denmark	84, during or following systemic treatment, 93% metastatic disease	Lung, pancreatic, biliary tract	Exercise 12 weeks, supervised (resistance) and home-based (walking with a pedometer). Resistance (machine-based weights, 7 exercises for UL and LL) and stretching. F: ×2/week supervised and daily home-based. I: commenced at 15 RM × 2 sets and progressed to 10RM × 3 sets T: 60 minutes/session Nutrition Dietary counseling bi-weekly to achieve 200-300 calories, 12-18 g protein Other Two sessions of health education from nurses	Usual care (not asked to refrain from exercise)	Physical function (patient-reported and performance-based (30 seconds STS*)), feasibility, physical capacity (6 MWT), handgrip strength, body composition (DEXA and BIA), symptom burden, health-related quality of life, mood, toxicities, hospital re-admissions	Pre-, mid-, and post-intervention. The significant difference in LM change of 0.9 kg (SE 0.4), P = .033 favoring IG.
Molenaar et al.39 (2022) International	251, operable, non-metastatic	Colorectal	Prehab Exercise 4-weeks, supervised. Aerobic (bicycle) and resistance (machines, body weight, bands for major muscle groups, 2 sets × 10 reps). F: x3 sessions/week. I: aerobic (HIIT—85%-90% peak power); resistance (65%-70% 1RM). T: 60 minutes/session Nutrition Education to balance macronutrients and achieve 1.5 g per kg of protein daily. ONS: 30 g whey protein supplement taken within 60 minutes of exercise. Multivitamin and Vitamin D supplements. Other Anxiety coping interventions—relaxation and deep breathing. Smoking cessation (if required)	Standard care ERAS pathway	30-day post-operative pulmonary complications*, 6MWT distance*, cardiorespiratory fitness, muscle strength (1RM and handgrip), nutritional status (PG-SGA), mental health (GAD-7 and PHQ-9), HRQoL (EORTC-QLQ-C30), hospital LOS, readmissions and mortality at 30 days.	Muscle mass not assessed. No significant differences in nutritional status (PG-SGA (median [IQR] post-intervention (pre-op) 0 [0,2] both groups).
O’Neill et al40 (2018) Ireland	43, post-operative (25 had neoadjuvant Rx and 9 adjuvant Rx)	Oesophageal	Exercise 12-week, supervised and unsupervised. Aerobic (commenced 30%-45% HRR and progressed weekly to 45-60% HRR) and resistance (2 sets 12 RM and progressed to 6 sets of 17RM) training. F: 2-3×/week. I: aerobic (start 30%-45% HRR and progress weekly to 45%-60% HRR). T: NR. Nutrition Dietary counseling and education on GI symptoms. Nutrition prescription NR.	Usual care (standard care as per best practice).	Cardiorespiratory fitness (CPET)*, body composition (anthropometrics and bioimpedance), HRQoL, PA (objective), adverse events.	Baseline, post-intervention, and 3 months post-intervention. No significant changes in body composition or anthropometrics at either timepoint apart from MUAC post-intervention P = .019 favoring IG (stable) vs decrease in UC.
Solheim et al41 (2017) Norway	46, during chemotherapy, stage III-IV	Lung and pancreatic	Exercise 6-week, home-based with weekly telephone contact for adherence. Aerobic (patient’s choice 30 minutes ×2/week) and resistance (6 UL and LL exercises with weights and body weight, 20 minutes) × 3/week. I: NR Nutrition Single nutritional counseling to increase meal frequency and energy intake. ONS 2× daily 220 mL of 1 g EPA. Other: Daily anti-inflammatories (celecoxib).	Standard care offered intervention after 6 weeks.	Feasibility*, weight, muscle mass (CT at L3), PA (objectively using accelerometry and 6MWT), handgrip strength, nutritional status, fatigue, safety and survival.	Pre-post intervention. Mean (SD) % change: weight 1.29 (3.41) vs −3.91 (3.67), P < .001 favoring IG; muscle mass −0.02 (0.07) vs −0.04 (0.06), P = .03.
Balstad et al42 (2020) (Secondary analysis of Solheim et al)					Estimates of sensitivity to change and between-group effect sizes for body weight, body composition, physical function, and metabolism.	Body weight ES large (1.2, P < .001), body composition ES small (range for different outcomes between 0.15 and 0.26, P > .05).

Abbreviations: AROM, active range of motion; BIA, bioelectrical impedance analysis; BP, blood pressure; CI, confidence interval; CPET, cardiopulmonary exercise testing; CT, computerized tomography; DHA, Docosahexaenoic acid; EPA, eicosapentaenoic acid; EN, enteral nutrition; ES, effect size; EORTC-QLQ, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; DEXA, dual-energy x-ray absorptiometry; F, frequency; GAD-7, general anxiety disorder; GI, gastrointestinal; HNC, head and neck cancer; HRQoL, health-related quality of life; HRR, heart-rate resting; I, intensity; IBW, ideal body weight; IQR, interquartile range; IG, intervention group; KE, kinetic energy; LL, lower limbs; LOS, length of stay; LM, lean mass; L3, lumbar vertebra 3; MUAC, mid-upper arm circumference; NA, not applicable; NMES, neuromuscular electrical stimulation; NR, not reported; ONS, oral nutrition supplement; PA, physical activity; PG-SGA, patient generated-subjective global assessment; PHQ-9, patient health questionnaire; UC, usual care; UL, upper limbs; RF CSA, rectus femoris cross-sectional area; RM, repetition maximum; RPE, rating of perceived exertion; RT, resistance training; RTx radiotherapy; SD, standard deviation; SGA, subjective global assessment; SMI, skeletal muscle index; STS, sit to stand test; T, time; TUG, timed up and go test; VL CSA, vastus lateralis cross-sectional area; 6MWT, 6-minute walk test.

Oral nutrition supplements (ONS) are recommended if oral intake is inadequate to meet estimated energy and protein requirements to maintain weight and muscle mass with continued dietary counseling.⁴⁵ A meta-analysis of 12 RCTs evaluating the effects of dietary counseling with ONS (protein with or without omega-3) on malnutrition found body weight was maintained (MD + 1.31 kg; P = .02) during chemoradiotherapy.⁴⁶ No benefit was found in terms of survival (n = 4), or treatment-related toxicity (n = 3), and there were inconsistent effects on muscle mass (n = 2).⁴⁶ Another systematic review in head and neck cancers found ONS with dietary counseling maintain weight for up to 12 months post-treatment⁴⁷; however, other clinical outcomes were not assessed. In 159 newly diagnosed patients with head and neck cancer, dietary counseling with ONS compared to dietary counseling only showed smaller reductions in body weight at the end of radiotherapy (67.7 vs 65.7 kg) and 3-months follow-up (68.3 vs 64.4 kg).¹⁶ The intervention arm reported less treatment change (radiotherapy dose-reduction) and improved completion (HR = 0.40; P = .029). Preventing unintentional weight loss through dietary counseling with ONS may improve treatment tolerance and completion and requires further investigation into other cancers and treatments. In addition, future trials must consider evaluating muscle mass given its relationship to chemotherapy-related toxicity and surgical complications to advance our understanding in this area.^48-50

A large RCT (n = 506) evaluated an early, individualized dietary counseling or EN (if meeting < 75% estimated energy and protein requirements) intervention for malnourished patients during hospitalization, vs usual care, found reduced mortality (OR: 0.57; P = .027) in the intervention arm.⁵¹ Recent attention has turned to the economic benefit of nutrition intervention for people with cancer,⁵² and secondary analysis of the aforementioned RCT suggested that the intervention was cost-effective relative to usual care (CHF 43 711 vs 46 420 per patient).⁵³ This emerging evidence of economic benefit calls for further international evaluations to reinforce the allocation of resources to dietetic services within cancer centers.

Specialized oral nutrition supplements

Omega-3 long-chain polyunsaturated fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), offer anti-inflammatory properties which may counteract muscle loss and maintain body weight.^46,54 A recent meta-analysis of 31 RCT’s evaluating ONS containing >600 mg of omega-3 consumed for >3 weeks compared to a control supplement showed no benefit on muscle mass (MD −0.47 kg; P = .59) or body weight (MD 4.02 kg; P = .06).⁵⁵ However, adherence to the ONS was low. Participants in the control group were taking omega-3 supplements, and the majority of studies did not account for energy and protein intakes.⁵⁵ Recently, β‐hydroxy β‐methylbutyrate (HMB), a compound supplemented in doses up to 3.0 g/day, has been used to prevent muscle deterioration by increasing muscle protein synthesis and decreasing protein breakdown.^56-58 A systematic review evaluating HMB in ONS showed preliminary benefits for improving muscle mass, strength, and other clinical outcomes, however, improvements in body weight were not found.⁵⁸ The additional benefits of omega-3 or HMB ONS, or a potential future combination of these with other nutrients, compounds, or ingredients,^59,60 require further evaluation through well-designed, adequately powered RCT’s. These trials should be powered to detect clinically important differences in body weight and muscle mass, measure adherence to the ONS, and assess concurrent dietary intake.

Enteral and parenteral nutrition support

There are limited randomized trials or reviews evaluating EN or PN during cancer treatment within the past 5 years and evidence directly evaluating changes in body weight or muscle mass within a hospital setting is scarce. These feeding approaches must be patient-centered and consider the psychosocial state, gastrointestinal function, nutrition impact symptoms, and the location and treatment of the tumor.^61,62 Home EN improves the quality of life and reduces time spent in the hospital during cancer treatment. Meta-analysis of 4 RCTs shows that EN maintained BMI (WMD 0.70 kg; P = .02) and muscle mass (WMD 0.76 kg; P = .04) compared to normal oral intake after esophageal cancer surgery.⁶³ Enteral nutrition supplemented with nutrients including omega-3, Vitamins A, D, or E, and amino acids arginine and glutamine, has potential benefits on immune function. A systematic review of 7 randomized trials evaluated if EN enhanced with omega-3, arginine, and/or glutamine, preserves weight, and potentially muscle mass.⁶⁴ However only a few studies (n = 4) measured muscle mass. Two meta-analyses in gastrointestinal cancers found a reduction in postoperative complications from EN enhanced with omega-3, arginine, glutamine, and/or ribonucleic acid (RR = 0.29; P = .001) compared to standard EN,⁶⁵ and showed reduced length of hospital stay (MD -−.03 days; P < .001) when compared to dietary counseling.⁶⁶ However, changes in weight or muscle mass were not examined in the included studies highlighting a gap to be addressed in future trials.

Exercise approaches to unintentional weight loss and loss of muscle mass

For people with cancer, the World Health Organization guidelines recommend 150-300 minutes of moderate or 75-150 minutes of vigorous, intensity aerobic exercise/week, and moderate intensity muscle strengthening activities ≥2 days/week (≥3 days/week in ≥65-year-olds) to achieve health benefits.⁶⁷ In discussing the evidence for the role of exercise in managing unintentional weight loss and loss of muscle mass, interventions focusing on resistance exercise (either alone or combined with aerobic) are highlighted. Myofibrillar protein synthesis is stimulated by resistance training, making it more effective in achieving skeletal muscle hypertrophy than aerobic exercise.⁶⁸ It is noted, however, that aerobic exercise plays an important role in preserving skeletal muscle mitochondrial function⁶⁹ and may reduce circulating inflammatory markers such as C-reactive protein.⁷⁰ Interventions are in progress (clincaltrials.gov NCT05307367) to provide a further understanding of the effects of resistance training on inflammatory markers and muscle mass in lung cancer.

Systematic review evidence of exercise-only interventions to prevent muscle loss, from the last 5 years, addressing ASCO, ESPEN, and COSA guideline future research areas is limited, interventions are heterogenous and effectiveness findings are mixed. During and following treatment non-significant between-group differences were reported in 3 systematic reviews.^71-73 Meta-analysis of 34 resistance training trials during and after cancer treatment report increases in muscle mass favoring the intervention (MD 0.85 kg 0.26 to 1.43; P = .004).⁷⁴ Details of relevant RCTs are summarized in Table 1 and include resistance-focused interventions during and following treatment in hematological,²⁸ head and neck,^27,30,35 esophageal,²⁴ pancreatic,^29,33,34 lung³² and mixed^25,26,31 cancers. Resistance training interventions vary, but most include supervised sessions (alone or combined with unsupervised, home-based exercise), prescribe moderate-intensity concentric (muscle shortening) exercise, and range from 6 weeks²⁸ to 6 months³³ duration. Findings for anthropometry and body composition (weight, BMI, muscle mass, and fat mass) outcomes post-program are mixed with some RCTs reporting non-significant between-group differences,^{24,27,28,32-34} while others find significant effects favoring the intervention group.^26,29-31,35 Differing modality effects, as highlighted in ESPEN guidelines, were investigated in a 4-arm RCT (aerobic, resistance, combined aerobic, and resistance and usual care) >1 year post definitive lung cancer treatment. Resistance exercise was superior to aerobic for body composition outcomes (aerobic vs resistance muscle mass MD (SD) (−2% (3), P = .04) and fat mass (−2% (3), P = .04)), with no difference in weight and no additional benefit of combined aerobic and resistance exercise.³² Greater effects on body composition were found for high compared to low-intensity Tai Chi (P < .05) in a mixed tumor group during chemotherapy.²⁶ Longer-term effects of exercise interventions have not been investigated and further trials are required to determine the most effective resistance exercise type (eg, eccentric (muscle lengthening), used in one RCT,³⁰ vs concentric) and exercise prescription needed to increase muscle mass.⁷⁵ In broad terms, exercise interventions in cancer are reported in one study to be cost-effective.⁷⁶ In the future, health economic evaluations should be run alongside RCTs to understand the cost-effectiveness of interventions specifically aimed at preventing muscle loss.

Safety considerations

Individual patient assessment is critical to prescribing safe exercise in any patient, including those with a cancer diagnosis. Systematic review evidence from 65 trials supports a low risk (3.5%) of adverse events from exercise,⁷⁷ with musculoskeletal injury or pain being the most common. Although few of these trials measured the impact on unintentional weight loss. In the presence of fever, infection, and chest pain exercise should not be undertaken. For patients with bony metastases care needs to be taken to avoid loading the malignant bone lesion site. Patients with cancer may fluctuate in their symptomology and exercise intensity and/or duration may need to be varied. More detailed criteria may be found in the Exercise and Sports Science Australia position statement⁷⁸ and also the American College of Sports Medicine guidelines papers.⁷⁹

Multimodal approaches to unintentional weight loss/malnutrition

Multimodal interventions (combination of 2 or more therapies) are often used prior to cancer treatment (prehabilitation), during or after treatment (rehabilitation) where deconditioning and risk of malnutrition are heightened.⁸⁰ Several systematic reviews show multimodal rehabilitation interventions can maintain weight and muscle mass through individualized dietary counseling, ONS, and structured resistance training.^81-84 A meta-analysis shows multimodal interventions during cancer treatment showed no between-group differences in weight (MD 0.46 kg; P = .549) and muscle (MD 0.11 kg; P = .864).⁸¹ Other reviews show multimodal rehabilitation interventions are safe and maintain weight and muscle mass in a broad mix of cancers,⁸³ yet varied effects were reported in upper gastrointestinal cancers specifically.⁸⁴ Included studies in gastrointestinal cancer⁸⁴ used a range of multimodal interventions; these were predominantly 1:1 dietary counseling, however, the exercise interventions varied between supervised and unsupervised home-based combined resistance and aerobic exercise which may explain the mixed findings.

Results from multimodal rehabilitation RCTs (Table 1) on weight and muscle mass are varied and limited to esophageal,⁴⁰ and a mixed group of advanced cancers.^37,38 An RCT (n = 84) showed supervised resistance training and home-based walking, with dietary counseling, compared to usual care, increased weight (1.4 kg vs 0.4 kg), and muscle mass (1.3 kg vs 0.4 kg) during systemic treatment for advanced cancer.³⁸ While 12-week multimodal rehabilitation post esophageal surgery, showed no benefits to weight and muscle mass compared to the usual care group.⁴⁰ Research interest has turned to the implementation of multimodal rehabilitation in health services. A pilot study showed that nurse-led malnutrition screening and referral to multidisciplinary treatment for patients with head and neck cancer increased the proportion of patients identified with malnutrition from 14% to 88% for appropriate management, avoided 3.92 unplanned admissions on average, and reduced healthcare expenditure by approximately $121K AU per annum.⁸⁵ Evidence supports the use of multimodal interventions during or after cancer treatment to maintain or increase weight and muscle mass, and new models of care to prevent malnutrition and muscle loss and support the COSA position statement¹³ and add new evidence to the ASCO guidelines.¹⁴

Prehabilitation is a multidisciplinary bundle of care that identifies impairments and provides targeted interventions to improve patient outcomes^86-88 and evidence has substantially grown in the last 5 years in oncology. Systematic reviews suggest that prehabilitation interventions maintain muscle mass following gastrointestinal cancer surgery,⁸⁷ however, more broadly, weight and muscle mass are not typically reported in prehabilitation interventions.⁸⁹ A large (n = 251) prehabilitation trial prior to colorectal cancer surgery, involving 4-week supervised inpatient high-intensity aerobic and resistance exercise, dietary counseling, ONS, and psychosocial support, showed no change in malnutrition (PG-SGA median (IQR) 1 (0-4), intervention vs 1 (0-3), control). While strength was increased post-operatively, weight and muscle mass were not assessed.³⁹ Pooled analysis of 2 RCTs comparing multimodal prehabilitation to rehabilitation in patients with colorectal cancer scheduled for surgery showed an increase in muscle mass prior to surgery (estimated MD + 0.4 vs −0.1 kg), and attenuation in losses in muscle mass 4-weeks (−0.6 vs −1.5 kg) and 8-weeks (−0.1 kg vs −1.1 kg) post-surgery, relative to the rehabilitation-only group.³⁶ Recent trials further support the current guidelines, and new evidence is needed in other cancer treatments (ie, chemoradiotherapy) and tumors where malnutrition risk is high to address ASCO guidelines and future research recommendations.

Conclusion and future directions

The evidence for managing, treating, and preventing unintentional weight and muscle loss, and malnutrition is strong for nutrition, emerging for multimodal interventions, and limited and for exercise-only trials. Dietary counseling with ONS shows benefits for maintaining weight in cancers and treatments where malnutrition risk is high. Protein and omega-3 ONS, with or without dietary counseling may mitigate muscle loss during cancer treatment, but the evidence is low and across the nutrition literature body composition is rarely measured. The optimal dose of protein (ie, type of protein, amino acid profile, and timing) and other dietary ingredients/nutrients (ie, HMB) effects on muscle mass require further investigation, and several trials are underway.⁹⁰ Exercise, particularly resistance training, may offer great benefits in preserving and building muscle when weight loss is present during cancer treatment. However, further research identifying the optimal prescription (ie, frequency, intensity, type, and time) for achieving muscle hypertrophy is needed for patients at risk or with malnutrition. Multimodal trials prevent weight and muscle loss across multiple cancer types and treatments. Prehabilitation interventions potentially offset some or all of the unintentional weight and muscle loss developed after cancer surgery, however, changes in body composition and malnutrition have not been the primary outcome and are often only reported at baseline. Lastly, models of care that involve validated screening, assessment, and multimodal interventions for malnutrition in new treatments (eg, immunotherapy and targeted treatments) and new delivery modes such as online are needed to reflect recent changes in practice.

Author contributions

All authors contributed to the concept/design. Brenton J. Baguley drafted the manuscript, Lara Edbrooke drafted the exercise section, and all authors revised and approved the final version of the manuscript.

Funding

No specific funding was received for the conduct of this study. Brenton Baguley and Lara Edbrooke are recipients of Victorian Government Early Career Fellowships through the Victorian Cancer Agency. Nicole Kiss is supported by a Victorian Cancer Agency Nursing and Allied Health Clinical Research Fellowship.

Conflicts of interest

The authors declare no competing interests.

Data availability

No new data were generated or analysed in support of this research.