Mediterranean-style dietary interventions in adults with cancer: a systematic review of the methodological approaches, feasibility, and preliminary efficacy

Background Cancer and its treatments can lead to excess body fat, decreases in lean mass, cardiotoxicity, and other side effects. The Mediterranean diet (MED-diet) has the potential to improve clinical and supportive care outcomes. The aim of this systematic review was to evaluate the feasibility, safety, and efficacy of the MED-diet on health outcomes in adults with cancer. Methods Three databases were searched from inception to February 2023. Eligible studies included randomised controlled trials testing a MED-diet intervention among adults with cancer. Within- and between-group differences for adherence, dietary intake and health outcomes were extracted. Results Fifteen studies describing fourteen interventions were included, and there were considerable differences in study design and implementation of the MED-diet. Studies were predominately in women with a history of breast cancer. The MED-diet was safe with no adverse events reported, and feasible with high adherence and/or increases in MED-diet-compliant foods. The MED-diet when applied with an energy restriction below estimated requirements for weight loss demonstrated reductions in body weight (range: −3.9 kg to −0.7 kg). Interventions that showed significant reductions in body weight also improved quality of life. There is limited evidence to evaluating the MED-diet on cardiovascular and inflammatory markers, and heterogenous MED-diet prescriptions impede definitive conclusions on these health outcomes. Conclusion The MED-diet was feasible and safe for adults with cancer. There were reported benefits for weight loss following a MED-diet when an energy restriction was applied, however further evaluation to determine the effects on cardiometabolic biomarkers and other outcomes are required.


INTRODUCTION
Globally, 19.3 million people were diagnosed with cancer in 2020 and cancer is now the leading cause of morbidity and mortality worldwide [1].After cancer treatment, many adults are faced with adverse treatment-related side effects that accelerate aging, increase risk of co-morbidities, and reduce quality of life [2].These side effects include cardiomyopathy, persistent fatigue, reduced muscle mass with simultaneous increases in fat mass, cognitive impairment, and early menopause for women with breast cancer (which includes risks for bone health and cardiovascular disease) [2][3][4].Several guidelines suggest nutrition and exercise interventions are important strategies to address persistent treatmentrelated toxicities and late side effects from cancer treatment [5,6].However, despite clear evidence for nutritional interventions in adults with cancer who are at risk of malnutrition [7], the optimal nutrition prescription to address other treatment-related toxicities (i.e., body composition, cardiovascular and metabolic health) after cancer treatment is yet to be determined.
The Mediterranean style diet (MED-diet) is a high-quality pattern of eating, with consistent observational evidence associating the MED-diet with reduced risk of chronic disease [8,9].There are many forms of the MED-diet, but it is typically characterised by (i) a high intake of fish, vegetables, fruits, legumes, nuts, and extra virgin olive oil; (ii) moderate intake of dairy products and red wine, and (iii) low consumption of added sugar, processed foods, and red meats [10].Traditional versions of the MED-diet specify that dairy products are to be fermented, however, recent interpretations have been updated to include 'low-fat' dairy products [11].The high antioxidant and antiinflammatory properties of the MED-diet are proposed to offer synergistic benefits to cardiometabolic and body composition health [12,13].Observational evidence suggests the MED-diet can extend cancer survivorship, where high adherence to a MED-diet has shown a 22% and 13% reduction in prostate cancer and breast cancer mortality, respectively [14,15].The survivorship benefits from the MED-diet are potentially clinically important given the negative cardiometabolic and body composition changes from hormone therapy in breast and prostate cancer [16,17].Nutrition interventions in general, usually in combination with physical exercise, have shown promising results, particularly for patients with breast or prostate cancer by reducing body weight and fat mass [18] and improving quality of life [19].However, despite several studies indicating the MED-diet may offer improvements to body composition and cardiometabolic health predominately after cancer treatment, the potential health benefits from the MED-diet in adults with cancer is yet to be systematically evaluated [13].The aim of this review was to determine the feasibility (i.e., prescription, intervention design and support, participant adherence, safety) of delivering a MED-diet in adults with cancer, during or after treatment, and synthesise health outcomes from MED-diet intervention trials.

Protocol and registration
This systematic review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [20].The protocol was registered in the PROSPERO database (registration ID: 376985).
Information sources and search strategy Embase, CINAHL, and Scopus databases were systematically searched on 17/02/2023.The search strategy was based on the Population Intervention Comparison and Outcomes (PICO) framework [21] and the specific search strategy was adjusted according to each database outlined in Supplementary Material 1.Each search concept included search terms relating to: (i) Mediterranean-style diet, (ii) adults with cancer, and (iii) randomised controlled trials.To summarise the evidence as a collective, outcome measures were not included in the search term strategy.Keyword search terms and Medical Subject Headings (MeSH) were applied to all search engines where applicable.Reference lists of identified articles were manually searched.There were no search restrictions on dates or language.

Eligibility criteria
The inclusion criteria follows the PICO framework: (i) population: participants aged ≥18 years, of any sex, had a histological cancer diagnosis (any cancer type) prior to the intervention, and underwent any type of cancer treatment or were about to start treatment; (ii) intervention: any lifestyle intervention that included the MED-diet prescribed alone or in conjunction with exercise and/or psychosocial support; (iii) study design: randomised controlled trials where the control group received either no intervention or another intervention, a different dietary intervention, or a supplement, and (iv) reported the adherence, dietary intake, and/or any health-related outcome.Importantly, the nutrition intervention had to self-identify as the MED-diet or be based on the MED-diet principles outlined in the methods.Articles with similar dietary goals or nutritional targets to the MED-diet, yet did not explicitly mention the MED-diet, were excluded.Articles were also excluded if the intervention included the MED-diet plus a dietary supplement or medication, and/or both the intervention and control group received the MED-diet.

Study selection
Four independent reviewers screened titles and abstracts for inclusion (AM, ES, BG, and PR).Studies that were not clearly excluded progressed to full text screening where the study was reviewed in detail against the inclusion criteria.Where discrepancies in inclusion occurred between reviewers, a fifth reviewer was sourced (BB) and issues were reconciled with discussion.Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia, available at www.covidence.org) was used to organize the paper identification and complete data extraction.

Data extraction
Data extracted included author(s), sample characteristics, trial length and design, data collection time points, control group, intervention methodology, and MED-diet prescription (macro and micronutrients and food groups).The primary outcome was extracted along with the intent of the MED-diet intervention on body weight.Descriptive data were extracted to report the feasibility of the MED-diet interventions (i.e., completion, consult attendance).Mean, standard deviation (SD) and/or 95% confidence interval for baseline values (where applicable), change within the intervention group, and between-group differences were extracted for changes in diet, health-related outcomes (weight and body composition), cardiovascular biomarkers, and quality of life.

Quality assessment
The methodological quality was assessed using the Cochrane Risk of Bias Tool [21].This tool looks at risk of bias in the following domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other potential sources of systematic bias.Each study was rated against these domains and ranked as low, high, or unclear risk of bias.Blinding of participants to the intervention was assessed as "low risk" for all studies because it is not possible for the participant to be blinded to a dietary intervention supported by a health professional.

Data synthesis
Continuous variables are presented as means and deviation from the mean (i.e., SD, Standard Error of Mean, range).Feasibility data are reported by the percentage of completion and attendance.Outcome variables (MED-diet adherence, body composition, biomarkers, quality of life) are reported as either an increase or decrease and whether statistically significant.Statistical significance was deemed where the p-value was <0.05.

DISCUSSION
This review showed that the MED-diet is safe (zero adverse events), feasible, and well adhered to, however heterogeneity in the prescription of the MED-diet and intervention design precludes identifying the optimal approach to supporting individual health outcomes for adult cancer survivors.Hypocaloric MED-diets show particularly promising results for reducing body weight (range: −3.9 kg to −0.7 kg) in overweight or obese adults who have finished cancer treatment or currently treated with hormone therapy for breast or prostate cancer.Interventions with the goal to maintain weight showed promising findings in preventing weight loss during chemotherapy, however, both studies were small in sample size and individualised to manage nutritional impact symptoms (i.e., nausea and vomiting).Whilst evidence for weight loss from the MED-diet is in accordance with several guidelines advocating for healthy body weight posttreatment to reduce the risk of mortality and morbidity [5,6], the current evidence for the MED-diet in patients with cancer is limited to mostly women who have finished breast cancer treatment.Despite the evidence to support the MED-diet for preventing and managing chronic diseases, translation of this evidence to cancer survivors, where chronic disease risk is high, requires further investigation.

Feasibility of Mediterranean diet interventions
The MED-diet interventions in this review were safe (zero adverse events), feasible with a high completion rate (range: 64% to 98%), and showed high attendance to consultations or educational workshops (>75%).These factors likely contributed to the high adherence to the MED-diet food groups across interventions in this review.Most studies provided dietary goals for food groups that participants could follow and all studies incorporated guidance or accountability check-ins with trained staff, though the frequency of informative workshops or interaction with a trained nutrition professional.More intense intervention delivery may account for the improvement in MED-diet adherence scores amongst these studies [22,23,27,28,36], as behaviour change is more likely when dietary advice is paired with improved nutritional literacy [39].Interventions delivered by a nutrition professional, with accompanied education material (i.e., recipes and cooking demonstrations), offers the chance to build rapport and iteratively change dietary behaviours across consultations, and is likely a contributing factor to the high adherence seen in these studies.

Body weight and composition
This review indicates that the MED-diet when prescribed with an energy reduction has weight loss benefits (range: −3.9 kg to −0.7 kg).Similar reductions in weight were reported in a metaanalysis that evaluated the effects of MED-diet interventions compared to low fat diets (−4.1 to 10.1 kg vs. 2.9 to −5.0 kg) in overweight or obese adults [40].Whilst MED-diet interventions have shown long term weight loss (≥12 months) in overweight or obese adults at risk of chronic disease [40,41], the long term effect in cancer survivors are limited.Two 12-month MED-diet interventions prescribed by a nutrition specialist has demonstrated significant weight loss in women with breast cancer that are treated with hormone therapy (−2.4 kg vs. −0.9kg) [25] or that are post-surgery and treated with adjuvant hormone and/or chemotherapy (home-based: −1.5 kg vs. 0.8 kg and communitybased: −1.6 kg vs. 0.8 kg) [28].The present review also suggests the MED-diet can prevent weight gain from hormone therapy in prostate cancer [22], however this study was underpowered in sample size.Whilst most studies in the present review were designed to promote weight loss, the methodological differences in intervention prescription, behaviour change support techniques, and reporting of dietary adherence varied.As such it is plausible that improvements in diet quality from the MED-diet, characterised by an increased consumption of vegetables, fruits, and whole grains led to weight loss.
Interventions that measured body composition showed reductions in fat mass but also lean mass.Whilst reductions in weight and fat mass is beneficial for optimising body composition, the reductions in lean mass seen in some studies in concerning for maintaining strength, physical function, and quality of life following or during treatment.Nonetheless, reductions in lean mass from weight loss interventions are expected [42], and our findings are in line with a previous meta-analysis evaluating nutrition and exercise interventions on body composition in adults with cancer reporting muscle loss (mean difference −0.58 kg) from weight-loss focused interventions [18].Efforts to attenuate Increased protein intake (1.0-1.5 g/kg/day), and/or supplemental approaches (i.e., β-hydroxy β-methylbutyrate at 3 g/day) may protect muscle or increase muscle when paired with exercise [43].
Yet whether these approaches protect muscle mass within a MEDdiet that intends to reduce body weight and fat mass requires investigation.

Cardiometabolic health
The MED-diet promotes improvements in cardiometabolic health by encouraging foods high in monounsaturated and polyunsaturated fats and fibre, which play an important role in lowering lowdensity lipoprotein (LDL) and triglycerides and increasing HDL cholesterols [8,9,44].A limited number of studies showed improvements in cardiovascular biomarkers, however results were inconsistent and varying intervention components preclude identifying whether the benefits in cardiovascular health were primarily attributable to the MED-diet.For example, studies varied in the MED-diet prescription, with some promoting a specified amount of olive leaf extract [24], flaxseed, and green tea consumption per day [34], or including macrobiotic foods like soy and miso [25], whilst others included an exercise program with the MED-diet [28,33].Secondly, most interventions ranged between 12 and 26 weeks, which may not be a sufficient duration needed for the MED-diet to see changes to cardiometabolic biomarkers.Whilst a larger body of evidence supports the use of the MED-diet in reducing cardiovascular biomarkers (LDL, triglycerides and cholesterol) in adults who already have chronic disease(s) [39,45,46], the benefits of the MED-diet in adults with cancer who are at a higher risk of chronic diseases however may not have clinically elevated biomarkers at baseline may be less sensitive to change in a short timeframe and therefore requires further investigation.Chronic inflammation and oxidative stress are known predictive risk factors of cardiovascular disease [47].The MED-diet effects on cardiometabolic health are theorised to be associated with dietary properties high in bioactive nutrients and phenolic compounds, which combat oxidation and lower circulating inflammatory markers [48][49][50].Several biomarkers are used to identify endothelial cell damage and systemic inflammation, for example, interleukins (IL-6, IL-8, IL-1β), however, the types of inflammatory markers measured from the MED-diet in adults with cancer in this review varied and were often secondary or tertiary outcome measures.Inflammatory pathways and networks are complex and can be influenced by cancer treatment.As such, studies that are powered to investigate the effects of the MED-diet on inflammatory markers, considering covariates (i.e., medications and treatment), are needed before definitive conclusions can be made.

Quality of life
This review provides preliminary evidence for quality-of-life benefits from the MED-diet in adults with cancer and corroborates previous reports of mixed benefits to quality of life from lifestyle interventions in cancer [51][52][53].The studies that demonstrate high adherence to the MED-diet and improved global and domains of quality of life (i.e., fatigue, physical and cognitive functioning) also had improvements to body weight and composition (free fat mass, weight, BMI) [22,23,28,33].Our results suggest that weight loss from the MED-diet might have additional benefits in improving mental domains of quality of life and body image, which is a research priority highlighted elsewhere [54].Most MEDdiet interventions that were delivered by a dietitian showed improvements in quality of life or domains of quality of life (i.e., role, emotional).These findings may be attributable to the benefits of interaction with a health care professional, which offers individualisation of dietary preferences, social and environmental influences on dietary intake.The utilisation of behaviour change strategies within a consultation, where participants are empowerment to be actively involved in their cancer health, may contribute to the improvements seen in quality of life [55].Whilst the MED-diet is likely to have improved quality of life, weight loss and interactions with a health professional may be mediators, and further research is needed to optimize the components of a MEDdiet intervention for quality-of-life outcomes.

Future directions and clinical implications
The results of this systematic review should be considered in light of its strengths and limitations.This review followed the PRISMA guidelines in reporting a systematic review and provides a high level of evidence for the benefits of the MED-diet compared to usual care across health outcomes.Whilst this review demonstrates that hypocaloric MED-diets may reduce weight for people with cancer that are overweight or obese, the effects on body composition (i.e., fat mass and muscle mass) are limited.The heterogeneity in MED-diet prescription, the intent of each intervention on body weight, and the use of co-interventions (i.e., exercise) precluded pooling the mean difference in a metaanalysis.This highlights the importance for future interventions to report MED-diet prescriptions using calculating estimated energy requirements, nutrient targets along with food groups to identify components of the MED-diet to health outcomes.Translation of the MED-diet in patients with cancer are limited to reducing or maintaining body weight.However, whether the benefits in weight control are attributable to the energy restriction or the MED-diet itself is unknown.Future longer term RCTs should focus on reducing the risk of, or managing, cardiovascular or metabolic disease after cancer treatment to improve the potential clinical implications of the MED-diet.

CONCLUSION
This systematic review showed that the MED-diet is safe, feasible, and well adhered to among adult cancer survivors during and after treatment.Collectively, there was considerable variation in the MED-diet prescription (i.e., macronutrients, micronutrients, and food groups), health outcomes measured, resulting in mixed findings from the heterogeneity in intervention design.Interventions that prescribed an energy restriction in addition to the MEDdiet showed reductions in body weight, however, whether the benefits in weight loss can be attributable to the MED-diet over and above the energy restriction requires further investigation.Whilst the MED-diet is consistent with dietary recommendations for cancer survivors, there is limited evidence to indicate that the MED-diet offers benefits to managing side effects, chronic disease prevention, or improving quality of life.Attention to reporting the MED-diet prescription and adherence on other important outcomes, such as cardiometabolic function, is important for evidence-based recommendations across multiple health outcomes for cancer survivors.

Fig. 1 PRISMA
Fig. 1 PRISMA flow diagram showing the study selection process.Preferred reporting items for systematic review and meta-analysis (PRISMA) statement flow diagram.

Table 1 .
Study characteristics of Mediterranean-style dietary interventions in adults with cancer.
MED-diet plus olive oil life extract had monthly group education sessions with an unspecified instructor, for 6-months.Low fat diet group had the same monthly group educations, plus rice bran oil.

Table 2 .
The effects of Mediterranean-style dietary interventions on health-related outcomes in adults with cancer.

Table 2 .
continued denotes significant increase between MED-diet and control groups at endpoint.↓denotessignificantdecreasebetween MED-diet and control groups at endpoint.denotesnon-significantchangesbothwithin group and between groups.Data for LongParma et al. representedin this table is at the 6-month timepoint.Data for Harvie et al. is comparing between-group differences in community vs. control and home vs.control.ALI advanced lung cancer inflammation index, BCS breast cancer scale, BFI brief fatigue inventory, BFM body fat mass, BMI body mass index, BMR basal metabolic rate, BP blood pressure, CHO carbohydrate, CoQ10 Coenzyme Q10, CRP C-reactive protein, EORTC QLQ-C30 & BR23 The European Organisation for Research and Treatment -Quality of Life -Cancer & Breast cancer specific, FACIT functional assessment of chronic illness therapy, FACT TOI-BC functional assessment of cancer therapytrial outcome indicator for breast cancer, FACT-G functional assessment of cancer therapygeneral, FFM fat free mass, FM fat mass, FFQ food frequency questionnaire, HADS Hospital anxiety and depression scale, HC hip circumference, HDL high density lipo-protein, IL-6 & IL-8 interlukin-6 & −8, LCN3FA long chain n-3 fatty acids, LDL low density lipo-protein, LMM lean muscle mass, MDA plasma malondialdehyde, MEDAS Mediterranean diet adherence score, MUFA mono-unsaturated fatty acid, NR not reported, PUFA poly-unsaturated fatty acids, QoL quality of life, RBC red blood cells, SFA saturated fatty acids, SI symptom inventory, TG triglyceride, TP1 end of first chemotherapy cycle, TP2 end of chemotherapy, WBC white blood cell, WC waist circumference.