Nutritional Interventions during Chemotherapy for Pancreatic Cancer: A Systematic Review of Prospective Studies

Pancreatic cancer (PC) is the 12th most common tumor worldwide and the seventh leading cause of cancer mortality, with 495,773 new cases in 2020. Incidence is higher in industrialized countries, implicating environmental factors. Recognized modifiable risk factors include smoking, alcohol, physical inactivity, obesity, hypertension, chronic pancreatitis, diabetes, and hypercholesterolemia, in addition to age, gender, ethnicity, and genetic syndromes. The prognosis remains poor with a 5-year survival rate of around 10.8%, largely due to late diagnosis and limited eligibility for surgical resection. Although chemotherapy offers hope for improved outcomes, it is associated with significant toxicity and often only fit patients complete planned treatments. Malnutrition and sarcopenia are common in cancer, especially when the gastrointestinal tract is involved, and are highly prevalent in PC (malnutrition 33.7–70.6%; sarcopenia up to 74%). Pancreatic exocrine and endocrine dysfunction can cause maldigestion and malabsorption leading to weight loss and poor nutritional status. Malnutrition and sarcopenia increase chemotherapy-related toxicity, postoperative morbidity, reduce survival, and impair quality of life. Nutritional support during chemotherapy may therefore play an important role. The aim of this systematic review was to analyze the impact of different nutritional interventions on clinical outcomes in PC patients during chemotherapy.

Prior evidence indicates malnutrition and sarcopenia adversely affect toxicity, survival, and quality of life in oncology, including pancreatic cancer. ESPEN guidelines recommend energy intakes of 25–30 kcal/kg/day and proteins of 1.0–1.5 g/kg/day for cancer patients, yet few studies assess requirements or malnutrition risk systematically in PC. In gastrointestinal cancers, evidence on oral nutritional supplements (ONS) is heterogeneous: some reviews report limited but potential benefits on weight and energy intake around surgery, and meta-analyses in gastric cancer suggest reduced postoperative weight loss with ONS. An amino acid-enriched formula may reduce treatment-induced oral mucositis in GI and head–neck cancers. Across malignancies, nutritional interventions can improve body weight and composition, but optimal timing and formulation remain unclear. In PC specifically, pancreatic exocrine insufficiency is common (≈72% in advanced disease) and pancreatic enzyme replacement therapy (PERT) may improve survival and quality of life, yet PERT is often under-prescribed; notably, none of the included studies incorporated PERT. Evidence linking ONS to survival in PC is limited and inconsistent, though protein intake <1.1 g/kg/day during chemotherapy has been identified as a poor prognostic factor in unresectable PC.

This systematic review followed the Cochrane Handbook and PRISMA guidelines and was registered in PROSPERO (CRD42020185706). Electronic searches were conducted on 2 December 2022 in MedLine (PubMed), Web of Science, and EMBASE, using predefined search strings (English language, no date restriction). Records were imported into Mendeley, duplicates removed, and titles/abstracts screened independently by three reviewers (M.C., F.G., M.P.) according to PICOS-based eligibility criteria. Full texts of 43 studies were assessed; 34 were excluded (14 not prospective, 17 not during chemotherapy, 3 no full text), leaving nine prospective studies included. Data were extracted into a standardized Excel spreadsheet. Risk of bias for randomized and nonrandomized prospective studies was assessed independently by two reviewers (M.C., F.G.) using the Cochrane risk-of-bias domains (random sequence generation, allocation concealment, blinding of participants/personnel and outcome assessment, incomplete outcome data, selective reporting, other bias). Due to heterogeneity in interventions, measures, and outcomes, meta-analysis was not feasible; a narrative synthesis was performed outlining populations, interventions (e.g., ONS; parenteral n-3 fatty acids; oral L-carnitine; broccoli sprout-derived sulforaphane/glucoraphanin), comparators, and outcomes.

- Evidence base: Nine prospective studies were included (sample sizes 7–201; six enrolled only PC patients). Interventions included: four ONS studies (liquid or powder; 310–691 kcal/day; 16–45.75 g protein/day; some EPA-enriched); two parenteral n-3 fatty acid emulsion studies; one oral L-carnitine study; one broccoli sprout (sulforaphane/glucoraphanin) study. Controls varied (placebo, isocaloric/normal diet, or none). Meta-analysis was not possible due to heterogeneity. - Survival: L-carnitine showed a non-significant trend toward longer OS (median 519 ± 50 vs 399 ± 43 days). Broccoli sprouts showed lower early death rate over three months (25% IG vs 45% CG). High baseline IL-6 and IL-8 correlated with shorter OS; reductions in FGF were associated with improved PFS; PDGF reduction tended to improve OS in n-3 parenteral supplementation. - Quality of life (EORTC QLQ-C30 ± PAN-26): Mixed but generally favorable signals. Improvements reported in cognitive function and global health, with reduced GI symptoms (L-carnitine); stabilization then increase in global score at 8 weeks (EPA-enriched ONS); slight, mostly non-significant improvements in several subscales (n-3 ONS), and decreased hepatic subscale in PAN-26 in one trial; another ONS study showed non-significant global QoL increase with decreased fatigue in IG and pain reduction in CG. - Chemotherapy-induced toxicity: No significant differences between intervention and control in two trials (glutamine+TGF-β2 ONS; EPA-enriched ONS during neoadjuvant chemoradiotherapy). - Nutritional status (PG-SGA): Significant PG-SGA score reductions after 8 weeks with ONS: Bauer et al. median 13 (4–19) to 4 (1–16), p=0.019; Kim et al. 9.5 ± 0.9 to 5.6 ± 0.8, p=0.002. Improvements correlated with QoL (p=0.020), KPS (p=0.009), and lean body mass (p=0.040) in one study. - Body composition and weight: ONS or supplements led to stabilization or gains. Higher skeletal muscle mass in patients consuming >50% prescribed EPA-enriched ONS (p=0.042) and improved psoas muscle ratio; significant body weight stabilization, with half gaining weight (n-3 ONS), though no significant changes in fat or muscle mass in that study. Another ONS trial showed increased fat mass with stabilization of FFM, SMM, and BCM. L-carnitine increased body cell mass and body fat mass, and BMI at 12 weeks; body weight increased in IG. - Oral intake: ONS increased macronutrient intake. Kim et al.: calories 1488.1→1946.4 kcal (p=0.001), protein 64.1→89.9 g (p=0.001), carbohydrates 247.9→289.2 g (p=0.015), lipids 38.6→51.9 g (p=0.023) over 8 weeks in ONS group; between-group changes vs non-ONS were not significant. EPA-enriched products stabilized appetite; meal portions increased significantly (FO p=0.02; MPL p=0.05). Bauer et al. observed total protein intake ~1.4 g/kg/day and energy ~33 kcal/kg/day at 8 weeks without reducing meal intake. - Functional status (KPS): Improved after 8 weeks with EPA-containing high-protein, high-calorie ONS (p=0.01); another study reported KPS decreased in both IG and CG with broccoli sprouts, indicating no severe impact on self-care. - Across studies, reported benefits included: increased dietary intake; reduced fatigue in one study (p=0.041); improved PG-SGA grade ratio (p<0.05); increases in BW (p=0.049), FFM (p=0.034), SMM (p=0.049), and BCM (p=0.049) in specific interventions. Overall, nutritional support was associated with improvements in QoL, nutritional status, body composition, oral intake, and KPS; effects on survival and chemotherapy toxicity were inconclusive.

This review addressed whether nutritional interventions during chemotherapy improve clinical outcomes in pancreatic cancer. Despite heterogeneity, signals suggest nutritional support can stabilize or improve quality of life, nutritional status (PG-SGA), body composition, oral intake, and functional performance (KPS), which are clinically relevant in a population at high risk for malnutrition and sarcopenia. Survival benefits were not consistently demonstrated; only trends or early benefits were observed with L-carnitine and broccoli sprouts, and biomarker changes with parenteral n-3 fatty acids correlated with outcomes. No consistent reductions in chemotherapy-induced toxicity were shown. These findings support integrating structured nutritional assessment and support into oncology care for PC, targeting ESPEN-recommended energy and protein intakes. Given the high prevalence of pancreatic exocrine insufficiency in advanced PC and evidence for PERT improving survival and QoL, comprehensive care should consider enzyme replacement, though it was absent from included trials. The variability in interventions, populations, and outcomes, alongside small sample sizes and few randomized trials, limits generalizability. Well-designed prospective RCTs with standardized nutritional protocols, inclusion of PERT where indicated, and clinically meaningful endpoints (survival, toxicity, QoL, functional status, body composition) are needed to define optimal strategies and timing.

Due to the limited number and heterogeneity of prospective studies, firm conclusions on the role of nutritional support during chemotherapy for pancreatic cancer cannot be drawn. Nonetheless, the review indicates that nutritional interventions can improve quality of life, nutritional status, body composition, oral intake, and performance status, supporting their use as part of comprehensive oncologic care. Further robust, well-designed prospective studies are required to clarify the impact of specific nutritional strategies, optimize intervention timing and composition, and reduce the burden of malnutrition in this population.

- Only nine studies met inclusion criteria, many with small sample sizes. - Heterogeneity in patient populations (some mixed gastrointestinal cancers), nutritional interventions (type, dose, route, duration), and outcome measures precluded meta-analysis. - Limited number of randomized controlled trials; risk of bias varied across domains. - Survival and chemotherapy toxicity outcomes were inconsistently reported and inconclusive. - Pancreatic enzyme replacement therapy, relevant in PC with exocrine insufficiency, was not considered in included studies, potentially confounding nutritional outcomes.