Pancreatic cancer (PC) is a significant global health concern, ranking as the 12th most common cancer and the seventh leading cause of cancer-related deaths in 2020. Its incidence is higher in developed nations, suggesting a strong influence of environmental factors. Modifiable risk factors include smoking, alcohol consumption, physical inactivity, obesity, hypertension, chronic pancreatitis, diabetes, and high cholesterol. Non-modifiable risk factors encompass age, gender, ethnicity, and inherited genetic syndromes. The prognosis for PC remains poor, with a 5-year survival rate of only 10.8%. This grim statistic stems from the difficulty in early detection; most cases are diagnosed at advanced stages, limiting the effectiveness of surgical resection. While advancements in diagnostic techniques and chemotherapy offer hope, chemotherapy (CHT) itself often carries substantial toxicity, hindering treatment completion for many patients. Malnutrition is a prevalent complication in cancer patients, exacerbated by the disease and its treatments. In PC, both exocrine and endocrine pancreatic functions can be impaired, leading to gastrointestinal symptoms like pain, bloating, delayed gastric emptying, diarrhea, appetite loss, nausea, dyspepsia, and malabsorption. These symptoms often result in significant weight loss. Studies report malnutrition prevalence ranging from 33.7% to 70.6% in PC patients, with sarcopenia affecting up to 74%. These conditions are associated with increased chemotherapy-related toxicity (CIT), poorer survival, increased post-operative morbidity, and reduced quality of life (QoL). Given the detrimental impact of malnutrition and sarcopenia on PC patient outcomes, nutritional support during CHT is crucial. This systematic review aims to assess the effects of various nutritional interventions on clinical outcomes in PC patients undergoing CHT.

The literature review section is not explicitly detailed in the provided text. However, the introduction section heavily relies on existing literature to establish the background and context for the study. The introduction cites numerous studies regarding the incidence and mortality of pancreatic cancer, risk factors, survival rates, the prevalence of malnutrition and sarcopenia in pancreatic cancer patients, and the negative impact of these conditions on patient outcomes. The review implicitly draws from this body of work to support the rationale for the current systematic review.

This systematic review followed the Cochrane Handbook for systematic reviews and the PRISMA statement guidelines. It was registered in the International Prospective Register of Systematic Reviews PROSPERO (CRD42020185706). The search, conducted on December 2, 2022, utilized three databases: Medline (via PubMed), Web of Science, and EMBASE. The search was limited to English-language publications with no date restrictions. A detailed search string for each database is provided in the supplementary materials. The study selection process involved three reviewers independently screening titles and abstracts based on pre-defined PICOS criteria (Population, Intervention, Comparison, Outcome, Study design). After an initial screening, a second, more in-depth abstract screening was performed, followed by a full-text review of eligible articles. Discrepancies were resolved through consensus discussion among the reviewers. A total of 5704 articles were initially identified, with nine ultimately included in the systematic review. Data extraction used a custom Excel spreadsheet. Reviewers independently assessed the risk of bias using appropriate instruments for randomized controlled trials and non-randomized comparative prospective studies. The Cochrane Handbook for Systematic Reviews of Interventions guided the risk of bias assessment across seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The assessment results were inputted into Review Manager 5.3.5 software. Due to high heterogeneity in study measures, nutritional interventions, and outcomes, a meta-analysis was deemed infeasible. Instead, the findings are presented as a systematic review, summarizing the characteristics, interventions, outcome measures, and results of each included study.

Nine prospective studies were included in this systematic review. These studies varied in sample size (7–201 patients), the proportion of patients with pancreatic cancer (7%–100%), and the type of nutritional intervention (oral nutritional supplements (ONS), parenteral supplementation of fatty acids, oral carnitine, or oral sulforaphane/glucoraphanin/methylcellulose). A meta-analysis was not possible due to significant heterogeneity. **Survival:** Three studies examined the impact of nutritional support on survival. While one study showed a non-significant trend towards increased overall survival (OS) with L-carnitine supplementation, another demonstrated longer survival in the intervention group during the first three months of the study. A third study found a correlation between high expression of inflammatory cytokines (IL-6 and IL-8) and shorter OS, with decreased growth factors (PDGF and FGF) associated with improved progression-free survival (PFS) and a tendency towards improved OS. **Quality of Life (QoL):** Four studies evaluated QoL using the EORTC QLQ-C30, with two also employing the PAN-26. Findings were inconsistent, with some studies showing improvements in certain QoL aspects (cognitive function, global health status, gastrointestinal symptoms), while others revealed no significant differences or improvements only in specific subscales (fatigue). **Chemotherapy-Induced Toxicity (CIT):** Two studies assessed CIT. Neither found significant differences in CIT between groups receiving nutritional intervention and control groups. **Nutritional Status:** Two studies used the PG-SGA score. Both showed significant improvements in nutritional status following intervention. **Body Composition:** Five studies evaluated body weight and/or body composition. Overall, studies showed improvement in parameters such as skeletal muscle mass, body weight, and fat-free mass, although the consistency of these findings varied across studies. **Oral Intake:** Three studies assessed oral intake. These studies generally indicated an increase in dietary intake of macronutrients (calories, proteins, carbohydrates, lipids) with nutritional supplementation, although this was not consistently observed across all studies. **Karnofsky Performance Status (KPS):** Two studies measured KPS; both demonstrated improvements in functional capacity following nutritional intervention.

This systematic review, the first of its kind to focus solely on prospective studies of nutritional interventions in PC patients undergoing CHT, highlights the need for further robust research. Although nutritional support should be standard practice, the scarcity of high-quality evidence limits definitive conclusions. The inconsistent findings across studies underscore the complexity of nutritional interventions in PC, requiring a personalized approach guided by nutritional assessment and counseling by trained professionals. While the ESPEN guidelines recommend specific energy and protein intakes for cancer patients, this review highlights the lack of studies evaluating PC patients’ specific requirements and conducting malnutrition risk assessments. QoL improvements were observed in some studies but remained inconclusive due to variability in outcomes. Similarly, while improved KPS and body composition were observed, further investigation is needed to confirm their consistency and clinical relevance. The lack of clear association between nutritional interventions and CIT requires further examination. While some studies showed a potential link between nutritional status and survival, conclusive evidence remains lacking. The use of ONS showed promise in improving dietary intake and malnutrition, but larger, well-designed studies are crucial for confirming these benefits.

This systematic review, while not providing conclusive evidence on the efficacy of nutritional interventions, strongly suggests their advisability in PC patients during CHT. The observed improvements in QoL, nutritional status, body composition, oral intake, and KPS warrant further investigation. Future research should focus on well-designed prospective studies, including adequately powered randomized controlled trials, to establish effective nutritional support strategies and clarify their impact on survival and other important patient outcomes in this challenging population. The heterogeneity of existing studies necessitates the development of standardized protocols for nutritional intervention and outcome measurement in future research.

This systematic review has several limitations. The small number of included studies (only nine) limits the statistical power of the analysis and the generalizability of the findings. The heterogeneity of study designs, interventions, and outcome measures hindered the possibility of performing a meta-analysis. The inclusion of some studies that enrolled patients with gastrointestinal cancers other than PC introduces some level of heterogeneity. Future research should address these limitations through larger, more homogeneous studies with clearly defined interventions and standardized outcome measures.