Pancreatic cancer (PC) remains a lethal malignancy (1), with a 5-year survival rate of around 30% after surgical resection and multimodal treatment (2). Furthermore, pancreatic surgery's morbidity and mortality rates are still high (3, 4), making the scenario even more problematic.

Pancreatic resections are recognized as one of the most challenging operations due to the magnitude of dissection and resection, the resultant global stress, and the high morbidity rate. Major surgery produces an intense metabolic response and nutritional status changes by activating an inflammatory cascade and releasing stress hormones. Appropriate tissue healing and recovery/maintenance of organ function after such operations necessitate adequate qualitative and quantitative nutritional substrates to be effective. Furthermore, when PC is cephalic, obstructive jaundice is almost invariably present and associated with impaired absorption, nutritional state, and homeostasis (5).

The preoperative identification of patients at risk of malnutrition, and the adoption of nutritional corrective actions, especially in patients receiving systemic therapy before surgery, provides a window of intervention (6) that may mitigate the risk of poor postoperative outcome. Sarcopenia, a progressive decline in skeletal muscle mass, strength, and performance (7), is a direct consequence of impaired nutritional and metabolic status. Based on the patients' populations considered and the cutoff used, the prevalence of sarcopenia in PC patients at diagnosis is variable (8). Research on the association of sarcopenia with surgical outcomes after pancreatic surgery has produced conflicting results (9–11).

Computed tomography (CT) is an accurate tool to quantify whole-body composition (12); moreover, it is routinely used for staging and restaging of PC. Therefore, it is readily available without additional cost, radiation exposure, or inconvenience to the patient. In PC patients, the effects of neoadjuvant therapy (NAT) on body composition have been increasingly investigated, with contrasting results (13–16). In general, lean muscle mass depletion is typical in patients with energetic imbalance and metabolic derangement and may be the driver of a worse surgical outcome.

Chronic systemic inflammation is the theoretical substrate of muscle depletion, sarcopenia, and cachexia (17), and many immunonutritional biochemical parameters have been developed to quantify it (18). Cutoff values of such immunonutritional indexes might serve as a proxy for immunonutritional impairment. Thus, they may help identify fragile patients with an increased pro-inflammatory status, assign patients to appropriate therapies, and even identify early pre-cachexia by offering a multimodal treatment. Among these indexes, the prognostic nutritional index (PNI) (19), the neutrophil-to-lymphocyte ratio (NLR) (20), the platelet-to-lymphocyte ratio (PLR) (21), and the lymphocyte-to-monocyte ratio (LMR) (22) have all been shown to be predictive of surgical or oncological outcome of PC patients.

The current study investigated whether changes in body composition during NAT and multiple preoperative nutritional indexes predict the surgical outcome of locally advanced PC patients who underwent pancreaticoduodenectomy after NAT.

Body composition analysis and a careful nutritional assessment are invaluable tools that help identify cancer patients at risk of major postoperative complications. PC patients are not an exception. Typically, they are malnourished and sarcopenic, already at diagnosis. In this study, about one-third of the included patients had a low muscle mass at diagnosis, and this rate remained substantially stable after NAT. The absence of a worsening of sarcopenia, reported by other surgical series (9), may be due to the always increased awareness among patients, caregivers, and healthcare providers of the importance of nutritional status in oncology, especially in PC patients (the majority of the present study patients were enrolled during the last year of the study period).

Regarding the body composition changes that occur during NAT, it was found that both the muscular and the fat compartments were significantly impacted by NAT. These findings have already been reported for PC patients receiving chemotherapy (14, 35–39), demonstrating energetic dyshomeostasis. Therefore, attention must be paid to the body composition changes that occur during NAT in an attempt to maintain patients' body homeostasis, energetic balance, and appropriate metabolism. Radiological reevaluations performed periodically during NAT allow clinicians to achieve it.

When it comes to the study's primary endpoint, while any body composition parameter change did not influence the occurrence of any complications, patients experiencing major complications had a lower pre-NAT SMI value compared with those not facing major complications (p < 0.05); additionally, patients having a positive delta SMI (those who gained lean muscle mass) were less likely to experience major postoperative complications. The opposite was true for patients gaining subcutaneous fat tissues after NAT that were more exposed to major complications (all p < 0.05). These results align with the fact that the presence of sarcopenia post-NAT predicts a longer length of stay (11). That gaining SAT exposed patients to a greater risk of major postoperative complications is not easily explained because, despite being non-statistically significant, a tendency toward fat tissue loss during NAT was found for both VAT and SAT (Table 1). This finding is likely to be clinically meaningless.

A longer stay was also associated with high VAT values. This finding may be explainable by some factors or events not collected for this study (surgical site infections and, in general, infectious complications), so that patients with a high component of adipose tissue experience a longer hospitalization and, in general, failure to rescue. Instead, an increase in albumin was associated with a shorter length of stay. This recalls previous reports that associated low preoperative albumin levels with a worse postoperative outcome after pancreatic surgery (43–45). However, other studies did not report the same finding (46), and a recent randomized controlled trial demonstrated that the routine correction of preoperative hypoalbuminemia did not lead to a better postoperative outcome (40).

This study presents a novel dynamic model that can identify patients with the greater benefit of gaining lean muscle mass, namely those who move from an SMI of 35 to an SMI of 40 cm²/m². This positive change may reduce the odds of experiencing any postoperative complication by about 60%. This aspect points attention to the need to identify patients at high risk of postoperative complications, focusing on those with low SMI who can concretely benefit from a tailored nutritional intervention to reduce the probability of postoperative complications, following a nutritional path, and setting a goal. The other fluctuations of the SMI to values >40 did not show any protective factor vs. major postoperative complications, since at these values of the SMI it is likely that the body can better resist surgical stress and sooner reach homeostasis. However, our results need to be confirmed prospectively.

Among the immunonutritional values, none predicted the postoperative outcome. This result probably reflects the heterogeneity of the study population when it comes to neutrophil and lymphocyte values with respect to having suffered from inflammatory, infectious events before and close to surgery that could have altered these values in the preoperative period (65% of patients had a biliary stent, 25% received multiple endoscopic procedures in the biliary tract, and 15% had had cholangitis).

Of note, we found that a decrease in SMI has to be expected with the increase in age (Supplementary Figure 1). About one-third of 60-year-old patients are sarcopenic (41), and a decrease in lean muscle mass must be expected at a rate of 15% per decade over 70 years (42). Considering that the highest peak of PC incidence occurs between 60 and 80 years, our results underline that nutritional evaluation at the time of diagnosis and during NAT may be fundamental, especially in elderly patients. Pre-habilitation regimens based on exercise (aerobic and resistance activity) and nutritional support focused on maximizing energy and protein intake should focus especially on these subgroups of patients to improve the outcome.

This study has some limitations. First, its retrospective nature does not allow avoiding a selection bias. Second, while the study covers a long period, there was an imbalance toward the last year, when more than half of the cases were recruited. This may have generated a selection and management bias. Third, it cannot be excluded that the enrolled patients could have received nutritional counseling and support during chemotherapy, thus creating another source of bias. Fourth, the assessment of muscle quality (strength or performance) was not done nor feasible, highlighting that muscle mass was evaluated in terms of quantity (low muscle mass) and not quality. Fifth, comparing the results of the present study with the available literature might be inaccurate, as populations are very heterogeneous in terms of disease stages and treatments. Last, the study population is heterogeneous in terms of neoadjuvant treatment and stage disease, and this may impact the results obtained.

In conclusion, in our experience, the muscle compartment may decrease during NAT, and the delta of variation may provide useful predictive information for the preoperative risk assessment analysis of PC patients undergoing pancreaticoduodenectomy after NAT. For the first time, we identified a subset of patients that may benefit the most from a gain in SMI during NAT, creating a nutritional trajectory to follow and a goal for clinicians to optimize postoperative outcomes. This study failed to prove the ability of the immunonutritional indexes to predict the postoperative outcome; their application may be more appropriate in non-cephalic PC.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.