We clarified the effect of perioperative nutritional and inflammatory status on the clinical course of postoperative adjuvant chemotherapy using PNI. Our major finding was that preoperative PNI affected adjuvant chemotherapy continuation in patients with pancreatic cancer who received neoadjuvant chemotherapy and curative resection. Additionally, the preoperative PNI status affects adverse events caused by adjuvant chemotherapy. Therefore, preoperative PNI affects the clinical course of adjuvant chemotherapy in patients with pancreatic cancer. Moreover, additional perioperative anti-inflammatory management and nutritional support may be required to improve the clinical course of postoperative adjuvant chemotherapy and the survival of patients with pancreatic cancer.

In this study, preoperative PNI was a significant independent risk factor for continuing S-1 adjuvant chemotherapy in patients with pancreatic cancer who underwent perioperative adjuvant chemotherapy and surgical resection (HR = 2.435, 95% CI = 1.229 − 4.824, p = 0.011). This score meant that if the patients were the low PNI group, S-1 continuation was 41.1% decreased. In addition, low PNI was associated with lower S-1 completion (p = 0.02) and higher withdrawal (p = 0.031). Sakamoto et al. evaluated the geriatric nutritional risk index (GNRI), a nutritional and inflammatory marker, in 77 patients with pancreatic cancer who underwent curative resection and S-1 adjuvant chemotherapy [6]; higher GNRI was significantly associated with S-1 completion (p = 0.013). Matsumoto et al. investigated the independent risk factors for incomplete adjuvant chemotherapy in 105 patients with pancreatic cancer who underwent curative resection and adjuvant chemotherapy [7]. The postoperative serum albumin level was an independent risk factor for incomplete adjuvant chemotherapy (p < 0.0001). These reports did not include neoadjuvant chemotherapy; nonetheless, they highlighted the importance of perioperative nutritional and inflammatory statuses affecting the clinical course of adjuvant chemotherapy. The nutritional and inflammatory statuses of patients receiving neoadjuvant chemotherapy are more severe than those of patients undergoing surgery alone. This is because the patients experience relatively severe adverse events caused by neoadjuvant chemotherapy. Thus, the preoperative nutrition and inflammatory statuses dramatically changed in patients receiving neoadjuvant chemotherapy than in patients who did not receive neoadjuvant chemotherapy. However, researchers have not evaluated the clinical impact of postoperative adjuvant chemotherapy on the nutritional and inflammatory statuses and clinical course of patients with pancreatic cancer who underwent neoadjuvant chemotherapy and curative resection. Thus, our results will exert an impact on pancreatic cancer treatment strategies.

The PNI status also affected adverse events caused by adjuvant chemotherapy. S-1, which is used for adjuvant chemotherapy, is metabolized in the liver and kidneys; adverse events are more frequent in patients with hepatic or renal impairment. Aoyama et al. reported that renal impairment is an independent risk factor for continuing S-1 [4]. Therefore, patients with CCr < 60 ml/min were excluded from the study; however, we observed a higher proportion ≥ grade 2 adverse events and non-hematologic toxicity (p < 0.001). Shimizu et al. investigated the association between preoperative GNRI and adverse events in 59 patients with colorectal cancer who underwent curative resection and postoperative adjuvant chemotherapy [12]. Low GNRI affected leukopenia (p = 0.03) and peripheral neuropathy (p = 0.04) in patients with ≥ grade 2 adverse events. Poor nutritional and inflammatory statuses increased the incidence of adverse events caused by adjuvant chemotherapy. Patients with low albumin levels or high inflammation may develop ascites and edema, which may lead to body weight overestimation. Because the chemotherapy dose is determined by the body surface area, i.e., the body weight, patients with malnourishment may receive excessive doses, leading to increased toxicity [13]. Prado et al. reported that a decrease in the lean body mass owing to malnutrition may result in a lower distribution of cytotoxic drugs, leading to higher toxicity [14]. We previously reported that the PNI status affected the postoperative recurrence of pancreatic cancer [15]; however, S-1 continuation was significantly lower in the low PNI group even excluding of S-1 discontinuation because of early disease recurrence (Fig. 2). Low PNI causes ≥ grade 2 adverse events, making it difficult to continue S-1 and resulting in lower S-1 completion. In this study, failure of S-1 completion resulted in markedly worse overall survival (OS) (1449 days vs. 642 days, p < 0.001). In other words, low PNI was found to be associated with poor OS as a result.

On the other hand, a subgroup analysis on resectable and borderline resectable pancreatic cancers showed that low PNI was a risk factor for continuing S-1 adjuvant chemotherapy only for resectable (p = 0.006) and not for borderline resectable pancreatic cancer (p = 0.431). This may be because preoperative treatment for borderline resectable pancreatic cancer is longer, and the patients experience more adverse events and have more severe nutritional statuses. In addition, subgroup analysis on DP and PD/TP showed that low PNI was a risk factor for continuing S-1 adjuvant chemotherapy only for PD/TP (p = 0.017) and not for DP (p = 0.413). This may be because PD and TP are more invasive to patients than DP, which may be linked to poor continuation rates of adjuvant chemotherapy.

Future research suggestions are as follows: First, the optimal PNI cut-off value was unclear. We set the cut-off value at 45 according to the ROC curve and previous survival analysis reports. However, the clinically meaningful cut-off value ranges from 36 to 53.1 [16]. The number of patients, patient background, and treatment methods differed between our study and previous studies. Therefore, future studies are needed to clarify the optimal PNI cut-off value. Second, it is unclear whether improving the perioperative PNI advances the continuity of postoperative adjuvant chemotherapy and the prognosis of patients with pancreatic cancer. Previously, the PNI status affected the survival of patients with pancreatic cancer because of incomplete postoperative adjuvant chemotherapy [15], similar to that reported by Matsumoto et al. [7]. Although nutritional interventions and other interventions may be considered to improve perioperative PNI, a systematic review of prospective studies of nutritional interventions during chemotherapy for pancreatic cancer by Cintoni et al. found limited and heterogeneous effects of high-energy oral nutritional supplements on survival outcomes, and no consensus has been reached [17]. Oral L-carnitine (4 g/day) for 12 weeks in patients with advanced pancreatic cancer is associated with prolonged OS, and daily protein intake has been reported to influence prognosis in patients with unresectable pancreatic cancer undergoing chemotherapy [18, 19]. Future studies should prospectively investigate whether improved albumin through nutritional intervention improves PNI and consequently affects the continuation of postoperative adjuvant chemotherapy and patient survival. Third, in the present study, we focused on the patients who complete neoadjuvant chemotherapy. Thus, we could not evaluate the clinical relation between PNI status before the start of neoadjuvant treatment and clinical course of neoadjuvant chemotherapy. PNI status before the start of neoadjuvant treatment might become the predictive values for neoadjuvant chemotherapy and give us the chance to enhance neoadjuvant chemotherapy in patients at risk who may not complete adjuvant chemotherapy. Future studies will focus on these issues.

The present study has some limitations. First, we performed a retrospective single-center study with a relatively small sample size. Second, most patients had a good performance status. Patients with a poor performance status (e.g. Eastern Cooperative Oncology Group performance status ≥ 3, severe dementia, and swallowing difficulty) could not be treated at our hospital. This is because we specialize in cancer treatment. This drawback could have resulted in selection bias during data collection. Third, the data on resectable and borderline resectable pancreatic cancers were mixed; i.e., various neoadjuvant chemotherapy regimens were mixed. Fourth, the use of S-1 is only valid in Asia, including Japan. Due to genetic differences in the metabolic enzyme cytochrome P450 2A6, Westerners convert S-1 to 5-fluorouracil more rapidly than Asians, resulting in lower maximum tolerated doses than in Asians. This is why it is not known whether similar results can be obtained in Westerners. Fifth, when we compared the OS and relapse-free survival (RFS), there were no significant differences (p = 0.596, p = 0.498). However, there were marginal differences between OS and RFS between two groups. Thus, the number of patients is increased and follow up periods is much longer, marginally differences might become significant.

In conclusion, preoperative PNI affects adjuvant chemotherapy continuation and related adverse events in patients with pancreatic cancer who receive neoadjuvant chemotherapy and curative resection. Additional perioperative anti-inflammatory management and nutritional support are supposedly required to improve the clinical course of postoperative adjuvant chemotherapy and the survival of patients with pancreatic cancer. Further validation of the association between inflammation-based prognostic scores and adjuvant chemotherapy is required in prospective studies.