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Prognostic nutritional index is an independent risk factor for continuing S-1 adjuvant chemotherapy in patients with pancreatic cancer who received neoadjuvant chemotherapy and surgical resection

BMC Cancer volume 24, Article number: 1469 (2024) Cite this article

Abstract

Purpose

Reports on the association of perioperative nutritional and inflammatory status with the clinical course of adjuvant chemotherapy did not include neoadjuvant chemotherapy. We aimed to clarify the mechanism by which perioperative nutritional and inflammatory status affect the clinical course of postoperative adjuvant chemotherapy in patients with pancreatic cancer.

Methods

We enrolled 123 patients with pancreatic cancer retrospectively who underwent surgical resection with neoadjuvant and S-1 adjuvant chemotherapy between January 2013 and December 2022. The duration of continuing S-1 treatment and the continuation rates at 3 and 6 months after initiating adjuvant chemotherapy were calculated using the Kaplan–Meier method. The log-rank test was used to evaluate statistical differences between the high and low prognostic nutritional index (PNI) groups. Univariable and multivariable analyses were performed to determine the risk factors for continuing S-1 adjuvant chemotherapy.

Results

The optimal cut-off value for preoperative PNI was 45. Preoperative PNI was an independent risk factor for continuing S-1 adjuvant chemotherapy in patients who underwent perioperative adjuvant chemotherapy and surgical resection (hazard ratio = 2.435, 95% confidence interval = 1.229 − 4.824, p = 0.011). Low PNI was associated with lower S-1completion (p = 0.02) and higher S-1 withdrawal (p = 0.031). Additionally, the preoperative PNI status affected ≥ grade 2 adverse events caused by adjuvant chemotherapy (p < 0.001).

Conclusion

Preoperative PNI affected adjuvant chemotherapy continuation and related adverse events in patients who underwent neoadjuvant chemotherapy and curative resection. Additional perioperative anti-inflammatory management and nutritional support may be required to improve the clinical course of postoperative adjuvant chemotherapy and patient survival.

Peer Review reports

Introduction

Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide [1]. It has poor prognosis, with a 5-year survival rate < 5%, which is the lowest among all cancers [2], and a median survival time of 6 to 8 months [3]. According to pivotal phase III trials, standard treatments for resectable pancreatic cancer include neoadjuvant chemotherapy, curative resection, and postoperative adjuvant chemotherapy. Pretreatment renal function and body weight are the independent risk factors for continuing adjuvant chemotherapy in pancreatic cancer [4, 5]. However, patients in the previous studies did not receive neoadjuvant chemotherapy because curative resection or postoperative adjuvant chemotherapy were considered the standard treatment. The standard treatment of resectable pancreatic cancer includes neoadjuvant chemotherapy. The introduction of neoadjuvant chemotherapy has improved patient survival; nonetheless, the nutritional and inflammatory statuses may dramatically change during the perioperative period. Additionally, the perioperative nutritional and inflammatory statuses during perioperative periods affect the introduction and continuation of postoperative adjuvant chemotherapy [6, 7]. Thus, more sensitive risk factors are supposedly related to the nutritional and inflammatory statuses associated with continuing adjuvant chemotherapy.

Therefore, we hypothesized that nutritional and inflammatory markers and the prognostic nutritional index (PNI) before adjuvant chemotherapy affect adjuvant chemotherapy continuation and related adverse events. To confirm our hypothesis, we evaluated the effect of preoperative PNI on the clinical course of postoperative S-1 adjuvant chemotherapy in patients who underwent perioperative adjuvant chemotherapy and surgical resection.

Materials and methods

Patients

Patients with pancreatic cancer who underwent pancreatic resection after neoadjuvant chemotherapy, followed by adjuvant chemotherapy at the Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan, between January 2013 and December 2022 were included. The inclusion criteria were as follows: (1) initially diagnosed with “resectable” or “borderline resectable” pancreatic cancer according to the Japanese General Rules for the Clinical and Pathological Study of Pancreatic Cancer, seventh edition (JGR), (2) pathologically diagnosed with pancreatic ductal adenocarcinoma (PDAC), (3) underwent pancreatic resection with regional lymph node dissection, (4) tumor status described by the residual tumor classification was no residual tumor (R0) or microscopic residual tumor (R1), (5) underwent S-1 adjuvant chemotherapy, and (6) did not have renal impairment, i.e., creatinine clearance (CCr) level ≥ 60 ml/min, calculated by the formula proposed by Cockroft-Gault [8]. All the clinical records were reviewed retrospectively.

Neoadjuvant chemotherapy

Patients diagnosed with resectable pancreatic cancer received gemcitabine plus S-1 (GS), according to the Prep-02/JSAP-05 trial [9]. The GS regimen was as follows: 1,000 mg/m2 of transvenous gemcitabine on days 1 and 8; 40 mg, 50 mg, and 60 mg of S-1 according to the body surface area orally twice a day for 2 weeks, followed by 1 week of rest. This regimen was continued for two cycles. Patients diagnosed with borderline resectable pancreatic cancer received gemcitabine plus nab-paclitaxel (GnP) or S-1 plus radiation therapy, according to the GABARNANCE trial. The GnP regimen was as follows: 1,000 mg/m2 gemcitabine and 125 mg/m2 transvenous nab-paclitaxel on days 1, 8, and 15, followed by 1 week of rest. This regimen was continued for two cycles. After completing neoadjuvant chemotherapy, abdominal computed tomography (CT) was performed to re-evaluate the tumor size and degree of vascular invasion to re-determine the clinical tumor-node-metastasis stage according to the eighth edition of the Union for International Cancer Control.

Surgical treatment

All patients underwent standard pancreatic resection with regional lymph node dissection according to the seventh edition of the JGR. Surgical procedures, such as pancreaticoduodenectomy (PD), distal pancreatectomy (DP), and total pancreatectomy (TP), were based on the tumor location. Our standard surgical procedure for PD consists of an open subtotal stomach-preserving pancreaticoduodenectomy with digestive tract reconstruction using a modified child procedure. All the procedures were performed by gastrointestinal surgeons.

Adjuvant chemotherapy

The patients diagnosed with “resectable” and “borderline resectable” pancreatic cancer received S-1 according to the JASPAC-01 trial [10]. The regimen was as follows: 40 mg, 50 mg, and 60 mg of S-1 according to the body surface area orally twice a day for 4 weeks, followed by 2 weeks of rest. This regimen was continued for four cycles. The patients who received S-1 underwent blood tests and clinical symptom evaluation every 2 weeks. Adverse events related to adjuvant chemotherapy were evaluated according to the Common Terminology Criteria for Adverse Events, version 5.0. Recurrence was determined using tumor markers, such as carcinoembryonic antigen and carbohydrate antigen 19–9, and imaging studies, such as CT.

Evaluation and statistical analyses

The PNI was calculated as the serum albumin level (g/dL) times 10 + total lymphocyte count (/µL) times 0.005, obtained from blood test data within 2 weeks before surgery. The optimal PNI cut-off value was defined using the receiver operating characteristic (ROC) curve analysis. Clinical factors, such as PNI, were described as the totals and percentages and compared using the Fisher’s exact test. Additionally, the duration of continuing S-1 treatment, i.e., the time to S-1 treatment failure, and the continuation rates at 3 and 6 months after initiating adjuvant chemotherapy were calculated using the Kaplan–Meier method. The log-rank test was used to evaluate statistical differences between the high and low PNI groups. We defined the event occurrence date of S-1 discontinuation as the last day of S-1 administration according to the protocol, patient refusal caused by adverse events or other reasons, disease recurrence, or patient death. Furthermore, significant variables in the univariable analysis were analyzed using a multivariable analysis with Cox proportional hazard regression models and stepwise methods to determine the risk factors for continuing S-1 adjuvant chemotherapy. The results are presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Statistical significance was set at p < 0.05. EZR version 4.20 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) was used for all statistical analyses [11].

Results

Study population

A total of 200 patients who were pathologically diagnosed with PDAC underwent pancreatic resection after neoadjuvant chemotherapy, followed by S-1 adjuvant chemotherapy at our institution from January 2013 to December 2022. We excluded 34 patients diagnosed with unresectable pancreatic cancer, four patients diagnosed with pStage IV pancreatic cancer, and 39 patients with CCr < 60 ml/min. Therefore, only 123 patients were included in this study.

Patient characteristics related to S-1 continuation

Table 1 presents the patient characteristics related to S-1 continuation as total and percentages. A comparison of the continuation rate at 6 months by each clinical factor using Fisher’s exact test indicated differences in the surgical procedure (p = 0.046) and PNI (p = 0.019) between the patients who continued and discontinued S-1 adjuvant chemotherapy.

Table 1 Patient characteristics related to S-1 continuation
Full size table

Other patient characteristics were as follows: the proportion of neoadjuvant chemotherapy regimens was GS, GnP, S-1 plus radiation, and gemcitabine in 82 (66.7%), 27 (22.0%), 12 (9.8%), and 2 (1.6%) patients, respectively. The optimal PNI cut-off value was 45 using ROC curve analysis; 41 (33.3%) patients had a preoperative PNI < 45.

Clinicopathological characteristics related to PNI

Table 2 presents the clinicopathological characteristics related to the PNI with a cut-off value of 45. The age ≥ 75 was more in the PNI < 45 group (p < 0.001) than in the PNI ≥ 45 group. However, there were no significant differences in sex, surgical procedure, postoperative complications, histological type, pStage, or residual tumor.

Table 2 Clinicopathological characteristics related to PNI with a cut-off value of 45
Full size table

Univariable and multivariable analyses of clinicopathological variables related to of S-1 continuation

Table 3 presents the univariable and multivariable analyses results of the clinicopathological variables related to S-1 continuation. In the univariable and multivariable analyses, only PNI < 45 was an independent risk factor (p = 0.011).

Table 3 Univariable and multivariable analyses of clinicopathological variables related to S-1 continuation
Full size table

Figure 1 depicts the Kaplan–Meier curves for S-1 continuation between PNI < 45 and ≥ 45 groups. In the PNI < 45 group, the continuation rate after initiating S-1 adjuvant chemotherapy was low (p = 0.008). Additionally, excluding of S-1 discontinuation because of disease recurrence, patients with PNI < 45 had a lower continuation rate after initiating S-1 adjuvant chemotherapy (p = 0.003) (Fig. 2).

Fig. 1
figure 1

Kaplan–Meier curve for continuation of S-1 between PNI < 45 and ≥ 45 groups

Full size image
Fig. 2
figure 2

Kaplan–Meier curve for continuation of S-1 between PNI < 45 and ≥ 45 groups, excluding discontinuation of S-1 due to disease recurrence

Full size image

Clinical course of S-1 related to PNI

Table 4 summarizes the clinical course of S-1 related to the PNI with a cut-off value of 45. In patients with PNI < 45, S-1 adjuvant chemotherapy completion rate was lower (p = 0.02) and withdrawal rate was higher (p = 0.031), compared with patients with PNI ≥ 45. Moreover, the proportion of adverse events and non-hematologic toxicity (both ≥ grade 2) were higher (p < 0.001) in patients with PNI < 45 than in patients with PNI ≥ 45. Whereas there were no differences in adverse events in patients with ≥ grade 3 and hematologic toxicity (≥ grade 2).

Table 4 Clinical course of S-1 related to PNI with a cut-off value of 45
Full size table

Discussion

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.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

PNI:

Prognostic nutritional index

JGR:

The Japanese General Rules for the Clinical and Pathological Study of Pancreatic Cancer

PDAC:

Pancreatic ductal adenocarcinoma

R0:

No residual tumor

R1:

Microscopic residual tumor

CCr:

Creatinine clearance

GS:

Gemcitabine plus S-1

GnP:

Gemcitabine plus nab-Paclitaxel

CT:

Computed tomography

DP:

Distal pancreatectomy

TP:

Total pancreatectomy

ROC:

Receiver operating characteristic

HR:

Hazard ratio

CI:

Confidence interval

pStage IV:

Pathological Stage IV

GNRI:

Geriatric nutritional risk index

OS:

Overall survival

RFS:

Relapse-free survival

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Acknowledgements

We express our gratitude to the staff of our department for their assistance with the collection and registration of data and samples. This study was supported in part by the nonprofit Yokoyama Surgical Research Group.

Funding

None of the authors have anything to disclose.

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Author notes

  1. Shinnosuke Kawahara and Toru Aoyama contributed equally to this work.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-Ku, Yokohama, 241-8515, Japan

    Shinnosuke Kawahara, Masaaki Murakawa, Rei Kanemoto, Daishi Takahashi, Yuto Kamioka, Naoto Yamamoto, Takashi Oshima & Soichiro Morinaga

  2. Department of Surgery, Yokohama City University, 3-9 Fukuura, Kanazawa-Ku, Yokohama, 236-0004, Japan

    Toru Aoyama, Itaru Hashimoto, Yukio Maezawa, Norio Yukawa, Yasushi Rino & Aya Saito

  3. Department of Gastroenterology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-Ku, Yokohama, 241-8515, Japan

    Satoshi Kobayashi & Makoto Ueno

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  1. Shinnosuke Kawahara
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Contributions

Shinnosuke Kawahara, TA, and MM made substantial contributions to the conception and design. Shinnosuke Kawahara, MM, RK, DT, YK and Naoto Yamamoto made substantial contributions to data collection and entry. Shinnosuke Kawahara, TA, MM, IH, YM, Satoshi Kobayashi, MU, and SM made substantial contributions to the data analysis and interpretation. Shinnosuke Kawahara, TA, MM, IH, YM, TO, Norio Yukawa, YR, SM, and AS contributed substantially to drafting the article and figures. All authors have contributed to writing the manuscript and approved this submission.

Corresponding authors

Correspondence to Shinnosuke Kawahara or Toru Aoyama.

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Ethics approval and consent to participate

All protocols were approved by the Ethics Committee of Kanagawa Cancer Center (approval number: 2023 epidemiologic study-169). All procedures were conducted in accordance with the tenets of the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all the patients.

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Not applicable.

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The authors declare no competing interests.

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Kawahara, S., Aoyama, T., Murakawa, M. et al. Prognostic nutritional index is an independent risk factor for continuing S-1 adjuvant chemotherapy in patients with pancreatic cancer who received neoadjuvant chemotherapy and surgical resection. BMC Cancer 24, 1469 (2024). https://doi.org/10.1186/s12885-024-13244-z

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  • DOI: https://doi.org/10.1186/s12885-024-13244-z

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BMC Cancer

ISSN: 1471-2407

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