Efficacy and safety of neoadjuvant S-1-based chemoradiotherapy in resectable and borderline- resectable pancreatic cancer: A long-term follow-up study

doi:10.21203/rs.3.rs-4873302/v1

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Efficacy and safety of neoadjuvant S-1-based chemoradiotherapy in resectable and borderline- resectable pancreatic cancer: A long-term follow-up study

https://doi.org/10.21203/rs.3.rs-4873302/v1

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Background/Objectives:

This study aimed to evaluate the safety, efficacy, and long-term outcomes of S-1-based neoadjuvant chemoradiotherapy (NACRT) in patients with resectable or borderline-resectable pancreatic ductal adenocarcinoma (PDAC).

Methods

This retrospective study included patients with PDAC who underwent S-1-based NACRT at our institute between 2010 and 2017.

Results

Forty patients were included in the study, including 15 (37.5%) with resectable PDAC and 25 (62.5%) with borderline-resectable PDAC. The NACRT completion and resection rates were 85.0% (n = 34) and 67.5% (n = 27), respectively. Several grade 3 adverse events were observed, including leukopenia (25.0%), anorexia (17.5%), neutropenia (10.0%), thrombocytopenia (7.5%), febrile neutropenia (2.5%), elevated aspartate aminotransferase/alanine aminotransferase (2.5%) levels, and hyponatremia (2.5%). The R0 resection rate was 70.4% (n = 19/27) in patients who underwent pancreatectomy. Grades 1, 2, and 3 according to the College of American Pathologists grading system were observed in 1 (3.7%), 12 (44.4%), and 14 (51.9%) patients, respectively. Over a median follow-up period of 32.9 months (interquartile range, 9.1–68.0), the 1-, 3-, and 5-year OS rates were 81.4%, 45.5%, and 30.3%, respectively, in the intention-to-treat analysis. In the curative-intent surgery cohort (n = 27), the 1-, 3-, and 5-year OS rates were 88.9%, 48.2%, and 37.0%, respectively.

Conclusions

S-1-based NACRT is safe and yields acceptable long-term outcomes for patients with resectable or borderline-resectable PDAC.

S-1-based neoadjuvant chemoradiotherapy

pancreatic ductal adenocarcinoma

resection

retrospective study

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is the leading cause of cancer-related mortality in the United States and Japan. (1, 2) Despite undergoing curative resection, patients with PDAC show unsatisfactory long-term survival outcomes, primarily owing to the significant recurrence rate. The 5-year survival rate for this cancer ranges from 20–30%. (1, 3) Multidisciplinary strategies incorporating neoadjuvant therapy (NAT) and surgery followed by adjuvant therapy (AT) are essential to address this challenge. Specifically, NAT has garnered significant interest, since this therapy may lead to early implementation of anticancer treatment and higher rates of margin-negative resection. (4) Recent retrospective and randomized controlled trials have demonstrated the effectiveness of NAT for resectable and borderline-resectable PDAC with promising long-term survival benefits compared with upfront surgery. (5–8)

Previous studies have proposed numerous treatment regimens for NAT. Katz et al. reported that preoperative chemoradiotherapy was associated with a median survival period of 40 months in patients who underwent resection. (6) The safety and efficacy of a neoadjuvant chemoradiotherapy (NACRT) regimen that included 5-fluorouracil (FU), cisplatin, and mitomycin C has also been reported. (7) Another report showed favorable local disease control and a low rate of lymph node metastasis, with 8% of patients achieving pathological complete response. (9) S-1, an oral anticancer prodrug that is converted into the active anticancer agent 5-FU, is being increasingly utilized since it has shown promising survival outcomes for patients with metastatic or unresectable locally advanced PDAC. (10–12) S-1 may be considered as an alternative for intravenous 5-FU. However, the efficacy and safety of S-1-based NACRT regimens have not yet been fully elucidated. In this study, we aimed to evaluate the efficacy, safety and long-term outcomes of S-1-based NACRT for patients with resectable and borderline-resectable PDAC.

Patients and data collection

Data from patients who received S-1-based NACRT at the Keio University Hospital (Tokyo, Japan) between 2010 and 2017 were retrospectively analyzed to assess the efficacy and safety of this treatment. S-1-based NACRT was specifically implemented in a selected group of patients with T3/T4 PDAC according to the American Joint Committee of Cancer 7th edition. (13) Eligibility criteria included prior therapy for PDAC, performance status of 0 or 1, age between 2 and 85 years, and adequate organ function (with no abnormal laboratory findings for chemoradiotherapy). This study was approved by the institutional review board of Keio University School of Medicine (#20090127) and registered with the UMIN Center (trial number: UMIN000003000). All patients provided informed consent to undergo the treatment. Before NACRT and surgery, all patients underwent staging based on imaging assessments, including contrast-enhanced multidetector-row computed tomography (MDCT) or positron emission tomography-computed tomography. Resectability was determined according to the National Comprehensive Cancer Network criteria for PDAC and the 7th edition of the Japanese Pancreatic Cancer Guideline and was assessed in a multidisciplinary conference with a team of pancreatic surgeons, gastroenterologists, and radiologists. (14, 15)

Patient demographics and clinicopathological data, including age, sex, American Society of Anesthesiologists physical status, radiological findings (tumor location, tumor size, resectability, and lymph node enlargement), pathological findings (tumor size, differentiation, lymphovascular invasion, perineural invasion, portal vein invasion, artery invasion, nodal involvement, and surgical resection margin), and laboratory findings (carcinoembryonic antigen [CEA], carbohydrate antigen 19 − 9 [CA19-9] levels, and the neutrophil-to-lymphocyte ratio [NLR]) were collected. The efficacy of NACRT was pathologically evaluated on the basis of the College of American Pathologists (CAP) grading system by assessing residual viable tumor cells. (16) Laboratory testing was performed both before and after NACRT. These data were obtained within two weeks before NACRT and within two to four weeks after NACRT. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count.

The primary endpoints were completion rate of NACRT, adverse effects, and overall survival (OS). Secondary endpoints were recurrence-free survival (RFS) and the first recurrence site. OS was calculated from the date of NACRT initiation to the date of death or last follow-up. RFS was calculated from the date of surgery until recurrence or death.

Treatment protocol

The NACRT protocol is shown in Fig. 1. The NACRT schedule consisted of a combination of S-1-based chemotherapy and concurrent radiotherapy (40.0 Gy in 20 fractions). S-1 was administered orally at a dose of 60 mg/m² on the day of radiotherapy. Intravenous chemotherapy was administered as follows: cisplatin (10 mg/day) on days 5, 12, 19, and 26, and mitomycin (4 mg/day) on days 6, 13, 20, and 27. Heparin (6000 Units/day) was continuously administered via the peripheral venous route on days 1 to 28. After completing NACRT, the patients were restaged using contrast-enhanced MDCT. Approximately two weeks after completing NACRT, patients without evidence of progressive disease or distant metastasis were considered candidates for curative-intent surgery.

Assessment of NACRT

Adverse effects of and responses to NACRT were evaluated based on The Common Terminology Criteria for Adverse Events version 4.0. (17) and the Response Evaluation Criteria in Solid Tumors (18), respectively.

Surgical and postoperative management

Surgery included pylorus-preserving, subtotal stomach-preserving pancreatoduodenectomy, distal pancreatectomy, or total pancreatectomy accompanied by extensive lymphatic and connective tissue clearance with or without postoperative liver perfusion chemotherapy and adjuvant chemotherapy, as described previously. (19–22)

Patients were followed up monthly after surgery at an outpatient clinic. Clinical examinations and laboratory investigations were performed at every hospital visit, and computed tomography (CT) scans were performed every three months after pancreatectomy. In cases showing potential signs of recurrence during the postoperative follow-up, the diagnosis of recurrence was determined at a multidisciplinary team conference. Histological confirmation was not obligatory as part of the diagnostic process if recurrence was suspected on the basis of radiological findings.

Statistical analyses

Continuous variables are presented as medians with interquartile ranges (IQRs), and categorical variables as frequency and percentages. RFS and OS were estimated using the Kaplan–Meier method, and differences in survival curves were analyzed using the log-rank test. Multivariate logistic regression analysis was used to investigate the risk factors associated with noncurative resection after NACRT. Significant factors (P < 0.2 in the univariable analysis) were entered into the multivariate model. Statistical significance was set at P < 0.05. All analyses were performed using JMP®ฎ pro 17 (SAS Institute Inc., Cary, NC, USA).

Clinical characteristics

The clinical characteristics of the patients before NACRT are summarized in Table 1. The median age of the 40 patients was 67 years (IQR: 62–75 years), and 32 patients (80.0%) were male. Although 15 patients (37.5%) were diagnosed with resectable PDAC, the majority (n = 25; 62.5%) had borderline-resectable PDAC. Among patients with borderline-resectable PDAC, 10 (25.0%) showed portal vein invasion and 15 (37.5%) showed arterial abutment in the pre-NACRT evaluation. Nine patients (22.5%) showed clinically suspicious lymph nodes on imaging. Before NACRT, the median NLR and CA19-9 and CEA levels were 2.96 (IQR: 1.88–3.85), 148 (IQR: 52–398), and 3.5 (IQR: 2.4–6.0), respectively; after NACRT, these values were 3.54 (IQR: 1.81–5.54), 42 (IQR: 21–135), and 3.1 (IQR: 1.9–5.8), respectively.

Table 1

Patients’ clinical characteristics (n = 40)
Variables		n = 40
Age, years old		67 (62–75)
Sex	male	32 (80.0)
	female	8 (20.0)
ASA-PS	1	4 (10.0)
	2	30 (75.0)
	3	6 (15.0)
Location of tumor	head	34 (85.0)
	body/ tail	6 (15.0)
Tumor size
Resectability	R	15 (37.5)
	BR	25 (62.5)
	BR-A	15 (37.5)
	BR-PV	10 (25.0)
cN	negative	31 (77.5)
	positive	9 (22.5)
cStage	ⅠA	0 (0.0)
	ⅠB	0 (0.0)
	ⅡA	21 (52.5)
	ⅡB	8 (20.0)
	Ⅲ	11 (27.5)
	Ⅳ	0 (0.0)
pre NACRT NLR		2.96 (1.88–3.85)
pre NACRT CA19-9, IU/ml		148 (52–398)
pre NACRT CEA, IU/ml		3.5 (2.4–6.0)
post NACRT NLR		3.54 (1.81–5.54)
post NACRT CA19-9, IU/ml		42 (21–135)
post NACRT CEA, IU/ml		3.1 (1.9–5.8)
Completion of chemotherapy		34 (85.0)
Completion of radiotherapy		40 (100)
ASA-PS: American Society of anesthesiologists physical status, R: Resectable, BR: borderline resectable, NACRT: neoadjuvant chemoradiotherapy, NLR: Neutrophil to Lymphocyte Ratio, CA19-9: carbohydrate antigen 19 − 9, CEA: carcinoembryonic antigen

A flowchart of the study protocol is shown in Fig. 2. Of the 40 patients, 27 (67.5%) underwent curative-intent resection. Three patients developed unresectable locally advanced PDAC, and four patients showed distant metastasis on restaging CT scans. PDAC treatment was discontinued for four patients at their request, and one patient did not undergo curative-intent surgery because of a decline in their general condition. One patient underwent palliative gastrojejunal bypass surgery because of unresectable locally advanced PDAC with tumor invasion of both the superior mesenteric and proper hepatic arteries.

Adverse events during NACRT

Adverse events of any grade occurred in 34 (85.0%) patients. No cases of grade 4 or 5 adverse events or NACRT-related mortalities occurred. Grade 3 adverse events occurred in 17 patients (42.5%), and the common grade 3 adverse events were leukopenia (n = 10, 25.0%), anorexia (n = 7, 17.5%), neutropenia (n = 4, 10.0%), thrombocytopenia (n = 3, 7.5%), febrile neutropenia (n = 1, 2.5%), elevated aspartate aminotransferase/alanine aminotransferase levels (n = 1, 2.5%), and hyponatremia (n = 1, 2.5%) (Table 2). Of the 40 patients, 34 (85.0%) completed NAC. The reasons for failure to complete the chemotherapy protocol included neutropenia (n = 3, 7.5%), anorexia (n = 2, 5.0%), and cholangitis (n = 1, 2.5%). All patients successfully underwent radiotherapy.

Table 2

Adverse events during neoadjuvant chemoradiotherapy (n = 40)
CTCAE v 4.0 grade	Grade					AE	AE ≥ 3
CTCAE v 4.0 grade	1	2	3	4	5	34 (85.0)	17 (42.5)
Hematological
Leukopenia	0	14	10	0	0	24 (60.0)	10 (25.0)
Neutropenia	3	15	4	0	0	22 (55.0)	4 (10.0)
Anemia	0	2	0	0	0	2 (5.0)	0 (0.0)
Thrombocytopenia	1	4	3	0	0	8 (20.0)	3 (7.5)
Febrile neutropenia	0	0	1	0	0	1 (2.5)	1 (2.5)
Non-hematological
Anorexia	1	3	7	0	0	11 (27.5)	7 (17.5)
Creatinine increased	0	0	0	0	0	0 (0.0)	0 (0.0)
AST/ALT increased	0	4	1	0	0	5 (12.5)	1 (2.5)
Hyponatremia	5	0	1	0	0	6 (15.0)	1 (2.5)
Hypokalemia	1	0	0	0	0	1 (2.5)	0 (0.0)
Diarrhea	0	0	0	0	0	0 (0.0)	0 (0.0)
Tingling sensation	0	1	0	0	0	1 (2.5)	0 (0.0)
Alopecia	0	0	0	0	0	0 (0.0)	0 (0.0)
Rash maculopapular	2	0	0	0	0	2 (5.0)	0 (0.0)
Nail loss	0	0	0	0	0	0 (0.0)	0 (0.0)
Mucositis oral	0	3	0	0	0	3 (7.5)	0 (0.0)
DVT	0	1	0	0	0	1 (2.5)	0 (0.0)
CTCAE: Common Terminology Criteria for Adverse Events, AE: adverse effect, AST: aspartate aminotransferase, ALT: alanine aminotransferase, DVT: deep vein thrombosis

Treatment responses

The waterfall plot based on the changes in primary tumor size from baseline showed that three patients (7.5%) had a partial response, 32 (80.0%) had stable disease, and five (12.5%) had progressive disease based on the RECIST criteria (Fig. 3). Disease control and response rates were 87.5% and 7.5%, respectively. Distant metastasis occurred in four patients (10.0%): three (7.5%) in the liver and one (2.5%) in both the liver and lungs.

Of the 27 patients who underwent curative-intent resection, 17 (63.0%), seven (25.9%), and three (11.1%) underwent pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy, respectively. Among these patients, six (22.2%) underwent concomitant portal vein resection and three (11.1%) underwent concomitant arterial resection. The median operation time was 456 min (IQR, 415–520 min) and the estimated blood loss was 447 mL (IQR, 235–614 mL). Pathological findings are summarized in Table 3. The median tumor size was 25 mm (IQR: 20–33 mm). Most patients had lymph node metastases (n = 18, 66.7%). Eleven (40.7%) patients showed portal vein invasion and one (3.7%) showed arterial invasion. Regarding the histologic interpretation of the resected specimens, CAP grades 1, 2, and 3 were observed in 1 (3.7%), 12 (44.4%), and 14 (51.9%) patient samples, respectively (Table 3). Negative microscopic resection margins were found in 19 of the 27 patients (70.4%).

Table 3

Peri-operative outcome in patients who underwent surgery(n = 27)
Variables		n = 27
Surgical outcome
Procedure
Pancreaticoduodenectomy		17 (63.0)
	with portal vein resection	3 (11.1)
	with artery resection	1 (3.7)
Distal pancreatectomy		7 (25.9)
	with portal vein resection	1 (3.7)
	with enbloc celiac axis resection	2 (7.4)
Total pancreatectomy		3 (11.1)
	with portal vein resection	2 (7.4)
Operation time, min		456 (415–520)
Bleeding, ml		447 (235–614)
Pathological findings
Tumor size (mm)		25 (20–33)
Differentiation	well, mod	11 (40.7)
	poor	16 (59.3)
Lymphvascular invasion	absent	13 (48.1)
	present	14 (51.9)
Perineural invasion	absent	11 (40.7)
	present	16 (59.3)
Portal vein invasion	absent	16 (59.3)
	present	11 (40.7)
Artery invasion	absent	26 (96.3)
	present	1 (3.7)
Nodal involvement	absent	9 (33.3)
	present	18 (66.7)
R0 resection		19 (70.4)
pStage	ⅠA	1 (3.7)
	ⅡA	9 (33.3)
	ⅡB	17 (63.0)
CAP grades	1	1 (3.7)
	2	12 (44.4)
	3	14 (51.9)

Survival analysis

With a median follow-up period of 32.9 months (IQR, 9.1–68.0 months), the 1-, 3-, and 5-year OS rates in the intention-to-treat (ITT) analysis were 81.4%, 45.5%, and 30.3%, respectively. The median OS was markedly worse in the noncurative resection group (OS: noncurative resection vs. curative resection, 12.7 months vs. 38.8 months, p < 0.001; Fig. 4). The risk factors associated with noncurative resection are listed in Supplemental table 1. In this analysis, the post-NACRT NLR (odds ratio [OR],1.473; 95% confidence interval [CI],1.033–2.163; p = 0.048) was identified as a significant factor for noncurative resection.

In the cohort that underwent curative-intent surgery (n = 27), the 1-, 3-, and 5-year RFS rates were 63.0%, 33.3%, and 33.3%, respectively (Supplemental Fig. 1a). The 1-, 3-, and 5-year OS rates were 88.9%, 48.2%, and 37.0%, respectively (Supplemental Fig. 1b). Postoperative recurrence occurred in 17 (63.0%) of the 27 patients who underwent curative resection. Recurrence was characterized as initial locoregional or lung recurrence in four patients (23.5%), peritoneal dissemination in three patients (17.6%), liver metastasis in two patients (11.8%), metastasis in the remnant pancreas in one patient (5.9%, 1/17), and metastasis in multiple sites in one patient (5.9%, 1/17) (Supplemental table 2).

Due to its ability to reduce infiltration into surrounding tissues and improve negative margin resection rates, NACRT is regarded as a promising treatment strategy for patients with PDAC. However, the optimal regimen for this therapy remains unclear. This retrospective study assessed the safety, efficacy, and long-term outcomes of NACRT consisting of S-1, cisplatin, and mitomycin C combined with concurrent chemoradiotherapy for resectable and borderline-resectable PDAC. We observed that the NACRT regimen was well-tolerated, with an 85% completion rate, and caused no grade 4 or higher adverse effects. Additionally, the long-term outcomes of this regimen were acceptable, with a negative resection margin of 70.4%. Noncurative resection was associated with worse long-term survival outcomes, and the post-NACRT NLR was a significant factor for noncurative resection. These findings emphasize the effectiveness and feasibility of NACRT for resectable and borderline-resectable PDAC and the importance of developing optimal regimens and strategies for these patients.

The safety and adverse effect rates of the treatment regimen were assessed to identify any potential risks and ensure the overall well-being of the patients undergoing the therapy. Previous studies have shown that the completion rate for NACRT ranges from 77–90%. (23, 24) Adverse effects ≥ grade 3 (CTCAE) in other NACRT regimens using S-1 were reported to be 23–43%. (25–27) In line with these findings, we found that the rates of competition and severe adverse effects (CTCAE ≥ grade 3) were 85.0% and 42.5%, respectively. The reasons for not completing NACRT in this study were neutropenia (5%, 2/40), anorexia (5%, 2/40), and cholangitis (2.5%, 1/40), which is consistent with the findings of previous studies. (10, 27, 28) As such, our S-1-based NACRT regimen may be safe and feasible in patients with potentially resectable PDAC. Implementation of NAT in patients with resectable or borderline-resectable PDAC can lead to various adverse effects, resulting in reduced food intake and exacerbation of malnutrition and sarcopenia. (29) These effects may significantly negatively impact the NAT treatment process, including completion rates, treatment outcomes, and the ability to undergo subsequent surgery. (30) Collectively, in order to improve the safety and feasibility of this NACRT regimen, intervention to decrease adverse effect rates, such as immuno-nutrition, pre-habilitation, and aerobic exercise, should be investigated further. (31, 32)

Several reports have described the use of NACRT in PDAC. Among these, previous studies reported 5-year OS rates from 20.5–60.9% based on ITT analysis, while the 2-year RFS ranged from 22.0–58.8%. (7, 33, 34) In particular, a meta-analysis showed that NACRT for PDAC has higher rates of curative resection and negative surgical margin achievement. (35) Positive surgical margins are widely recognized as significant prognostic factors for PDAC, making NACRT particularly beneficial for improving patient outcomes. (36) Previous studies involving NACRT for PDAC demonstrated R0 resection rates ranging from 61.1–82.4%. (5, 23, 24, 34) In our study, we found a 5-year OS rate of 37.0% and a 5-year RFS rate of 33.3%. The curative resection and negative surgical margin rates were 67.5% and 70.4%, respectively. These results suggest that despite comparable survival outcomes, our treatment regimen would lead to a slightly lower rate of negative surgical margin resection. Although the reasons for this are likely multifactorial, the difference may be due to the dosage of radiotherapy administered. A meta-analysis by Zhan et al. indicated that most previous studies with higher R0 resection rates utilized standard fractionated radiotherapy ranging from 50–60 Gy, which was higher than the dosage administered in our study. (35) To support this assumption, while NACRT is considered beneficial for local disease control, our study showed that locoregional recurrence is the most common pattern of recurrence. (24, 37) Thus, the optimal NACRT regimen should be identified to enhance local disease control and ultimately improve survival rates.

Non-resection has previously been shown to be one of the strongest predictors of poorer survival among patients with PDAC receiving NAT. (38) Consistent with these findings, the current study demonstrated that patients in the non-resection group were more likely to have lower survival than those in the resection group (Fig. 4). In this study, we analyzed factors associated with treatment response, since they may serve as a treatment guide for pancreatic cancer with NAT. (39, 39, 40) In this regard, biomarkers related to non-resection after NAT may be potentially useful for patient selection. We highlighted the significance of the NLR as a factor associated with noncurative resection. Each unit increase in NLR was associated with a 47% increase in the possibility of noncurative resection. Consistent with this finding, NLR has been recognized as a prognostic predictor in PDAC. (41) Therefore, post-treatment NLR and its transition should be carefully monitored. Recent studies have also highlighted a growing need for the development of more sensitive biomarkers. (42) For example, Nakano et al. reported that KRAS mutations in postoperative serum samples serve as an independent prognostic factor for disease-free survival. (43) Combining liquid biopsy with next-generation sequencing techniques may enhance the accuracy of patient selection. (44)

This study had some limitations. First, it was a retrospective, single-center study conducted with a relatively small cohort, which limits the generalizability of the findings. Although the small sample size limited some statistical analyses, we utilized a multivariable logistic progression model to evaluate the risk factors associated with noncurative resection. Second, patients were not consecutively enrolled in this study, potentially leading to selection bias. In addition, this study was a single-arm trial, which limited its ability to yield definitive conclusions regarding the optimal regimens for patients with PDAC. Multicenter randomized controlled studies are required to address these limitations.

In conclusion, preoperative administration of S-1-based concurrent chemotherapy followed by surgical resection was safe and tolerable in patients with PDAC. S-1-based NACRT shows favorable long-term outcomes in patients with resectable or borderline-resectable PDAC.

PDAC

pancreatic ductal adenocarcinoma

NAT

neoadjuvant therapy

NACRT

neoadjuvant chemoradiotherapy

adjuvant therapy

computed tomography

MDCT

multidetector-row computed tomography

CEA

carcinoembryonic antigen

CA19-9

carbohydrate antigen 19 − 9

NLR

neutrophil-to-lymphocyte ratio

CAP

the College of American Pathologists

overall survival

RFS

recurrence-free survival

IQR

interquartile ranges

ITT

intention-to-treat

odds ratio

confidence interval

Ethics approval and consent to participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study design was approved by the Institutional Review Board of Keio University School of Medicine (#20090127). Informed consent was obtained from all individual participants included in the study.

Consent for publication

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author.

Competing interests

Dr. Kitagawa reports grants and personal fees from CHUGAI PHARMACEUTICAL CO., LTD, grants and personal fees from Takeda Pharmaceutical Company Limited, grants and personal fees from DAIICHI SANKYO COMPANY, LIMITED, grants from Takeda Pharmaceutical Company Limited, grants from Yakult Honsha Co. Ltd., grants from Kyouwa Hakkou Kirin Co., Ltd., personal fees from Nippon Kayaku Co., Ltd., and personal fees from MSD K.K., outside the submitted work.

Funding

None.

Authors’ contributions

Gaku Shimane: Conceptualization, Date curation, Formal analysis, Visualization, Investigation, Methodology, Project administration, Writing-original draft, and Writing-review and editing. Minoru Kitago: Conceptualization, Supervision, Methodology, Project administration, Writing-original draft, and Writing-review and editing. Yutaka Endo: Conceptualization, Formal analysis, Methodology, Writing-original draft, and Writing-review and editing. Koichi Aiura: Conceptualization, Methodology, and Writing-review and editing. Hiroshi Yagi: Writing-review and editing. Yuta Abe: Writing-review and editing. Yasushi Hasegawa: Writing-review and editing. Shutaro Hori: Writing-review and editing. Masayuki Tanaka: Writing-review and editing. Yutaka Nakano: Writing-review and editing. Junichi Fukada: Conceptualization, Methodology, Supervision, and Writing-review and editing. Yohei Masugi: Conceptualization, Methodology, Supervision, and Writing-review and editing. Yuko Kitagawa: Supervision, Writing-review and editing.

Acknowledgments

We thank Kazumasa Fukuda, a staff member of the Department of Surgery at Keio School of Medicine, for their help in preparing this article. We also thank Editage (www.editage.jp) for their English language editing services.

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No competing interests reported.

Supplementaryfigure1a.tiff
Supplementary Figure 1a: Recurrence-free survival in per-protocol analysis of patients who underwent curative resection.
Supplementaryfigure1b.tiff
Supplementary Figure 1b: Overall survival in per-protocol analysis of patients who underwent curative resection.
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Supplementarytable2.docx

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Efficacy and safety of neoadjuvant S-1-based chemoradiotherapy in resectable and borderline- resectable pancreatic cancer: A long-term follow-up study

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BACKGROUND

METHODS

Patients and data collection

Treatment protocol

Assessment of NACRT

Surgical and postoperative management

Statistical analyses

Results

Clinical characteristics

Adverse events during NACRT

Treatment responses

Survival analysis

Discussion

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