Neoadjuvant therapy versus upfront surgery followed by adjuvant chemotherapy in resectable or borderline resectable PDAC: a systematic review and meta-analysis of RCTs

Abstract

Background:

Adjuvant chemotherapy remains the standard of care following resection of pancreatic ductal adenocarcinoma (PDAC). However, despite advances with modern multi-agent regimens, most patients relapse, underscoring the need for alternative strategies. Neoadjuvant therapy offers several theoretical advantages, but evidence directly comparing it with upfront surgery remains limited.

Objectives:

To compare efficacy and postoperative safety outcomes between neoadjuvant therapy and upfront surgery among patients with resectable or borderline resectable PDAC.

Design:

We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) evaluating outcomes in patients with resectable or borderline resectable PDAC treated with either neoadjuvant chemotherapy and/or chemoradiotherapy or upfront surgery followed by adjuvant chemotherapy.

Data sources and methods:

Outcomes of interest included overall survival, disease-free survival (DFS), R0 resection rate, and postoperative complication rates. Literature searches were performed in PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, supplemented by clinical trial registries, conference abstracts, and gray literature. Study selection and data extraction were conducted independently by two authors. Sensitivity and subgroup analyses were performed to assess sources of heterogeneity.

Results:

We included 13 RCTs, with one study excluded from the primary analysis due to high risk of bias. Neoadjuvant treatment did not confer a statistically significant benefit in overall survival (hazard ratio (HR) = 0.79; 95% confidence interval (95% CI), 0.58–1.10). However, neoadjuvant treatment was associated with improved DFS (HR = 0.79; 95% CI, 0.66–0.93) and a higher R0 resection rate (OR = 1.51; 95% CI, 1.04–2.19). There was no significant difference in the rate of major postoperative morbidity after resection (OR = 1.27; 95% CI, 0.61 – 2.62). Subgroup analyses revealed larger treatment effects in overall survival, DFS, and R0 resection rate in favor of neoadjuvant treatment among patients with borderline resectable PDAC.

Conclusion:

The survival advantage of neoadjuvant treatment in resectable or borderline resectable PDAC remains uncertain. Nonetheless, preoperative therapy improves DFS and R0 resection rates, with patients with borderline resectable disease deriving the greatest benefit. These findings should be interpreted with caution, given the limitations of the available evidence.

Plain language summary

Chemotherapy or radiotherapy before surgery compared with surgery first in pancreatic cancer: results from a review of clinical trials

People with pancreatic cancer that can be removed by surgery usually receive chemotherapy after the operation to reduce the risk of the cancer coming back. However, many patients still experience disease relapse. Giving chemotherapy before surgery - the so called neoadjuvant therapy - might help by treating the cancer earlier and selecting patients who are more likely to benefit from surgery. To understand whether this approach works better than the traditional surgery-first method, we combined results from 13 randomized clinical trials that compared these two strategies. We looked at how long patients lived overall, how long they stayed free from cancer, how often surgeons achieved complete tumor removal (called R0 resection), and whether there were more surgical complications. The analyses showed that giving treatment before surgery did not clearly make people live longer overall. However, it did help patients stay free from cancer for a longer time and increased the chances of a complete tumor removal. The risk of serious surgical complications was similar between groups. Patients whose cancers were harder to remove (called borderline resectable) seemed to benefit the most from getting treatment before surgery. In summary, giving chemotherapy before surgery improves some important results and may be especially helpful for people whose tumors are harder to remove. However, it is still not clear whether this approach actually helps patients live longer. So far, the available studies have not shown a clear increase in overall survival, and more large, carefully conducted studies are needed to know for sure whether it truly extends life.

Keywords

cancer chemotherapy neoadjuvant pancreatic radiotherapy surgery

Introduction

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies in humans. With an increasing epidemiological burden,¹ PDAC is expected to become the second most important cause of cancer-related death in developed countries by the end of this decade.² This malignancy is usually associated with an aggressive clinical course and insidious symptom presentation,^3,4 hindering curative therapies for most patients affected by the disease.

Surgery remains the cornerstone of treatment for resectable PDAC. However, multiple randomized trials have demonstrated improved survival with single-agent adjuvant chemotherapy.^5,6 More recently, polychemotherapy regimens (either modified FOLFIRINOX or gemcitabine plus capecitabine) have shown superior outcomes when compared to monotherapy,^7,8 becoming the new standard of care. Despite these improvements, most patients still experience disease relapse and death from the disease.

Given PDAC’s propensity for early dissemination, the use of neoadjuvant therapies has become increasingly appealing. Neoadjuvant chemotherapy or chemoradiation presents multiple potential advantages, including early treatment of metastatic disease, preoperative tumor downstaging, improved compliance with systemic therapy, and increased R0 resection rates.⁹ Nonetheless, randomized clinical trials (RCTs) assessing the role of neoadjuvant therapies for resectable or borderline resectable PDAC have found mixed results, with many studies failing to enroll the predicted number of patients, ultimately leading to insufficient power to detect differences in important outcomes.

Therefore, we conducted a systematic review and meta-analysis of RCTs comparing the overall survival, disease-free survival (DFS), R0 resection rates, and toxicity profiles of neoadjuvant therapies (chemotherapy or chemoradiotherapy) with those of upfront surgery followed by adjuvant chemotherapy for patients with anatomically resectable or borderline resectable PDAC. In addition, to investigate potential sources of heterogeneity, we performed sensitivity analyses and subgroup analyses based on clinically relevant covariates.

Methods

This report was prepared in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) 2020 guideline.¹⁰ The review was prospectively registered at the PROSPERO database (CRD42023387884), and its original protocol can be found at https://www.crd.york.ac.uk/PROSPERO/view/CRD42023387884. The main data underlying this article are available in the article and in its online Supplemental Material. Further data can be supplied by the authors upon reasonable request.

Inclusion and exclusion criteria

In accordance with the PICO framework (Supplemental Table 1), we included RCTs enrolling adult (age ⩾ 18 years) patients with resectable or anatomical borderline resectable pancreatic (ductal) adenocarcinoma that compared neoadjuvant therapy with the standard sequence of upfront surgery followed by adjuvant chemotherapy. Eligible studies included those published as full-text manuscripts or conference abstracts, disseminated from the inception of search databases until April 23, 2025, and we did not apply language restrictions. We excluded retrospective studies and those not undertaken in humans.

Neoadjuvant therapy was defined as the administration of chemotherapy, concomitant chemoradiation, or both prior to definitive surgery for pancreatic adenocarcinoma. In the upfront surgery groups, surgery constituted the initial treatment modality, followed by adjuvant chemotherapy. To be eligible, trials were required to report at least one of the following outcomes: overall survival (from randomization), DFS (from randomization), R0 resection rates, or rates of post-operative complications. Although DFS, progression-free survival, and event-free survival are not fully overlapping constructs and may differ across trials in terms of event definitions, we considered them sufficiently comparable for quantitative synthesis. This decision was supported by the relatively limited contribution of non-relapse events (e.g., second primary pancreatic tumors and deaths without documented relapse) to the overall event count,⁷ thereby justifying the meta-analytical pooling of relapse-related outcomes reported under these endpoints.

Information sources

We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from the inception to April 12, 2023. A second and final search of the medical databases was conducted on April 23, 2025. In addition, we searched ClinicalTrials.gov, EU Clinical Trials Register, International Clinical Trials Registry Platform (ICTRP), and International Standard Randomized Controlled Trial Number (ISRCNT) Registry from the inception to March 8, 2025. We also searched the Trip Medical Database and OPENGREY from the inception to March 9th. To capture relevant unpublished or ongoing studies, we reviewed meeting abstracts from major oncology conferences, including the Gastrointestinal Cancers Symposium (ASCO GI; 2011–2025), the American Society of Clinical Oncology (ASCO) Annual Meeting (2010–2024), the European Society of Medical Oncology (ESMO) Annual Congress (2010–2024), the World Congress on Gastrointestinal Cancer (2010–2024), the American Society for Radiation Oncology (ASTRO) Annual Meeting (2010–2024), and the European Society for Radiotherapy and Oncology (ESTRO) Annual Meeting (2010–2024). We used the handsearch method to identify relevant meeting abstracts. Finally, we performed backward citation tracking of included studies to identify any additional relevant trials.

Search strategy

We developed the search strategy based on the PICO framework, combining free-text and controlled vocabulary using Boolean operators. Complete search strategies for all databases are available in Supplemental Table 2. Strategies used for clinical trial registries and gray literature sources are detailed in Supplemental Tables 3 and 4, respectively.

Study selection

Citations retrieved from PubMed, EMBASE, and CENTRAL were merged, and then duplicated references were manually removed. Study selection was performed in two phases. In the first screening round, two authors (VHFJ and MPGC) independently screened titles and abstracts to identify potentially eligible studies. In the second round, the same reviewers independently selected manuscripts based on their full-text manuscripts, meeting presentations, or posters. In both phases of study selection, disagreements regarding eligibility were resolved through discussion to reach consensus. Then, relevant studies identified in other information sources (clinical trial registers, meeting abstracts, and gray literature) were added. No automated tools were used, and study screening was conducted using the Rayyan platform for systematic reviews.¹¹

Data collection process

Two authors (VHFJ and MPGC) independently extracted the data from all eligible studies using a standardized Microsoft Excel spreadsheet. Discrepancies were resolved through discussion until consensus was reached. When multiple reports of the same study were available, we prioritized the manuscript that included an intention-to-treat analysis, preferably with the longest follow-up. One of the authors (VHFJ) used WebPlotDigitizer to extract survival data (time and survival probabilities) from available Kaplan–Meier curves.

Data items

Overall survival was defined as the time from randomization to death or last follow-up visit. DFS was defined as the time from randomization to recurrence, disease progression, or death. For time-to-event outcomes (overall survival and DFS), we extracted hazard ratios (HRs) with 95% confidence intervals (95% CIs), median survival times (with 95% CIs whenever possible), and survival rates at 1, 2, 3, 4, and 5 years. When these data were not reported in the text, they were extracted from available Kaplan–Meier curves by one of the authors (VHFJ). R0 resection rate was defined as the proportion of patients submitted to resection with negative microscopic margins (R0 resection) among all randomized patients. Postoperative mortality rate was defined as the proportion of patients who died after resection among all patients who underwent resection. Postoperative morbidity rate was defined as the proportion of patients experiencing any postoperative complication after resection. Major postoperative morbidity rate was defined as the proportion of patients experiencing grade III or higher postoperative morbidity according to the Clavien–Dindo classification among all patients submitted to resection.¹² Postoperative pancreatic fistula rate was defined as the proportion of patients developing a clinically significant pancreatic fistula according to the 2017 guideline from the International Study Group in Pancreatic Fistula (ISGPF) among all patients submitted to resection.¹³

Study assessment of the risk of bias

Risk of bias was assessed for each of the outcomes using the RoB 2 tool.¹⁴ Briefly, it assesses the risk of bias across five different domains: bias arising in the randomization process, bias due to deviation from intended interventions, bias due to missing outcome data, bias in the measurement of outcome, and bias in the selection of reported results. Based on these domains, an overall risk of bias judgment was performed according to the RoB 2 guidance. Assessments were performed independently by two authors (VHFJ and ALO), with disagreements resolved through discussion to achieve consensus.

Effect measures

For the syntheses, we used HRs (and 95% CIs) as effect measures of time-to-event outcomes (overall survival and DFS) and for binary outcomes (R0 resection rate, postoperative mortality rate, postoperative morbidity rate, major postoperative morbidity rate, postoperative pancreatic fistula rate), we used odds ratios (and 95% CIs).

Synthesis methods

Details on the meta-analytical methods and models are provided in the Supplemental Material. Primary analyses excluded studies at high risk of bias according to the RoB2 tool.¹⁵ When HRs (and 95% CIs) were not reported, they were estimated using one of the currently validated algorithms.^16,17 We did not perform meta-analytical synthesis in cases of significant clinical heterogeneity or when less than five studies reported outcome data. We conducted sensitivity analyses to evaluate the impact of alternative meta-analytical models, the inclusion of all studies (regardless of risk of bias), and the results of studies that were prematurely terminated due to slow patient accrual. To investigate potential sources of heterogeneity, we performed subgroup analyses stratified by neoadjuvant therapy type (systemic chemotherapy vs chemoradiation; FOLFIRINOX vs other therapies) and resectability status (resectable vs anatomical borderline disease). Sensitivity and subgroup analyses were carried out only when at least 10 different groups were available for meta-analytical synthesis. Given the limited activity of single-agent neoadjuvant chemotherapy,¹⁸ we defined neoadjuvant systemic chemotherapy as therapy with at least two cytotoxic drugs for a minimum of 42 days (two 21-day cycles) prior to surgery. Anatomical resectability was classified according to NCCN guidelines; if not explicitly stated, we used the classification provided in the inclusion criteria of each RCT. Analyses were conducted using within-study contrasts. Subgroup analyses were undertaken using a random-effects model with pooled estimates of τ², given the relatively small number of studies per subgroup and the Q-test for heterogeneity. Statistical analyses were carried out using R version 4.3.1 (R Foundation for Statistical Computing) and the meta package.

Non-reporting bias

For time-to-event outcomes, we assessed publication bias using funnel plots of the standard error of the log hazard ratio (y-axis) against the log hazard ratio (x-axis), with asymmetry evaluated by Egger’s test. For binary outcomes, we constructed funnel plots of the standard error of the log odds ratio (y-axis) against the log odds ratio (x-axis), with asymmetry evaluated by Peter’s test.

Certainty of assessment

We assessed the certainty of evidence using the GRADE approach with the online GRADEpro tool (www.gdt.gradepro.org). Two reviewers independently developed a summary of findings (SoF) Table.¹⁹ Disagreements were resolved through discussion to achieve consensus. Further details are provided in the Supplemental Material.

Results

Study selection

The PRISMA diagram illustrates the study selection process—Figure 1. The initial search identified 2332 records from PubMed, EMBASE, and Central, of which 142 were duplicates. After de-duplication, 2137 were excluded in the first phase of screening—see Supplemental Material for detailed information on the study selection process. Fifty-three reports were assessed in full during the second screening phase, and 29 were included, corresponding to 11 studies. Prior to manuscript preparation, a second search was conducted, yielding nine additional reports (two studies). Detailed information on the second database search is shown in Supplemental Figure 1. The trial by Chen Y et al. was excluded due to unavailable data on overall survival, DFS, and postoperative complications. Furthermore, the absolute number of patients undergoing R0 resection was not reported, preventing calculation of the R0 resection rate on an intention-to-treat basis, despite attempts to contact the authors.²⁰ The study by Tachezy M et al. was prematurely terminated due to poor accrual and has no results published.²¹ After assessment of clinical trial registers, meeting abstracts, and gray literature, three additional reports (no additional study) were identified. In total, this systematic review includes 41 reports from 13 distinct studies. Detailed information on the results of searches for meeting abstracts, clinical trial registers, and gray literature websites can be found in Supplemental Tables 5 to 7. Precise explanations for abstract and manuscript exclusion in the first and second screening rounds are shown in Supplemental Tables 8 and 9, respectively.

Figure 1.

PRISMA flow chart for the systematic review.

Study characteristics

The following 13 studies have been identified: Golcher H et al. (NCT00335543),²² Casadei R et al.,²³ Birrer et al. (NEOPAC; NCT01314027),²⁴ Versteijne E et al. (PREOPANC; EudraCT 2012-003181-40),²⁵ Jang J-Y et al. (NCT01458717),²⁶ Reni M et al. (PACT-15; NCT01150630),²⁷ Unno M. et al (Prep-02/JSAP05; UMIN000009634),²⁸ Al-Batran SE et al. (NEPAFOX; NCT02172976),²⁹ Ghaneh P et al. (ESPAC-5F; ISRCTN89500674),³⁰ Seufferlein T et al. (NEONAX; NCT02047513),³¹ Schwarz C et al. (PRODIGE48; NCT02959879),³² Labori K, et al. (NorPACT-1; NCT02919787),³³ and Kumar V et al.³⁴

Table 1 summarizes data on population and clinical tumor features across studies. Supplemental Tables 10 to 15 provide details on bibliographical information, study design, clinical, and demographic characteristics, clinical tumor features, and pathological findings extracted from included reports. Seven studies enrolled only patients with resectable disease,^{22
–24,27,31
–33} two studies included only patients with anatomical borderline resectable disease,^26,30 and four studies included mixed populations of patients with resectable and anatomical borderline resectable disease.^25,28,29,34 In addition, Supplemental Table 16 describes the planned neoadjuvant and adjuvant treatments and Supplemental Table 17 summarizes systemic treatment compliance data from these studies. In the experimental arms, eight studies evaluated systemic chemotherapy,^24,27
–33 five studies evaluated neoadjuvant chemoradiation,^{22,23,25,26,30} and one study evaluated both neoadjuvant systemic chemotherapy and neoadjuvant chemoradiation.³⁴ The ESPAC-5F trial had three experimental arms: two testing neoadjuvant chemotherapy (gemcitabine plus capecitabine, or FOLFIRINOX) and one testing neoadjuvant chemoradiation.³⁰

Table 1.

Summarized population and clinical tumor features.

Study	Treatment arm	Sample size	Sex (%)		Age (Years)	Performance status (%)		Primary tumor site (%)	Clinical T staging (%)		Clinical N staging (%)
Study	Treatment arm	Sample size	Male	Female	Median (range)	ECOG 0	ECOG 1	Head/neck	cT1-2	cT3-4	cN1
Golcher et al. (2015)	Upfront surgery	33	17 (51.5)	16 (48.4)	65.1 (46–73)	22 (66.7)^@	11 (33.3)^@	33 (100.0)^¶	16 (48.5)	17 (51.5)	3 (9.1)
	Neoadjuvant treatment (CRT)	33	18 (54.5)	15 (45.5)	62.5 (33–76)	27 (81.8)^@	6 (18.2)^@	33 (100.0)^¶	16 (48.5)	17 (51.5)	11 (33.3)
Casadei et al. (2015)	Upfront surgery	20	14 (70.0)	6 (30.0)	67.5 (48–79)	—	—	20 (10.0)	1 (5.0)	19 (95.0)	16 (80.0)
	Neoadjuvant treatment (CRT)	18	8 (44.4)	10 (55.6)	71.5 (51–78)	—	—	15 (83.3)	8 (44.4)	10 (55.6)	14 (77.8)
Birrer et al. (2022)	Upfront surgery	21	—	—	—	—	—	21 (100.0)^¶	—	—	NA
	Neoadjuvant treatment (GEMOX)	17	—	—	—	—	—	17 (100.0)^¶	—	—	NA
Versteijne et al. (2020)	Upfront surgery	127	74 (58.3)	53 (41.7)	67 (60–73)^#	49 (38.6)	78 (61.4)	117 (92.1)	—	—	44 (34.6)
	Neoadjuvant treatment (CRT)	119	64 (53.8)	55 (46.2)	66 (59–71)^#	69 (58.0)	49 (41.2)	97 (81.5)	—	—	27 (22.7)
Jang et al. (2018)	Upfront surgery	23	15 (65.2)	8 (34.8)	58.9^$ (11.3)^&	17 (73.9)	4 (17.4)	17 (73.9)	0 (0.0)	23 (100.0)	15 (65.2)
	Neoadjuvant treatment (CRT)	27	17 (63.0)	10 (37.0)	59.4^$ (8.4)^&	18 (66.7)	9 (33.3)	23 (85.2)	0 (0.0)	27 (100.0)	10 (37.0)
Reni et al. (2018)	Upfront surgery (GEM)	26	14 (53.8)	12 (46.2)	65 (37–74)	24 (92.3)^@	2 (7.7)^@	25 (96.2)	—	—	NA
	Upfront surgery (PEXG)	30	13 (43.3)	17 (56.7)	68 (49–75)	27 (90.0)^@	3 (10.0)^@	26 (86.7)	—	—	NA
	Neoadjuvant treatment	32	25 (78.1)	7 (21.9)	64 (39–75)	29 (90.6)^@	3 (9.4)^@	28 (87.5)	—	—	NA
Unno et al. (2025)	Upfront surgery	179	95 (53.1)	84 (46.9)	66^$ (7.9)^&	169 (94.4)	10 (5.6)	129 (72.1)	47 (26.3)	132 (73.7)	39 (21.8)
	Neoadjuvant treatment (GS)	182	96 (52.7)	86 (47.3)	67.3^$ (8.2)^&	176 (96.7)	6 (3.3)	134 (73.6)	52 (28.6)	130 (71.4)	39 (21.4)
Al-Batran et al. (2024)	Upfront surgery	21	11 (52.4)	10 (47.6)	62 (46–84)	13 (61.9)	8 (38.1)	—	10 (47.6)	9 (42.9)	9 (42.9)
	Neoadjuvant treatment (FOLFIRINOX)	19	12 (38.7)	7 (61.3)	65 (49–76)	12 (63.2)	7 (36.8)	—	10 (52.6)	8 (42.1)	10 (52.6)
Ghaneh et al. (2023)	Upfront surgery	31	12 (38.7)	19 (61.3)	61 (54–66)^#	16 (51.6)	15 (48.4)	31 (100.0)^¶	—	—	NA
	Neoadjuvant treatment (CRT)	16	7 (43.8)	9 (56.3)	66 (59–69)^#	9 (56.3)	7 (43.8)	16 (100.0)^¶	—	—	NA
	Neoadjuvant treatment (GEM-CAP)	19	9 (47.4)	10 (52.6)	63 (58–70)^#	6 (31.6)	13 (68.4)	19 (100.0)^¶	—	—	NA
	Neoadjuvant treatment (FOLFIRINOX)	20	10 (50.0)	10 (50.0)	64 (63–70)^#	8 (40.0)	12 (60.0)	20 (100.0)^¶	—	—	NA
Seufferlein et al. (2023)	Upfront surgery	59	37 (62.7)	22 (37.3)	68 (41–88)	46 (78.0)	13 (22.0)	46 (78.0)	29 (49.2)	27 (45.8)	22 (37.3)
	Neoadjuvant treatment (GEM-NAB)	59	34 (57.6)	25 (42.4)	65 (48–82)	46 (78.0)	13 (22.0)	41 (69.5)	34 (57.6)	24 (40.7)	20 (33.9)
Schwarz et al. (2025)	Upfront surgery	28	19 (67.9)	9 (32.1)	68.1 (60.5–75.2)^#	24 (85.7)	4 (14.3)	20 (71.4)	—	—	1 (3.6)
	Neoadjuvant treatment (FOLFOX)	50	26 (52.0)	24 (48.0)	67.7 (62.1–73.3)^#	32 (64.0)	17 (34.0)	42 (84.0)	—	—	9 (18.0)
	Neoadjuvant treatment (FOLFIRINOX)	72	41 (56.9)	31 (43.1)	68.5 (61.3–71.9)^#	46 (63.9)	25 (34.7)	61 (84.7)	—	—	8 (11.1)
Labori et al. (2024)	Upfront surgery	63	27 (42.9)	36 (57.1)	66 (57–72)^#	51 (81.0)	12 (19.0)	63 (100.0)^¶	—	—	NA
	Neoadjuvant treatment (FOLFIRINOX)	77	43 (55.8)	34 (44.2)	68 (60–72)^#	64 (83.1)	13 (16.9)	77 (100.0)^¶	—	—	NA
Kumar et al. (2024)	Upfront surgery	39	19 (48.7)	20 (51.3)	61 (54–66)^#	12 (30.8)	27 (69.2)	39 (100.0)^¶	29 (74.4)	10 (25.6)	18 (46.2)
	Neoadjuvant treatment (GnP + CRT)	41	23 (56.1)	18 (43.9)	58.5 (52–64)^#	8 (19.5)	33 (80.5)	41 (100.0)^¶	22 (53.7)	19 (46.3)	15 (36.6)

All studies used AJCC 7th edition, except for the studies by Golcher et al, Casadei et al, and Kumar et al. The studies by Al-Batran et al and Seufferlein et al have missing data regarding clinical T and N staging.

Originally in Karnofsky Performance Status Scale and converted to ECOG Performance Status using the ECOG-ACRIN and ESMO conversion tables.

As per inclusion criteria.

Interquartile range.

Mean.

Standard deviation.

Risk of bias

Supplemental Figures 2 to 9 present the risk of bias for individual studies across specific outcomes. Most trials were judged to have some concerns regarding risk of bias. For overall survival, a greater proportion of studies were rated at low risk of bias, reflecting the objectivity of death as an endpoint and its reduced susceptibility to lack of blinding in surgical RCTs. The study by Kumar et al. was judged to be at high risk of bias, as outcome data were reported only per-protocol, which could have significantly impacted study results. Detailed justifications for each of the risk of bias judgments can be found in Supplemental Tables 18 to 22.

Results of individual studies and synthesis

Outcome definitions according to each trial are presented in Supplemental Tables 23 to 26. Data on overall survival from individual studies are summarized in Supplemental Table 27. In the primary analysis, 12 studies were included in the meta-analysis of overall survival. Neoadjuvant treatment was associated with a non-statistically significant improvement in overall survival (HR = 0.79; 95% CI, 0.58–1.10)—Figure 2. The 95% prediction interval (95% PI; 0.33–1.91) and the I² statistics (65%) indicate substantial heterogeneity for this outcome.

Figure 2.

Pooled estimate of hazard ratio (and 95% CI) for overall survival—intention-to-treat population.

Data from individual studies on DFS and R0 resection rate are summarized in Supplemental Tables 28 and 29, respectively. In the primary analysis, 11 studies were included in the meta-analysis of DFS. Neoadjuvant therapy was associated with a statistically significant improvement in DFS (HR = 0.79; 95% CI, 0.66–0.93)—Figure 3. The 95% PI (0.60–1.03) and the I2 statistics (23%) suggest low heterogeneity for this outcome. In the primary analysis of R0 resection rate, 11 studies were included. Neoadjuvant therapy significantly increased the likelihood of achieving an R0 resection (OR = 1.51; 95% CI, 1.04–2.19)—Figure 4. The 95% PI (1.04–2.19) and the I² statistics (47%) suggest low to moderate heterogeneity for this outcome.

Figure 3.

Pooled estimate of hazard ratio (and 95% CI) for disease-free survival—intention-to-treat population.

Figure 4.

Pooled estimate of odds ratio (and 95% CI) for R0 resection rate—intention-to-treat population.

Data from individual studies on postoperative mortality and morbidity among patients undergoing resection are summarized in Supplemental Table 30. In the primary analysis, five studies reported data on major postoperative morbidity rates (after resection). Neoadjuvant therapy was associated with a non-statistically significant increase in major morbidity after resection (OR = 1.27; 95% CI, 0.61–2.62)—Figure 5. The 95% PI (0.61–2.62) suggests significant heterogeneity in the analysis of this outcome. Meta-analyses of postoperative mortality, overall morbidity, and pancreatic fistula rates were not performed due to heterogeneity in outcome definition and/or limited number of studies with available data. Across studies, no significant differences in postoperative mortality were observed between patients undergoing neoadjuvant treatment and those treated with upfront surgery. For postoperative morbidity, some trials suggested numerically higher complication rates for patients undergoing upfront surgery,^22,27 while others suggested increased complication rates in the neoadjuvant treatment arms.^25,32,33 Regarding postoperative pancreatic fistula, several studies reported higher rates following upfront surgery.^26,29,35 Importantly, none of the studies found a higher incidence of pancreatic fistula in patients treated with neoadjuvant therapy.

Figure 5.

Pooled estimate of odds ratio (and 95% CI) for major postoperative morbidity rate—intention-to-treat population.

Supplemental Table 31 summarizes the data on the heterogeneity measures for the outcomes included in the meta-analytical syntheses of the primary analysis.

Sensitivity analyses

Supplemental Table 32 presents the results of the meta-analyses conducted using the Paule–Mandel method for τ² estimation and the DerSimonian–Laird method for the calculation of the 95% CI of the mean effect. No significant differences were observed in any outcome when using these alternative statistical approaches.

In sensitivity analyses including the study by Kumar et al., no significant impact was observed on overall survival (HR = 0.79; 95% CI, 0.60–1.05) or DFS (HR = 0.77; 95% CI, 0.67–0.89)—Supplemental Figures 10 and 11, respectively. However, its inclusion reduced the estimated mean effect of neoadjuvant treatment on R0 resection rate, with the 95% CI crossing the line of null effect (OR = 1.37; 95% CI, 0.80–2.32)—Supplemental Figure 12. Moreover, inclusion of this study increased the 95% PI (0.37–5.01) and the I² statistic (59%), suggesting greater heterogeneity with its addition.

Trials that completed patient enrollment demonstrated numerically larger mean treatment effects for overall survival (HR = 0.72; 95% CI, 0.48–1.07 vs HR = 1.04; 95% CI, 0.42–2.56), DFS (HR = 0.76; 95% CI, 0.60–0.94 vs HR = 0.93; 95% CI, 0.59–1.49), and R0 resection rate (OR = 1.64; 95% CI, 1.12–2.41 vs OR = 0.84; 95% CI, 0.07–10.21). However, formal tests for subgroup differences did not show statistical significance (p = 0.26, 0.22, and 0.27, respectively)—Supplemental Figures 13 to 15.

Subgroup analyses

In subgroup analyses, neoadjuvant treatment was associated with greater benefit among patients with anatomical borderline resectable disease compared with those with resectable disease. This effect was observed for overall survival (HR = 0.55; 95% CI, 0.31–0.98 vs HR = 0.85; 95% CI, 0.66–1.10; p = 0.04), DFS (HR = 0.57; 95% CI, 0.34–0.97 vs HR = 0.82; 95% CI, 0.66–1.03; p < 0.01), and R0 resection rate (OR = 5.33; 95% CI, 0.38–75.12 vs OR = 1.40; 95% CI, 1.01–1.96; p = 0.03)—Supplemental Figures 16 to 18.

No significant differences in efficacy outcomes were observed between trials evaluating neoadjuvant chemotherapy and those evaluating neoadjuvant chemoradiation. This was consistent across overall survival (HR = 0.86; 95% CI, 0.51–1.45 vs HR = 0.68; 95% CI, 0.47–0.98; p = 0.35), DFS (HR = 0.80; 95% CI, 0.61–1.04 vs HR = 0.77; 95% CI, 0.56–1.06; p = 0.78), and R0 resection rate (OR = 1.32; 95% CI, 0.82–2.13 vs OR = 1.94; 95% CI, 0.89–4.23; p = 0.27)—Supplemental Figures 19 to 21.

Finally, treatment with neoadjuvant FOLFIRINOX, compared with other regimens, was associated with inferior effects on overall survival (HR = 1.42; 95% CI, 0.60–3.34 vs HR = 0.72; 95% CI, 0.61–0.84; p = 0.01). However, no significant differences between groups were observed for DFS (HR = 1.06; 95% CI, 0.53–2.12 vs HR = 0.74; 95% CI, 0.67–0.82; p = 0.11) or R0 resection rate (OR = 1.02; 95% CI, 0.26–3.99 vs OR = 1.72; 95% CI, 1.16–2.55; p = 0.26)—Supplemental Figures 22 to 24.

Non-reporting bias

Supplemental Figures 25 to 28 present funnel plots for overall survival, DFS, R0 resection rate, and major postoperative morbidity rate. Overall, there was no evidence of selective reporting bias across these outcomes. Similarly, regression-based tests for publication bias did not identify significant asymmetry—Supplemental Table 33.

Summary of findings

The summary of findings for the primary analyses across different outcomes is presented in Tables 2 and 3.

Table 2.

SoF of outcomes with meta-analytical synthesis.

Neoadjuvant treatment compared to upfront surgery for resectable or borderline resectable pancreatic adenocarcinoma
Patient or population: Pancreatic adenocarcinomaSetting: Resectable or borderline resectable, treatment-naïveIntervention: Neoadjuvant TreatmentComparison: Upfront Surgery
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with upfront surgery	Risk with neoadjuvant treatment	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
OS assessed with: 3 years	Moderate		HR 0.79 (0.58 to 1.10) (death)	1411 (12 RCTs)	⨁Very low^a,b,c	Neoadjuvant treatment may increase/have little to no effect on OS but the evidence is very uncertain.
	17 per 100	25 per 100 (14 to 36)
DFS assessed with: 2 years	Moderate		HR 0.79 (0.66 to 0.93) (death or progression)	1371 (11 RCTs)	⨁⨁⨁Moderate^a,d,e	Neoadjuvant treatment likely increases DFS.
	15 per 100	22 per 100 (17–29)
R0RR	47 per 100	57 per 100 (48–66)	OR 1.51 (1.04–2.19)	1369 (11 RCTs)	⨁⨁⨁⨁High^a,f,g	Neoadjuvant treatment increases R0RR.
MPOMbR (after resection)	24 per 100	28 per 100 (16–45)	OR 1.27 (0.61–2.62)	502 (5 RCTs)	⨁Very low^h,i,j	The evidence is very uncertain about the effect of neoadjuvant treatment on MPOMbR (after resection).

GRADE Working Group grades of evidence: High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimated effect.

None of the studies in the primary analysis has a high risk of bias.

Absolute effects difference in OS at 3 years includes zero (95% CI = −3 to 19). OIS achieved.

Significant heterogeneity as assessed by the Prediction Interval (95% PI = 0.33–1.91); I2 = 65%. This means some populations might have no or minimal benefit from neoadjuvant treatment. Some populations might even be harmed by this therapy.

Absolute effects difference in DFS at 2 years does not include zero (95% CI = 2 to 14). OIS achieved.

Low to moderate heterogeneity as assessed by the Prediction Interval (95% PI = 0.60–1.03); I2 = 23%. This means some populations might have no or minimal benefit from neoadjuvant treatment.

Absolute effects difference in R0RR does not includes zero (95% CI = 1 to 19). OIS achieved.

Low heterogeneity as assessed by the Prediction Interval (95% PI = 1.04–2.19). This means most populations are likely to benefit from neoadjuvant treatment.

In three out of five included studies, postoperative complication rates were evaluated either in the per-protocol population or as the treated population.

Absolute effects difference in major postoperative complication rate includes zero (95% CI = −8 to 21). OIS possibly not achieved.

Significant heterogeneity as assessed by the Prediction Interval (95% PI = 0.61–2.62); I2 = 18%. This means some populations might benefit from neoadjuvant treatment while others might be harmed by neoadjuvant treatment.

The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; MPOMbR, major postoperative morbidity rate; OIS, optimal information size; OR, odds ratio; OS, overall survival; R0RR, R0 resection rate; SoF, summary of findings.

Table 3.

SoF of outcomes without meta-analytical synthesis.

Neoadjuvant treatment compared to upfront surgery for resectable or borderline resectable pancreatic adenocarcinoma
Patient or population: Pancreatic adenocarcinomaSetting: Resectable or borderline resectable, treatment-naïveIntervention: Neoadjuvant TreatmentComparison: Upfront surgery
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No of participants (studies)	Comments
Outcomes	Risk with upfront surgery	Risk with neoadjuvant treatment	Relative effect (95% CI)	No of participants (studies)	Comments
POMtR	We did not perform a meta-analysis due to heterogeneity in the time horizon for assessing POMtR. We only present the absolute risks of postoperative mortality with neoadjuvant treatment vs upfront surgery: Golcher 2015 (0.0% vs 3.8%), Versteijne 2020 (3.0% vs 4.1%), Reni 2018 (0.0% vs 4.1%), Unno 2025 (0.0% vs 0.0%), Ghaneh 2023^# (3.3% vs 0.0%), Seufferlein 2023 (2.4% vs 6.5%), Schwarz 2025 (1.2% vs 0.0%), and Labori 2024 (4.8% vs 1.8%).		—	953^$ (8 RCTs)	The evidence is very uncertain regarding the effect of neoadjuvant therapy on the POMtR after resection.^a
POMbR	We did not perform a meta-analysis due to the limited number of studies (4). We only present the absolute risks of postoperative morbidity with neoadjuvant treatment vs upfront surgery: Golcher 2015 (87.5% vs 88.5%), Reni 2018 (59.3% vs 63.3%), Unno 2025 (45.9% vs 49.4%), and Labori 2024 (50.8% vs 46.4%).		—	550^$ (4 RCTs)	The evidence is uncertain regarding the effect of neoadjuvant therapy on the POMbR after resection.^b
POPFR	We did not perform a meta-analysis due to heterogeneity in the classification of postoperative pancreatic fistulas. We only present the absolute risks of postoperative pancreatic fistula: Versteijne 2020 (0.0% vs 9.2%), Jang 2018 (0.0% vs 5.6%), Reni 2018 (11.1% vs 12.2%), Al-Batran 2024 (0.0% vs 11.8%), Ghaneh 2023 (0.0% vs 3.6%), and Seufferlein 2023 (14.6% vs 15.2%).		—	437^$,^@ (6 RCTs)	The evidence is uncertain regarding the effect of neoadjuvant therapy on the POPFR after resection.^c

GRADE Working Group grades of evidence—High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimated effect.

The different POMtRs after resection, with contradictory results across different studies and the relative rarity of events, suggest that there is much uncertainty regarding this outcome.

Despite the similarity between postoperative complication rates after resection in the neoadjuvant treatment and upfront surgery arms, the number of patients in this analysis is likely smaller than the required OIS. Therefore, it can be inferred that there is uncertainty regarding this outcome.

Most studies suggest a lower postoperative pancreatic fistula rate after resection in patients who underwent neoadjuvant treatment. However, the number of patients in this analysis is limited and likely smaller than the required OIS.

The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

90-Day mortality.

Submitted to resection.

The study by Kumar et al. was excluded due to its high risk of bias.

CI, confidence interval; HR, hazard ratio; OIS, optimal information size; OR, odds ratio; POMbR, postoperative morbidity rate; POMtR, postoperative mortality rate; POPFR, postoperative pancreatic fistula rate; SoF, summary of findings.

Discussion

In this updated meta-analysis of RCTs assessing neoadjuvant therapy in the management of resectable or anatomical borderline resectable PDAC, preoperative treatment was not associated with a statistically significant improvement in overall survival compared with upfront surgery. However, neoadjuvant therapy was associated with improved DFS and R0 resection rate, without an increase in the incidence of severe postoperative complications.

Although the improvements in DFS and R0 resection rate are encouraging, the absence of an overall survival benefit highlights the ongoing uncertainty regarding the true effect of neoadjuvant therapy in this setting. Indeed, the clinical significance of improvements in relapse-related endpoints in the absence of a demonstrable overall survival benefit remains uncertain. It has yet to be established whether DFS and related measures constitute valid surrogate endpoints for overall survival in the neoadjuvant setting. This consideration is particularly pertinent to our meta-analysis, given the potential bias arising from the aggregation of heterogeneous relapse-related outcomes under the designation of DFS, as well as the variability in endpoint definitions across trials. In addition, differences in post-relapse management strategies and the possibility of treatment crossover may further weaken the association between relapse-related outcomes and overall survival, thereby warranting a cautious interpretation of DFS findings.

While it is possible that the failure to detect an improvement in overall survival stems from the lack of statistical power, this analysis has a sample size many times larger than that of ongoing phase III RCTs assessing the role of neoadjuvant FOLFIRINOX in patients with resectable PDAC (both of which are not included in this systematic review).^36,37 Therefore, we believe the optimal information size was achieved, and other factors might be responsible for these results. Indeed, the analysis of overall survival showed strong meta-analytical heterogeneity, which is possibly behind the lack of survival benefit in our meta-analysis. Potential sources of heterogeneity included differences in interventions (chemotherapy vs chemoradiation), variability in enrolled populations (resectable vs anatomical borderline resectable), and premature trial termination due to slow accrual.³⁸ Importantly, methodological concerns such as inadequate randomization and publication bias were not evident.

Sensitivity analyses demonstrated consistent results across alternative statistical models, supporting the robustness of the primary findings. Likewise, inclusion of the study at high risk of bias had negligible influence on the pooled estimates, with the exception of the R0 resection rate. Although tests for subgroup differences were not statistically significant, pooled analyses of trials prematurely terminated due to slow recruitment did not indicate improvement in outcomes with neoadjuvant therapy. This may reflect random variations in effect estimates occurring during early patient accrual.³⁹ Importantly, these trials contributed relatively little statistical weight, suggesting minimal influence on the overall results.

The only subgroup analyses showing statistically significant tests for subgroup difference were the ones assessing the interaction between treatment sequence (neoadjuvant therapy vs upfront surgery) and resectability status (resectable vs anatomical borderline resectable). Despite minor differences in the definition of resectability across trials, greater relative benefits in overall survival, DFS, and R0 resection rate were observed among patients with anatomical borderline resectable PDAC. These patients are at high risk of microscopic positive margins (R1 resection),⁴⁰ an established prognostic factor for patients with resected PDAC, regardless of the treatment sequence.^41
–44 However, larger individual trials did not demonstrate significant within-trial differences in the benefit of neoadjuvant therapy according to resectability status. In both PREOPANC and Prep-02/JSAP-05 (both included in this systematic review), overall survival benefits associated with neoadjuvant therapy were comparable between patients with resectable and anatomically borderline resectable disease. Both studies indicated that patients with larger tumors (>3–4 cm) derived greater benefit from neoadjuvant therapy,^25,28 suggesting that tumor size rather than resectability status may be the main anatomical determinant of clinical benefit. Consistently, a recent large retrospective analysis of patients with resectable left-sided PDAC reported that the magnitude of benefit from neoadjuvant therapy increased with larger tumor size.⁴⁵ Although our subgroup analyses suggest a greater benefit of neoadjuvant therapy among patients with borderline resectable pancreatic cancer, these findings are based on a limited number of trials, are characterized by wide confidence intervals, and are affected by heterogeneity in the definitions of resectability. Moreover, two individual studies included in our synthesis did not demonstrate a clear differential effect according to resectability status. Taken together, these considerations indicate that the observed subgroup effect should be interpreted as exploratory and hypothesis-generating rather than conclusive.

Another noteworthy finding of our investigation concerns the role of neoadjuvant chemoradiation. Adjuvant radiotherapy has not been associated with survival benefits after upfront surgery.^46
–50 Moreover, PDAC is a systemic disease from its onset, with polychemotherapy regimens demonstrating established efficacy in the adjuvant, locally advanced, and metastatic settings. Accordingly, it could be hypothesized that neoadjuvant chemotherapy would provide superior outcomes compared with neoadjuvant chemoradiation in resectable or borderline resectable PDAC. However, our analyses did not demonstrate significant differences in efficacy between neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy in this setting. While these findings were largely driven by trials evaluating neoadjuvant chemoradiotherapy in borderline resectable PDAC, more recent studies have failed to demonstrate superior clinical outcomes for patients receiving chemotherapy alone. In both the PREOPANC-2 and JASPAC 04 trials, which were published before the final search but were not included in our systematic review because these investigations compared different neoadjuvant therapy strategies, neoadjuvant FOLFIRINOX or gemcitabine plus S-1 were not associated with improved overall survival compared with neoadjuvant chemoradiotherapy.^51,52 Notably, in the PREOPANC-2 study (not included in our review), subgroup analyses did not identify any population with a clear benefit from chemoradiation in terms of overall survival.⁵¹ In addition, retrospective evidence indicates that neoadjuvant chemotherapy and neoadjuvant chemoradiation yield similar overall and DFS outcomes, although radiotherapy-containing approaches may confer improved local control.^53,54 Altogether, while the absence of survival benefit with neoadjuvant chemotherapy observed in this meta-analysis may, in part, reflect limitations in trial design, our results indicate that chemoradiation remains a reasonable option in the neoadjuvant setting, particularly for patients less fit to undergo intensive multi-agent chemotherapy regimens. In addition, for patients at very high risk of R1 resection, neoadjuvant chemoradiation may be considered—particularly in the absence of clinically involved lymph nodes—given the increased risk of locoregional recurrence following margin-positive surgery and the potential for radiotherapy to improve local control.⁵⁵

Based on evidence from metastatic and adjuvant settings, FOLFIRINOX has been considered by many as the most active systemic regimen in PDAC. Consequently, it has been widely adopted in the neoadjuvant setting.^56
–59 Despite this, our pooled analyses did not demonstrate a survival advantage of neoadjuvant FOLFIRINOX over upfront surgery in patients with resectable or borderline resectable PDAC. This lack of observed benefit might be a consequence of the limited sample size, as three of the four available trials enrolled only small patient cohorts in the neoadjuvant FOLFIRINOX arm.^29,30,32 Moreover, the results of our pooled analyses were largely influenced by the NorPACT-1 trial, which has been criticized for its short duration of preoperative therapy and high rates of non-adherence to the planned FOLFIRINOX regimen.³³ However, caution is warranted in interpreting these findings, as they likely reflect limitations of the available evidence and should not be regarded as definitive proof of a lack of benefit of FOLFIRINOX in the neoadjuvant setting. Other studies highlight the lack of superiority of FOLFIRINOX over other chemotherapy regimens for patients with resectable or borderline resectable PDAC. Indeed, RCTs that compared FOLFIRINOX with gemcitabine plus nab-paclitaxel for patients with resectable (SWOG S1515) and anatomical borderline resectable (NUPAT-1) PDAC question the notion of FOLFIRINOX as the definitive standard neoadjuvant regimen (both not included in our systematic review).^60,61 Furthermore, preliminary results from the CASSANDRA/PACT-21 trial reported at the 2025 Annual Meeting from the American Society of Clinical Oncology (not included in our systematic review as this trial compares two different neoadjuvant chemotherapy regimens) suggested improved event-free survival in patients randomized to neoadjuvant PAXG (cisplatin, nab-paclitaxel, capecitabine, and gemcitabine) compared with those receiving FOLFIRINOX.⁶² While the performance of FOLFIRINOX in these trials appears disappointing, its limited efficacy may be partly explained by underlying molecular alterations driving PDAC development and progression. Recent evidence indicates that patients with low GATA6 expression—a transcription factor linked to early pancreatic embryogenesis and compatible with a basal-like gene expression profile—do not benefit from neoadjuvant FOLFIRINOX.⁶³ Furthermore, tumors harboring SMAD4 mutations appear more prone to disease progression under FOLFIRINOX (but not under gemcitabine plus nab-paclitaxel) in the neoadjuvant setting,^64,65 suggesting that certain molecularly defined subgroups of patients may not only fail to benefit but could even be harmed by this regimen. While further evidence is needed to clarify the role of neoadjuvant FOLFIRINOX in resectable and borderline resectable PDAC, the incorporation of tumor molecular features into treatment decision-making may prove essential for optimizing outcomes in this population.

Very recently, a Chinese single-center phase III randomized clinical trial (CISPD-1) was published, comparing two treatment strategies in the context of resectable PDAC: a neoadjuvant approach (one cycle of gemcitabine plus nab-paclitaxel at standard doses followed by two cycles of modified FOLFIRINOX) versus upfront surgery followed by adjuvant therapy (in which adjuvant chemotherapy consisted preferentially of gemcitabine plus capecitabine).⁶⁶ This study had previously been identified in our systematic search, with an “ongoing” status at the time of the last search, and was not included in our systematic review and meta-analysis as the full text was available only in October 2025. After a median follow-up of 18.7 months, neoadjuvant treatment was associated with a significant improvement in event-free survival (15.3 vs 10.9 months; HR = 0.71; 95% CI, 0.54–0.93; p = 0.0136) and a trend toward longer median overall survival (35.4 vs 27.2 months; HR = 0.73; 95% CI, 0.53–1.00; p = 0.0477). Although the alternation of these two chemotherapy regimens has a theoretical rationale–stemming from changes in tumor gene expression profiles following exposure to different treatment regimens⁶⁷—and empirical support from the R0 resection rate results of the German NEOLAP trial,⁶⁸ this is the second Asian study demonstrating a survival benefit associated with short-course chemotherapy in the setting of predominantly resectable disease. The other study, JSAP-02/Prep-05 (included in our systematic review),²⁸ also employed a combination of gemcitabine with a fluoropyrimidine, and together with the findings of the CASSANDRA/PACT-21 trial (not included in our systematic review),⁶² may point toward the necessity of incorporating gemcitabine and a fluoropyrimidine in the composition of the neoadjuvant therapy. However, based on the findings of our systematic review and meta-analysis, it remains uncertain whether neoadjuvant therapy confers an overall survival benefit. Moreover, data from more recent trials should be considered hypothesis generating rather than confirmatory.

In this investigation, we found no evidence of increased postoperative morbidity and mortality associated with neoadjuvant therapy. The pooled rates of severe complications (Clavien–Dindo grade ⩾3) overlapped between patients receiving neoadjuvant treatment and those undergoing upfront surgery. However, given the heterogeneity in the definitions of postoperative pancreatic fistula (POPF) across trials, we refrained from pooling fistula rates in the meta-analysis. However, inspection of within-trial results suggests that neoadjuvant therapy is not associated with increased rates of clinically relevant POPF, a feared complication due to its association with short-term and long-term survival.^69
–71 Indeed, in some trials, patients who received preoperative therapy experienced numerically lower rates of POPF. This finding is consistent with results from multiple retrospective studies and meta-analyses reporting decreased rates of POPF among patients undergoing neoadjuvant therapy,^71
–73 especially neoadjuvant chemoradiation.^74,75 Therefore, the current debate regarding the role of neoadjuvant therapy for localized PDAC appears to rest more on its efficacy rather than on safety concerns.

Recently, the Trans-Atlantic Pancreatic Surgery (TAPS) Consortium validated the classification of localized PDAC based on anatomical, biological, and clinical factors.⁷⁶ Within this framework, several authors have proposed that neoadjuvant therapy could be particularly valuable for patients with resectable PDAC who are at high risk of early relapse or futile pancreatectomy, as suggested by biological markers such as elevated CA 19-9 levels.⁷⁷ Interestingly, however, none of the available randomized trials with subgroup analyses have demonstrated an interaction between baseline CA 19-9 and the benefit from neoadjuvant therapy—even in studies in which CA 19-9 was a stratification factor at randomization, such as Prep-02/JSAP-05 (included in our systematic review).^25,28 Multiple large randomized clinical trials comparing neoadjuvant therapy to upfront surgery in this setting are currently ongoing—Supplementary Table 34. The results of the Alliance A021806 (NCT04340141; planned sample size = 352 patients), PREOPANC-3 (NCT04927780; planned sample size = 378 patients), and NeoFOL-R (NCT05529940, planned sample size = 609 patients) are expected to clarify the contribution of biological and clinical features to treatment selection for patients with resectable PDAC (none of them included in our systematic review). In particular, randomization in the PREOPANC-3 is stratified by baseline CA 19-9 level,³⁶ and we anticipate this trial will provide critical insight into whether patients with CA 19-9 > 300 UI/mL—representing a biologically defined high-risk subgroup—derive greater benefit from neoadjuvant therapy, thereby informing a more personalized treatment strategy.

Our study has limitations. Some important outcomes had missing data, and several coefficients required indirect estimation. In addition, due to clinical heterogeneity, estimates for certain endpoints could not be aggregated, and we acknowledge minor between-trial differences in the definitions of DFS, progression-free survival, and event-free survival may have influenced the pooled estimates of the relapse-related outcome. Also, between-trial differences in neoadjuvant and adjuvant regimens introduced additional clinical heterogeneity. Although we conducted multiple sensitivity and subgroup analyses, no correction for multiple testing was applied, which may increase the risk of type I error. Furthermore, variability in per-protocol population definitions across trials, together with missing per-protocol data in several studies, precluded as-treated (rather than intention-to-treat) analyses—an approach that some experts consider particularly relevant in the neoadjuvant setting for PDAC. Nevertheless, our study has strengths. We employed a highly sensitive search strategy combined with robust meta-analytical methods. We also conducted multiple sensitivity and subgroup analyses to explore heterogeneity in depth. Importantly, we systematically collected data on postoperative complications—outcomes frequently overlooked in systematic reviews of randomized controlled trials in this field.

Conclusion

To conclude, neoadjuvant therapy is associated with improved R0 resection rate and DFS in comparison with upfront surgery for patients with resectable or borderline resectable PDAC. The benefit of neoadjuvant therapy seems to be more pronounced for patients with anatomical borderline resectable PDAC. Also, the activity of FOLFIRINOX in the adjuvant setting so far has not been clearly demonstrated in the neoadjuvant setting. In light of the limitations of the available evidence, the results should be interpreted with caution. Ongoing large-scale randomized trials are expected to further clarify the role of neoadjuvant strategies in PDAC.

Supplemental Material

sj-docx-1-tam-10.1177_17588359261449077 – Supplemental material for Neoadjuvant therapy versus upfront surgery followed by adjuvant chemotherapy in resectable or borderline resectable PDAC: a systematic review and meta-analysis of RCTs

Supplemental material, sj-docx-1-tam-10.1177_17588359261449077 for Neoadjuvant therapy versus upfront surgery followed by adjuvant chemotherapy in resectable or borderline resectable PDAC: a systematic review and meta-analysis of RCTs by Victor Hugo Fonseca de Jesus, Marcos Pedro Guedes Camandaroba, Álvaro Lopes de Oliveira and Rachel P. Riechelmann in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

We thank Cristiane Rufino Macedo for the assistance in building the search strategy of this systematic review.

Declarations

ORCID iDs

Victor Hugo Fonseca de Jesus

Rachel P. Riechelmann

Supplemental material

Supplemental material for this article is available online.

References

Saika

Charvat

Projection of the number of new cases of pancreatic cancer in the world. Jpn J Clin Oncol 2024; 54(6): 737–738.

Rahib

Wehner

Matrisian

, et al. Estimated projection of US cancer incidence and death to 2040. JAMA Netw Open 2021; 4(4): e214708.

Koo

Hamilton

Walter

, et al. Symptom signatures and diagnostic timeliness in cancer patients: a review of current evidence. Neoplasia 2018; 20(2): 165–174.

Mills

Birt

Emery

, et al. Understanding symptom appraisal and help-seeking in people with symptoms suggestive of pancreatic cancer: a qualitative study. BMJ Open 2017; 7(9): e015682.

Neoptolemos

Stocken

Friess

, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Eng J Med 2004; 350(12): 1200–1210.

Oettle

Neuhaus

Hochhaus

, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013; 310(14): 1473–1481.

Conroy

Castan

Lopez

, et al. Five-year outcomes of FOLFIRINOX vs Gemcitabine as adjuvant therapy for pancreatic cancer: a randomized clinical trial. JAMA Oncol 2022; 8(11): 1571–1578.

Palmer

Jackson

Springfeld

, et al. Pancreatic adenocarcinoma: long-term outcomes of adjuvant therapy in the ESPAC4 phase III trial. J Clin Oncol 2025; 43(10): 1240–1253.

de Jesus

VHF

Riechelmann

. Current treatment of potentially resectable pancreatic ductal adenocarcinoma: a medical oncologist’s perspective. Cancer Control 2023; 30: 10732748231173212.

10.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71.

11.

Ouzzani

Hammady

Fedorowicz

, et al. Rayyan—a web and mobile app for systematic reviews. Syst Rev 2016; 5(1): 210.

12.

Dindo

Demartines

Clavien

PA.

Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240(2): 205–213.

13.

Bassi

Marchegiani

Dervenis

, et al. The 2016 update of the international study group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surgery 2017; 161(3): 584–591.

14.

Sterne

JAC

Savović

Page

, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: l4898.

15.

Boutron

Page

Higgins

JPT

, et al. Considering bias and conflicts of interest among the included study. In: Higgins JPT

Chandler

Cumpston

Page

Welch

(eds.) Cochrane handbook fos systematic reviews of interventions second ed. Hoboken, NJ: Wiley-Blackwell, 2019, pp. 190–192.

16.

Guyot

Ades

Ouwens

, et al. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan–Meier survival curves. BMC Med Res Methodol 2012; 12: 9.

17.

Tierney

Stewart

Ghersi

, et al. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 2007; 8: 16.

18.

Palmer

Stocken

Hewitt

, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol 2007; 14(7): 2088–2096.

19.

Schünemann

Higgins

Vist

, et al. Completing ‘Summary of findings’ tables and grading the certainty of the evidence. In: Higgins JPT

Chandler

Cumpston

Page

Welch

(eds.) Cochrane handbook for systematic reviews of interventions. 2nd ed. Oxford (UK): WileyBlackwell; 2019, pp. 375–402.

20.

Chen

Zhang

, et al. Sequential use of nab-paclitaxel plus gemcitabine and mFOLFIRINOX as neoadjuvant chemotherapy for resectable pancreatic cancer: a randomizedcontrol study (the CISPD-1 study). Pancreas 2024; 53(10): e856.

21.

Tachezy

Gebauer

Yekebas

, et al. Failure of a multi-centric clinical trial investigating neoadjuvant radio-chemotherapy in resectable pancreatic carcinoma (NEOPA-NCT01900327)-which lessons are learnt? Cancers (Basel) 2023; 15(17): 4262.

22.

Golcher

Brunner

Witzigmann

, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol 2015; 191(1): 7–16.

23.

Casadei

Di Marco

Ricci

, et al. Neoadjuvant chemoradiotherapy and surgery versus surgery alone in resectable pancreatic cancer: a single-center prospective, randomized, controlled trial which failed to achieve accrual targets. J Gastrointest Surg 2015; 19(10): 1802–1812.

24.

Birrer

Golcher

Casadei

, et al. Neoadjuvant Therapy for resectable pancreatic cancer: a new standard of care. Pooled data from 3 randomized controlled trials. Ann Surg 2021; 274(5): 713–720.

25.

Versteijne

van Dam

Suker

, et al. Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the dutch randomized PREOPANC trial. J Clin Oncol 2022; 40(11): 1220–1230.

26.

Jang

Han

Lee

, et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg 2018; 268(2): 215–222.

27.

Reni

Balzano

Zanon

, et al. Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2–3 trial. Lancet Gastroenterol Hepatol 2018; 3(6): 413–423.

28.

Unno

Motoi

Matsuyama

, et al. Neoadjuvant Chemotherapy with Gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer: results of the randomized phase II/III Prep-02/JSAP05 trial. Ann Surg 2026; 283(1): 57–64.

29.

Goetze

Reichart

Bankstahl

, et al. Adjuvant gemcitabine versus neoadjuvant/adjuvant FOLFIRINOX in resectable pancreatic cancer: the randomized multicenter phase II NEPAFOX trial. Ann Surg Oncol 2024; 31(6): 4073–4083.

30.

Ghaneh

Palmer

Cicconi

, et al. Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2023; 8(2): 157–168.

31.

Seufferlein

Uhl

Kornmann

, et al. Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group. Ann Oncol 2023; 34(1): 91–100.

32.

Schwarz

Bachet

Meurisse

, et al. Neoadjuvant FOLF(IRIN)OX chemotherapy for resectable pancreatic adenocarcinoma: a multicenter randomized noncomparative phase II trial (PANACHE01 FRENCH08 PRODIGE48 study). J Clin Oncol 2025: 43: 1984–1996.

33.

Labori

Bratlie

Andersson

, et al. Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2024; 9(3): 205–217.

34.

Kumar

Singh

Khosla

, et al. A prospective randomized control study of neo-adjuvant chemo radiation followed by surgery versus upfront surgery in resectable and borderline resectable pancreatic head cancer: pilot study. J Cancer Res Ther 2024; 20(6): 1803–1810.

35.

van Dongen

Suker

Versteijne

, et al. Surgical complications in a multicenter randomized trial comparing preoperative chemoradiotherapy and immediate surgery in patients with resectable and borderline resectable pancreatic cancer (PREOPANC trial). Ann Surg 2022; 275(5): 979–984.

36.

van Dam

Verkolf

EMM

Dekker

, et al. Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial. BMC Cancer 2023; 23(1): 728.

37.

Chawla

Shi

, et al. Alliance A021806: a phase III trial evaluating perioperative versus adjuvant therapy for resectable pancreatic cancer. J Clin Oncol 2023; 41(suppl. 16): TPS4204.

38.

Fletcher

What is heterogeneity and is it important?

BMJ 2007; 334(7584): 94–96.

39.

Bassler

Briel

Montori

, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA 2010; 303(12): 1180–1187.

40.

Versteijne

Vogel

Besselink

, et al. Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg 2018; 105(8): 946–958.

41.

Leonhardt

Hank

Pils

, et al. Prognostic impact of resection margin status on survival after neoadjuvant treatment for pancreatic cancer: systematic review and meta-analysis. Int J Surg 2024; 110(1): 453–463.

42.

Javed

Habib

Mahmud

, et al. Prognostic factors in localized pancreatic ductal adenocarcinoma after neoadjuvant therapy and resection: a systematic review and meta-analysis. J Natl Cancer Inst 2025; 117(5): 840–867.

43.

von Fritsch

Duhn

Abdalla

TSA

, et al. An R0 resection margin does improve overall survival after PDAC resection- real-world evidence from 6.000 cases from the German cancer registry group. Eur J Surg Oncol 2025; 51(6): 109693.

44.

Strobel

Hank

Hinz

, et al. Pancreatic cancer surgery: the new R-status counts. Ann Surg 2017; 265(3): 565–573.

45.

Rangelova

Stoop

van Ramshorst

TME

, et al. The impact of neoadjuvant therapy in patients with left-sided resectable pancreatic cancer: an international multicenter study. Ann Oncol 2025; 36(5): 529–542.

46.

Klinkenbijl

Jeekel

Sahmoud

, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 1999; 230(6): 776–782.

47.

Van Laethem

Hammel

Mornex

, et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol 2010; 28(29): 4450–4456.

48.

Chang

Chiu

Chen

, et al. Randomized, phase III trial comparing adjuvant gemcitabine (Gem) versus Gem plus chemoradiation (CCRT) in curatively resected pancreatic ductal adenocarcinoma (PDAC): a Taiwan cooperative oncology group study. Ann Oncol 2018; 29(suppl. 8): mdy282.010–mdy282.010.

49.

Schmidt

Abel

Debus

, et al. Open-label, multicenter, randomized phase III trial of adjuvant chemoradiation plus interferon Alfa-2b versus fluorouracil and folinic acid for patients with resected pancreatic adenocarcinoma. J Clin Oncol 2012; 30(33): 4077–4083.

50.

Abrams

Winter

Goodman

, et al. NRG oncology/RTOG 0848: results after adjuvant chemotherapy ± chemoradiation for patients with resected periampullary pancreatic adenocarcinoma (PA). J Clin Oncol 2024; 42(suppl. 16): LBA 4005.

51.

Groot Koerkamp

Janssen

van Dam

, et al. LBA83 Neoadjuvant chemotherapy with FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy for borderline resectable and resectable pancreatic cancer (PREOPANC-2): a multicenter randomized controlled trial. Ann Oncol 2023; 34: S1323.

52.

Sugiura

Toyama

Fukutomi

, et al. Randomized phase II trial of chemoradiotherapy with S-1 versus combination chemotherapy with gemcitabine and S-1 as neoadjuvant treatment for resectable pancreatic cancer (JASPAC 04). J Hepatobiliary Pancreat Sci 2023; 30(11): 1249–1260.

53.

Murakami

Toyama

Fukutomi

, et al. Comparison between neoadjuvant chemoradiotherapy and chemotherapy for patients with resectable pancreatic cancer. Ann Surg Oncol 2025; Online ahead of print.

54.

Cloyd

Chen

H-C

Wang

, et al. Chemotherapy versus chemoradiation as preoperative therapy for resectable pancreatic ductal adenocarcinoma: a propensity score adjusted analysis. Pancreas 2019; 48(2): 216–222.

55.

Groot

Rezaee

, et al. Patterns, timing, and predictors of recurrence following pancreatectomy for pancreatic ductal adenocarcinoma. Ann Surg 2018; 267(5): 936–945.

56.

Janssen

Buettner

Suker

, et al. Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis. J Natl Cancer Inst 2019; 111(8): 782–794.

57.

Janssen

van Dam

Doppenberg

, et al. FOLFIRINOX as initial treatment for localized pancreatic adenocarcinoma: a retrospective analysis by the trans-atlantic pancreatic surgery consortium. J Natl Cancer Inst 2022; 114(5): 695–703.

58.

Cecchini

Salem

Robert

, et al. Perioperative modified FOLFIRINOX for resectable pancreatic cancer: a nonrandomized controlled trial. JAMA Oncol 2024; 10(8): 1027–1035.

59.

Murphy

Ryan

, et al. Total neoadjuvant therapy With FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol 2018; 4(7): 963–969.

60.

Sohal

DPS

Duong

Ahmad

, et al. Efficacy of perioperative chemotherapy for resectable pancreatic adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol 2021; 7(3): 421–427.

61.

Yamaguchi

Yokoyama

Fujii

, et al. Results of a phase II study on the use of neoadjuvant chemotherapy (FOLFIRINOX or GEM/nab-PTX) for borderline-resectable pancreatic cancer (NUPAT-01). Ann Surg 2022; 275(6): 1043–1049.

62.

Reni

Macchini

Orsi

, et al. Results of a randomized phase III trial of pre-operative chemotherapy with mFOLFIRINOX or PAXG regimen for stage I-III pancreatic ductal adenocarcinoma. J Clin Oncol 2025; 43(suppl. 17): LBA4004.

63.

McLaughlin

Jonker

Karanicolas

, et al. NeoPancONE: GATA6 expression as a predictor of benefit to peri-operative modified FOLFIRINOX in resectable pancreatic adenocarcinoma (r-PDAC): a multicentre phase II study. J Clin Oncol 2025; 43(suppl. 16): LBA4011.

64.

Ecker

Tao

Janssen

, et al. Genomic biomarkers associated with response to induction chemotherapy in patients with localized pancreatic ductal adenocarcinoma. Clin Cancer Res 2023; 29(7): 1368–1374.

65.

Racu

Bernardi

Chaouche

, et al. SMAD4 positive pancreatic ductal adenocarcinomas are associated with better outcomes in patients receiving FOLFIRINOX-based neoadjuvant therapy. Cancers (Basel) 2023; 15(15): 3765.

66.

Bai

Chen

, et al. Neoadjuvant nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX for resectable pancreatic cancer: a randomized phase 3 trial. Cancer Cell 2025; 43: 2259–2267.

67.

Guo

Hoffman

Weekes

, et al. Refining the molecular framework for pancreatic cancer with single-cell and spatial technologies. Clin Cancer Res 2021; 27(14): 3825–3833.

68.

Kunzmann

Siveke

Algül

, et al. Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2021; 6(2): 128–138.

69.

Henry

Smits

Daamen

, et al. Root-cause analysis of mortality after pancreatic resection in a nationwide cohort. HPB (Oxford) 2025; 27(4): 461–469.

70.

Grego

Friziero

Serafini

, et al. Does pancreatic fistula affect long-term survival after resection for pancreatic cancer? A systematic review and meta-analysis. Cancers (Basel) 2021; 13(22).

71.

Hank

Sandini

Ferrone

, et al. Association between pancreatic fistula and long-term survival in the era of neoadjuvant chemotherapy. JAMA Surg 2019; 154(10): 943–51.

72.

Kamarajah

Bundred

Lin

, et al. Systematic review and meta-analysis of factors associated with post-operative pancreatic fistula following pancreatoduodenectomy. ANZ J Surg 2021; 91(5): 810–821.

73.

Dahdaleh

Naffouje

Hanna

, et al. Impact of neoadjuvant systemic therapy on pancreatic fistula rates following pancreatectomy: a population-based propensity-matched analysis. J Gastrointest Surg 2021; 25(3): 747–756.

74.

Wismans

Suurmeijer

van Dongen

, et al. Preoperative chemoradiotherapy but not chemotherapy is associated with reduced risk of postoperative pancreatic fistula after pancreatoduodenectomy for pancreatic ductal adenocarcinoma: a nationwide analysis. Surgery 2024; 175(6): 1580–1586.

75.

Mangieri

Strode

Moaven

, et al. Utilization of chemoradiation therapy provides strongest protective effect for avoidance of postoperative pancreatic fistula following pancreaticoduodenectomy: a NSQIP analysis. J Surg Oncol 2020; 122(8): 1604–1611.

76.

Dekker

van Dam

Janssen

, et al. Improved clinical staging system for localized pancreatic cancer using the ABC factors: a TAPS consortium study. J Clin Oncol 2024; 42(12): 1357–1367.

77.

Crippa

Malleo

Mazzaferro

, et al. Futility of up-front resection for anatomically resectable pancreatic cancer. JAMA Surg 2024; 159(10): 1139–1147.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

12.93 MB