Neoadjuvant radiotherapy after chemotherapy does not improve surgical or survival outcomes in borderline resectable pancreatic cancer

Introduction

Pancreatic cancer remains one of the most lethal malignancies worldwide, with a rising global incidence (1). Approximately 57% of patients present with metastatic disease at diagnosis. In the absence of metastases, tumors are anatomically classified as resectable, borderline resectable (BR-PDAC), or locally advanced based on the presence and extent of involvement of major peripancreatic vessels (2). For clearly resectable disease, current guidelines recommend upfront surgery followed by adjuvant chemotherapy—most often 6 months of FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) (3,4).

The concept of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) was introduced in 2006 to describe tumors with a high risk of margin-positive resection using a surgery-first approach (5). While initially based solely on vascular involvement, the definition has since expanded to include biological features [suspicious but not proven distant metastases, elevated carbohydrate antigen 19-9 (CA19-9) levels, and regional lymph node involvement] as well as clinical considerations (poor performance status) (6).

For such patients, neoadjuvant therapy has become a cornerstone of management (7). This approach increases the likelihood of achieving a margin-negative resection, allows early treatment of micrometastatic disease, and spares patients with early progression from the morbidity of futile surgery. Randomized trials (8-10) have consistently demonstrated that neoadjuvant therapy improves outcomes compared with upfront surgery in the borderline-resectable setting.

The optimal neoadjuvant regimen remains uncertain. Chemotherapy is well established as the backbone, but the role of radiotherapy (RT) is debated (11). While chemoradiotherapy (CRT) may improve local control (12) and R0 resection rates (13), contemporary data in the FOLFIRINOX era suggest limited added value. The PREOPANC (9) and ESPAC-5 (8) trials confirmed the benefit of neoadjuvant therapy overall, but were not designed to directly compare chemotherapy versus CRT. More recently, Alliance A021501 (14) and PANDAS-PRODIGE-44 (15) specifically tested RT after FOLFIRINOX and found no additional benefit. Both trials, however, have been criticized for methodological limitations, including early closure and use of non-standard hypofractionated regimens in Alliance A021501, and small sample size with limited power in PANDAS-PRODIGE-44.

Therefore, we evaluated the role of neoadjuvant RT following chemotherapy in BR-PDAC patients treated at a high-volume cancer center, focusing on real-world surgical and survival outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1018/rc).

Methods

We conducted a retrospective cohort study of patients with BR-PDAC who initiated neoadjuvant chemotherapy between 2011 and 2023 at A.C. Camargo Cancer Center. Eligible patients were ≥18 years old and had cytologically or histologically confirmed pancreatic adenocarcinoma classified as borderline resectable following multidisciplinary team (MDT) review. Borderline resectable status was defined using an integrated framework incorporating anatomic, biologic, and clinical criteria, consistent with contemporary National Comprehensive Cancer Network (NCCN)-based definitions (16) and international consensus recommendations (6). All patients received at least one cycle of systemic therapy in the neoadjuvant setting. Patients with metastatic disease or non-adenocarcinoma histology were excluded. Clinical, treatment, and outcome data were extracted from institutional medical records.

Neoadjuvant chemotherapy was administered according to institutional standards. Regimens included FOLFIRINOX or gemcitabine plus nab-paclitaxel, with regimen selection at the treating physician’s discretion. In selected cases, neoadjuvant RT was delivered following MDT discussion, often after assessment of response to neoadjuvant chemotherapy, using intensity-modulated radiotherapy (IMRT), three-dimensional conformal radiotherapy (3D-CRT), or stereotactic body radiotherapy (SBRT), with or without concurrent fluoropyrimidine-based radiosensitization. Patients without progression were considered for surgical exploration. Surgical details—including type of resection, need for vascular reconstruction, pathological margin status (R0 vs. R1), and early postoperative mortality (≤90 days after surgery) —were collected. Pathologic staging was recorded according to the American Joint Committee on Cancer (AJCC) 8th edition. Use of adjuvant chemotherapy, regimens, and number of cycles were also documented. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional ethics committee of A.C. Camargo Cancer Center (No. 2462/17) on 12 May 2017. The requirement for informed consent was waived due to the use of de-identified data.

Follow-up consisted of clinical assessments and imaging per institutional practice. Among patients who underwent resection, the first recurrence was classified as local or distant. For patients who did not undergo surgery, the first disease progression was categorized as local, distant, or unresectable primary. Overall survival (OS) was defined as the time from diagnosis to death from any cause or last follow-up. Event-free survival (EFS) was defined as the time from diagnosis to the first occurrence of any of the following events: disease progression during neoadjuvant treatment, recurrence after surgery, determination of unresectability (at any point during neoadjuvant therapy or intraoperatively), or death.

Statistical analysis

Baseline characteristics were summarized using descriptive statistics. Continuous variables were expressed as medians with ranges; categorical variables as counts with percentages. Categorical variables were compared using the χ² or Fisher’s exact test, and continuous variables using the Student’s t-test or Wilcoxon rank-sum test, as appropriate.

OS and EFS were estimated using the Kaplan-Meier method and compared between groups with the log-rank test. Univariable and multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). The multivariable model was prespecified to include age (<70 vs. ≥70 years), baseline CA19-9 (<500 vs. ≥500 U/mL), Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs. 1–2), surgical resection (yes vs no), neoadjuvant RT (yes vs. no), and vascular involvement (present vs. absent).

Logistic regression was used to evaluate factors associated with undergoing surgical resection and with achieving R0 margins, with odds ratios (ORs) and 95% CIs reported. Two-sided P values <0.05 were considered statistically significant. Missing data were reported and handled by complete-case analysis, without imputation or adjustment for missingness. All analyses were performed using R (version 2025; R Foundation for Statistical Computing, Vienna, Austria).

Results

A total of 132 patients were included. The median age was 63 years (range, 43–87 years), with 33 patients (25.0%) aged ≥70 years. Overall, 67 (50.8%) were female. ECOG PS was 0 in 76 (57.6%), 1 in 52 (39.4%), and 2 in 2 (1.5%). The primary tumor was located in the pancreatic head in 100 (75.8%) and in the body/tail in 32 (24.2%). According to MDT review, 114 (86.4%) were borderline-anatomic, 13 (9.8%) borderline-biologic, and 1 (0.8%) borderline-clinical; classification was unknown in 4 (3.0%). Vascular involvement was assessable in 130 cases: arterial in 14 (10.6%), venous in 39 (29.5%), both arterial and venous in 54 (40.9%), and absent in 23 (17.4%). Baseline CA19-9 was available in 127 patients (median 173 U/mL; range, 0–15,300 U/mL).

Among the 132 patients who received neoadjuvant chemotherapy, 120 (90.9%) were treated with FOLFIRINOX administered every 2 weeks, and 12 (9.1%) received gemcitabine plus nab-paclitaxel on a 4-week cycle. The median number of chemotherapy cycles was 7 (range, 1–23). During chemotherapy, 4 (3.0%) developed local progression, 9 (6.8%) distant progression, 13 (9.8%) were reassessed as unresectable, 3 (2.3%) died, and 2 (1.5%) were lost to follow-up. Two additional patients with local progression nonetheless proceeded to potentially curative management.

Of the remaining 101 patients, 68 (67.3%) received neoadjuvant RT: 33 (48.5%) with IMRT, 33 (48.5%) with 3D-CRT and 1 (1.5%) with SBRT. The median radiation dose was 50 Gy (1.8 Gy per fraction), and 65 (95.6%) received concurrent fluoropyrimidine-based CRT. After RT, 1 patient (1.5%) developed local progression, 12 (17.6%) distant progression, 7 (10.3%) were considered unresectable, and 1 (1.5%) died.

Surgical exploration was attempted in 80 patients. In nine cases, the procedure was aborted—six due to distant progression and three due to intraoperative unresectability. Ultimately, 71 (53.8% of the total cohort) underwent resection (52 pancreaticoduodenectomies and 19 distal pancreatectomies). An R0 resection was achieved in 57 (43.2% of the total cohort; 80.3% of those resected), and 13 (9.8% of the total cohort; 18.3% of those resected) had an R1 resection; margin status was indeterminate in 1. Vascular reconstruction was required in 33 (46.5%); 35 (49.3%) did not require reconstruction; and data were not recorded in 3 (4.2%). Among resected patients, AJCC pathologic stage was: stage 0 in 3 (4.2%), stage I in 35 (49.3%), stage II in 27 (38.0%), stage III in 4 (5.6%), and stage IV in 2 (2.8%).

Overall, 21 patients (15.9%) received adjuvant chemotherapy [10 FOLFIRINOX, 1 gemcitabine plus nab-paclitaxel, and 10 other regimens; median 3 cycles (range, 1–6)]. Among those who did not receive adjuvant therapy, 31 were deemed to have completed treatment and entered surveillance; 1 experienced early postoperative progression; 16 did not proceed due to postoperative complications (fatal or nonfatal); and 1 had severe toxicity during neoadjuvant therapy and was observed without further treatment. Figure 1 presents the CONSORT flow diagram detailing treatment allocation, neoadjuvant therapy, RT, and surgical outcomes.

Figure 1 CONSORT flowchart of patient selection and treatment pathways. BRPC, borderline resectable pancreatic cancer; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; Gem/Nab, gemcitabine plus nab-paclitaxel; PD, progressive disease; R0, margin-negative resection; R1, microscopically positive margin.

At data cutoff, events were observed in 108 patients (81.8%), and 77 (58.3%) had died. Among those who underwent resection (N=71), recurrence occurred in 42 (59.2%): 9 (21.4%) first recurred locally and 33 (78.6%) first recurred distantly.

The median follow-up was 42.9 months (95% CI, 34.2–49.0). Among patients alive at last contact, the median observed follow-up was 31.3 months. For the entire cohort (N=132), median OS was 24.8 months (95% CI, 19.9–31.8), with an estimated 3-year OS rate of 37.4% (95% CI, 29.2–48.0%). Among the 71 resected patients, median OS was 42.3 months (95% CI, 28.7–not reached), with a 3-year OS rate of 52.6% (95% CI, 41.7–66.5%). Median EFS for the entire cohort was 9.0 months (95% CI, 7.9–11.3) and 13.4 months (95% CI, 12.2–16.6) among resected patients.

Outcomes in patients without progression or death during neoadjuvant chemotherapy (N=101)

To evaluate the impact of neoadjuvant RT more specifically, we excluded the 31 patients who experienced progression or death during chemotherapy or were deemed unresectable and referred to palliative therapy. In this subset of 101 patients, 68 received RT and 33 did not.

Baseline characteristics were broadly comparable between groups. Female sex was more frequent in the RT group (58.8% vs. 36.4%; P=0.057). Age (median 61 vs. 61 years; P=0.99) and baseline CA19-9 (median 174 vs. 131 U/mL; P=0.66) were similar. ECOG PS (1–2: 37.9% vs. 21.2%; P=0.15) and primary tumor location (head vs. body/tail; P=0.74) did not differ significantly. Baseline patient demographics and clinical characteristics are summarized in Table 1.

Any vascular involvement was more common with RT (92.6% vs. 75.8%; P=0.04). Combined arterial and venous involvement was more frequent with RT (44.1% vs. 18.2%), whereas isolated venous involvement (32.4% vs. 45.5%) or no involvement (7.4% vs. 24.2%) predominated without RT (P=0.02). Borderline classification also differed (P=0.05), with biologic borderline disease more frequent without RT (18.2% vs. 4.4%) and anatomic borderline more common with RT (92.6% vs. 75.8%).

In univariable analyses, RT was associated with inferior survival (median OS 26.6 vs. 47.2 months; 3-year OS 33.9% vs. 65.2%; HR =2.31; 95% CI, 1.20–4.47; P=0.01). Elevated baseline CA19-9 (≥500 U/mL) predicted worse outcomes (median OS 20.2 vs. 34.2 months; 3-year OS 31.8% vs. 48.5%; HR =1.85; 95% CI, 1.06–3.23; P=0.03). ECOG PS 1–2 was strongly associated with poorer prognosis versus ECOG PS 0 (median OS 18.6 vs. 42.3 months; 3-year OS 25.4% vs. 53.5%; HR =2.68; 95% CI, 1.58–4.55; P<0.001). Surgical resection was strongly associated with improved survival (median OS 42.3 vs. 17.2 months; 3-year OS 52.6% vs. 14.9%; HR =0.33; 95% CI, 0.19–0.57; P<0.001). Age (P=0.88), sex (P=0.79), and vascular involvement (P=0.85) were not significantly associated with OS. Among patients who received RT (N=68), OS did not differ significantly according to RT technique (3D-CRT vs. IMRT; P=0.50); SBRT was not included in comparative analyses due to insufficient sample size.

In multivariable analysis, surgical resection remained the strongest protective factor for OS (HR =0.38; 95% CI, 0.21–0.71; p<0.01). Baseline CA19-9 ≥500 U/mL (HR =1.86; 95% CI, 1.03–3.38; P=0.04) and ECOG PS 1–2 (HR =1.84; 95% CI, 1.04–3.25; P=0.04) were independently associated with worse outcomes. RT trended toward inferior survival (HR =2.10; 95% CI, 0.99–4.46; P=0.054). Neither age ≥70 years (P=0.50) nor vascular involvement (P=0.30) was significantly associated with survival. Figures 2,3 present univariable and multivariable analyses; Figure 4 shows OS.

Figure 2 Univariable and multivariable Cox regression analysis of overall survival. HRs with 95% CIs were estimated using Cox proportional hazards models. CA19-9, carbohydrate antigen 19-9; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio.

Figure 3 Forest plot of multivariable Cox regression analysis for overall survival. HRs with 95% CIs were estimated using multivariable Cox proportional hazards models, adjusted for age, baseline CA19-9, ECOG performance status, surgical resection, radiotherapy, and vascular involvement. CA19-9, carbohydrate antigen 19-9; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio.

Figure 4 Kaplan-Meier overall survival analysis. Survival was stratified by neoadjuvant radiotherapy, baseline CA19-9 (<500 vs. ≥500 U/mL), ECOG performance status (0 vs. 1–2), surgical resection (yes vs. no), sex, and vascular involvement (present vs. absent). P values were calculated using the log-rank test. Risk tables indicate the number of patients at risk at each time point. CA19-9, carbohydrate antigen 19-9; ECOG, Eastern Cooperative Oncology Group.

Among patients who received RT, 41/68 (60.3%) underwent resection, compared with 30/33 (90.9%) without RT (P<0.01). In logistic regression, the absence of RT was independently associated with higher odds of resection (OR =6.59; 95% CI, 2.08–29.38; P=0.004). Vascular reconstruction was performed in 24/41 (58.5%) resected patients after RT versus 9/30 (33.3%) without RT (P=0.07).

Among the resected population (N=71), the R0 resection rate was comparable between groups, achieved in 80.5% of patients who received RT and 82.8% of those who did not (OR =0.86; 95% CI, 0.20–3.43; P>0.99). Early postoperative mortality was numerically higher in the RT group (19.5% vs. 6.7%; P=0.17). These findings are illustrated in Figure 5.

Figure 5 Surgical outcomes according to neoadjuvant radiotherapy. Comparison of resection rate (N=101), vascular reconstruction (N=71), R0 resection rate (N=71), and early postoperative mortality within 90 days (N=71) between patients who received neoadjuvant radiotherapy versus those who did not. R0, margin-negative resection; R1, microscopically positive margin.

Pathologic stage distribution according to the AJCC 8th edition was also similar between groups (P=0.69). In the RT group, most patients were classified as stage I (51.2%) or stage II (36.6%). In the non-RT group, stage I (46.7%) and stage II (36.7%) predominated. Differences were not statistically significant (P=0.69). Data are presented in Table 2.

Survival outcomes among resected patients were influenced by margin status. Those with R0 resections had a median OS of 47.2 months compared with 12.0 months in R1 resections (3-year OS 58.8% vs. 23.1%; HR =2.85; 95% CI, 1.36–5.95; P<0.01). Vascular reconstruction was not significantly associated with survival (median OS 34.2 months without reconstruction vs. 37.8 months with reconstruction; HR =1.11; 95% CI, 0.58–2.15; P=0.75). These findings are depicted in Figure 6.

Figure 6 Kaplan-Meier overall survival analysis in resected patients (N=71). Survival was stratified by margin status (R0 vs. R1) and vascular reconstruction (no vs. yes). P values were calculated using the log-rank test. Risk tables indicate the number of patients at risk at each time point. R0, margin-negative resection; R1, microscopically positive margin.

Discussion

This retrospective single-center study evaluated the role of neoadjuvant RT in BR-PDAC treated with modern systemic therapy. After initial chemotherapy in all patients, the addition of RT did not improve resection rates, R0 resection, or survival in a predefined multivariable model. Instead, RT was associated with a trend toward inferior OS in multivariable analysis and with numerically higher early postoperative mortality. These findings align with contemporary randomized data, suggesting that when systemic therapy is optimized, routine addition of preoperative RT does not consistently yield oncologic benefit in BR-PDAC.

A single-arm phase II trial (17) evaluated a total neoadjuvant strategy in BR-PDAC: eight cycles of FOLFIRINOX followed by individualized CRT—short-course for patients with resolution of vascular involvement or long-course conventional CRT otherwise. R0 resection was achieved in 65% of all eligible patients, with encouraging survival (median PFS 14.7 months; median OS 37.7 months). Interpretation, however, was limited by the single-arm design, small sample size, and heterogeneity introduced by response-adapted CRT regimens.

Alliance A021501 (14) randomized BR-PDAC patients to mFOLFIRINOX alone or mFOLFIRINOX followed by hypofractionated RT (33–40 Gy in five fractions). The RT arm was closed early for inferior R0 rates (45% vs. 63%), and final results showed worse OS with RT (17.1 vs. 31.0 months). Although baseline CA19-9 was higher in the RT group, potentially indicating greater disease burden, the trial reinforced mFOLFIRINOX as the neoadjuvant backbone; hypofractionated RT has not been adopted routinely.

PANDAS-PRODIGE-44, a phase II study (15), assigned patients to four cycles of mFOLFIRINOX, then randomized non-progressors to two additional cycles versus conventional CRT (50.4 Gy in 28 fractions with capecitabine) before pancreatectomy and adjuvant chemotherapy. Of 130 enrolled, 110 were randomized. Resection occurred in 69% with chemotherapy alone versus 55% with added CRT; R0 rates were similar (54.1% vs. 58.1%). Pathologic complete response was higher with CRT (29% vs. 8.1%) without survival benefit [median OS 32.8 vs. 30.0 months in the intention to treat (ITT) population]. Interpretation is constrained by small sample size, slow accrual, limited power for survival endpoints, higher baseline CA19-9 in the CRT arm, and lack of centralized RT quality assurance. A peer-reviewed full manuscript is pending.

The phase III CONKO-007 (13) trial extended these observations to locally advanced, initially unresectable PDAC. After induction chemotherapy (mostly FOLFIRINOX), 336 non-progressing patients were randomized to continued chemotherapy or gemcitabine-based CRT. R0 resection did not differ in the intention-to-treat population (25% vs. 18%). Among resected patients, CRT yielded higher R0 rates, more ypN0 resections, and more complete responses, yet without improvement in OS (15 vs. 14 months; HR =0.94) or disease-free survival. Locoregional control improved, but distant failure remained dominant. Mid-trial endpoint changes, lack of centralized RT review, and heterogeneous induction regimens complicate interpretation.

Meta-analyses show that neoadjuvant therapy may increase R0 rates compared with upfront surgery, but much of this effect reflects older CRT-based regimens (18-20). Contemporary data focusing on RT after FOLFIRINOX suggest possible gains in R0 resection without survival benefit, with conclusions limited by selection bias.

In our adjusted analyses, surgical resection remained the strongest predictor of survival, whereas ECOG PS 1–2 and CA19-9 ≥500 U/mL independently predicted poor outcomes. Recurrence was overwhelmingly distant, reinforcing that maintaining systemic dose intensity is more decisive for disease control than routine locoregional intensification (21,22).

The role of postoperative CRT also remains debated. Early studies suggested benefit (23), but subsequent trials (24,25) did not confirm survival gains and even suggested potential harm, shifting practice toward only adjuvant chemotherapy. More contemporary data (RTOG 0848) also failed to demonstrate an OS benefit with adjuvant CRT (26), though node-negative subsets may derive benefit. Notably, none of these studies evaluated patients who had already received neoadjuvant chemotherapy.

Our study has several important limitations, most notably its retrospective design and substantial baseline imbalances between treatment groups. RT was selected through multidisciplinary discussion in routine clinical practice and was more frequently offered to patients with greater vascular involvement, reflecting a higher-risk disease profile. This clinically driven selection process likely influenced both treatment allocation and outcomes, introducing confounding factors that cannot be fully addressed by statistical adjustment. In addition, RT techniques were heterogeneous, with a substantial proportion of patients treated with three-dimensional conformal RT rather than more contemporary approaches, which may have affected treatment tolerance and outcomes.

To partially account for measured imbalances, survival analyses were performed using a forced-entry multivariable model incorporating age, baseline CA19-9, ECOG performance status, vascular involvement, surgical resection, and receipt of neoadjuvant RT. Nonetheless, residual confounding related to unmeasured or incompletely captured factors remains likely.

Within these limitations, we did not observe a clear association between neoadjuvant RT and improved oncologic outcomes in patients with BR-PDAC. This finding should be interpreted cautiously and viewed as hypothesis-generating rather than definitive, given the non-randomized design and imbalanced baseline characteristics.

Conclusions

In this single-center cohort of patients with BR-PDAC treated with contemporary chemotherapy, the addition of neoadjuvant RT was not associated with higher resection rates, improved margin status, or prolonged survival. Given the baseline imbalances between treatment groups and the retrospective nature of the analysis, these findings should not be interpreted as definitive. Rather, they underscore the central role of systemic therapy in the neoadjuvant management of BR-PDAC and highlight the need for well-designed prospective studies incorporating modern RT techniques, standardized quality assurance, and objective selection criteria to better define whether specific subgroups may derive meaningful benefit.

Acknowledgments

The authors thank the multidisciplinary team at A.C. Camargo Cancer Center for their support in patient care and data collection.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1018/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1018/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1018/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-1-1018/coif). reports that. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional ethics committee of A.C. Camargo Cancer Center (No. 2462/17) and the requirement for informed consent was waived due to the use of de-identified data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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