Very early recurrence after pancreatic cancer resection: Unmasking the "biological R2" enigma and rethinking prognostic paradigms

Abstract

Pancreatic ductal adenocarcinoma (PDAC), a "silent killer" with elusive early symptoms and poor prognosis, sees nearly half of patients experience recurrence within a year post-curative-intent surgery. Very early recurrence (VER), defined as recurrence within 12 weeks postoperatively and first termed "biological R2 resection" by Belfiori et al, remains a clinical puzzle. Martlı et al’s recent retrospective cohort study offers crucial insights into this understudied issue, identifies predictive factors that challenge long-held beliefs, and calls for a rethink of risk stratification and postoperative management for PDAC patients. Martlı et al studied 303 PDAC patients at a high-volume center from 2019 to 2024, with VER affecting 9.24% (28 patients) of the cohort. The study’s strength lies in combining traditional statistical analyses and machine learning (random forest modeling) to capture nonlinear relationships between clinicopathological factors and VER risk. Key findings include: (1) Poorly differentiated (G3) tumors are the strongest VER predictor (OR = 2.43, P < 0.001; random forest importance score = 0.35), with 92.85% of VER patients having G3 tumors (vs 45.81% of non-VER patients); (2) Contrary to prior studies, pancreatic head tumors (89.28% of VER patients vs 83.66% of non-VER patients, P = 0.031) were linked to VER; (3) Elevated red cell distribution width is a weaker predictor (random forest importance score = 0.20, P = 0.03 for group difference, P = 0.079 in multivariate analysis); and (4) VER correlates with significantly higher 6-month mortality (32.44% vs 14.77% in non-VER patients, P = 0.032).

Key Words: Pancreatic ductal adenocarcinoma; Very early recurrence; Biological R2 resection; Risk stratification; Prognostic factors

Core Tip: Very early recurrence (VER) in pancreatic ductal adenocarcinoma (PDAC), a "biological R2 resection," occurs when macroscopically complete surgery fails to stop aggressive tumor progression. Martlı et al’s study of 303 PDAC patients identified G3 tumors (strongest predictor), pancreatic head location (contrary to prior assumptions), and elevated red cell distribution width as VER predictors, with VER doubling the 6-month mortality rate. These findings urge a shift to risk-stratified PDAC management, but the study’s retrospective, single-center design and lack of molecular data limit conclusions. Future research should validate predictors, test risk-stratified strategies, and explore VER’s molecular drivers.

TO THE EDITOR

Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, with nearly 50% of patients developing recurrence within a year post-curative-intent resection. Very early recurrence (VER), that is, recurrence within 12 weeks postoperatively, first termed "biological R2 resection" by Belfiori et al[1], occurs when macroscopically complete surgery (R0/R1) fails to prevent rapid tumor progression, leaving a critical clinical gap.

Historically, PDAC research has focused on advanced or unresectable disease, resulting in limited evidence on VER. The high post-resection recurrence rate and poor VER outcomes (6-month mortality over 30%) highlight the need to identify predictive factors[2]. Yet existing studies yield conflicting conclusions. For example, Belfiori et al[1] linked pancreatic body/tail tumors to higher VER risk, while Martlı et al[3] found the opposite, underscoring the need for further investigation into VER’s mechanisms.

Martlı et al’s retrospective cohort study[3] addresses this gap by analyzing 303 PDAC patients at a high-volume center (2019–2024). Its innovative use of traditional statistics and random forest machine learning clarifies VER predictors and provides a basis for redefining PDAC postoperative management.

Key findings on VER predictors and clinical impact

Martlı et al’s study identifies critical VER predictors and their impact on outcomes[3].

Poorly differentiated (G3) tumors: The strongest VER predictor is aligning with G3 tumors’ biological aggressiveness (enhanced proliferation, pro-metastatic molecule overexpression), elevates tumor grade from a "prognostic marker" to an "actionable predictor," warranting intensified monitoring and earlier adjuvant therapy for G3 patients[4-7].

Pancreatic head tumors: Contrary to prior studies, pancreatic head tumors are associated with VER. The cohort’s low proportion of body/tail tumors (10%, far below the approximately 25% in real-world PDAC populations) may reflect center-specific referral bias, but the discrepancy suggests location-specific tumor biology, e.g., unique molecular signatures or proximity to vital vasculature that facilitates microscopic spread[8,9].

Elevated red cell distribution width: A weaker predictor, red cell distribution width (RDW) reflects systemic inflammation and malnutrition, which create a "tumor-permissive" microenvironment. It offers a low-cost, accessible "red flag" to complement pathological findings in identifying high-risk patients[10].

VER’s impact on mortality

The 32.44% six-month mortality rate in VER patients (double that of non-VER patients) emphasizes the failure of current standardized follow-up, which detects recurrence too late to alter outcomes.

Transforming PDAC management: From "reactive" to "proactive"

The study’s greatest value is its potential to reshape PDAC clinical practice. For high-risk patients (G3 tumors, pancreatic head location, elevated RDW).

Intensified imaging surveillance: Initiate imaging at 4 weeks postoperatively (vs standard 3-6 months) and repeat every 2 weeks in the first 12 weeks for G3+ pancreatic head tumor patients; for those with isolated elevated RDW, initiate imaging at 6 weeks and repeat every 3 weeks. This balances early detection with practical concerns like radiation exposure (e.g., avoiding excessive computed tomography scans) and resource constraints in non-high-volume centers[11].

Earlier adjuvant therapy: Initiate adjuvant therapy within 2 weeks postoperatively for G3+ pancreatic head tumor patients (vs standard 4-8 weeks); for those with isolated elevated RDW, initiate adjuvant therapy at 3 weeks.

Multidisciplinary care: Involve surgeons, medical oncologists, and radiologists to integrate pathology, hematology, and imaging data for personalized decision-making.

Critical gaps: The need for molecular insights

A major limitation of Martlı et al’s study is the lack of molecular data[3]. Without genomic/proteomic profiling, we cannot distinguish whether G3 tumors’ association with VER stems from specific mutations (e.g., KRAS G12V) or general dedifferentiation, critical for developing targeted therapies. Future molecular research should prioritize: Identifying specific mutations (e.g., KRAS G12V) or overexpressed molecules (e.g., MMPs, EGFR) in VER tumors; exploring circulating tumor DNA (ctDNA) for early detection of minimal residual disease (MRD) before VER; investigating links between systemic inflammation (RDW, C-reactive protein) and tumor microenvironment features (stromal density, immune cell infiltration)[12].

Limitations and challenges of the study

Retrospective design and selection bias: The retrospective nature introduces selection bias (e.g., excluding patients with incomplete follow-up), which may skew the 9.24% VER rate. Non-random assignment of chemotherapy/adjuvant therapy (e.g., more aggressive treatment for perceived high-risk patients) confounds associations between predictors and VER, and the study lacks advanced statistical methods (e.g., propensity score matching) to adjust for this[5].

Single-center setting and limited generalizability: The high-volume center’s experienced surgeons, standardized protocols, and skewed patient selection (10% body/tail tumors vs approximately 25% in real-world cohorts) may overestimate the link between pancreatic head tumors and VER. Results may not apply to community hospitals or low-volume centers[8].

Lack of standardized imaging timing: Imaging timing varied (4-12 weeks), which could lead to overdiagnosis of VER in patients imaged earlier (e.g., 4 weeks) or underdiagnosis in those imaged later (e.g., 12 weeks). This may explain RDW’s weak correlation (P = 0.079 in multivariate analysis), as diagnostic timing rather than true biological relevance could bias results[11].

Absence of molecular and long-term survival data: Without molecular data, we cannot link histological predictors to biological mechanisms; lack of 1-year/2-year survival data prevents assessing whether risk-stratified interventions improve long-term outcomes.

Future research directions

Multi-institutional validation of VER predictors: Conduct multi-institutional retrospective studies with balanced head/body/tail tumor proportions (targeting approximately 25% body/tail tumors) and use propensity score matching to adjust for confounding factors (e.g., surgical technique, adjuvant therapy)[13].

Prospective trials of risk-stratified strategies: Imaging randomized controlled trial: Compare the early/frequent imaging (4-week initiation, every 2 weeks) vs standard imaging (3-month initiation) in G3+ pancreatic head tumor patients to assess survival benefits.

Adjuvant therapy randomized controlled trial: Compare the 2-week vs the 4-week adjuvant therapy initiation in G3+ pancreatic head tumor patients to reduce VER rates.

Molecular profiling of VER tumors: Conduct case-control molecular studies (genomic, transcriptomic, proteomic) comparing VER tumors to non-VER G3 tumors, and longitudinal studies of ctDNA in high-risk patients to detect MRD[12].

Development of a predictive model for VER

Develop a model integrating clinicopathological factors (G3 grade, tumor location, RDW) and molecular markers (ctDNA, KRAS mutations) to calculate individual VER risk scores[13].

CONCLUSION

Martlı et al’s study[3] provides a critical foundation for understanding VER in PDAC by identifying G3 tumors, pancreatic head location, and elevated RDW as key predictors and demonstrating VER’s mortality impact. It challenges established paradigms and calls for risk-stratified PDAC management, but limitations like the retrospective design, single-center setting, and lack of molecular data require caution in interpreting conclusions. Future research should prioritize multi-institutional validation, prospective trials of risk-stratified strategies, and molecular profiling to advance personalized PDAC care, which is critical for turning PDAC from a "silent killer" into a manageable condition.