The value of CA19-9 dynamics in decision making for treatment of locally advanced pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a dismal 5-year overall survival of only 12% across all stages of disease (1). Poor survival is primarily driven by its asymptomatic nature and early propensity of systemic spread of disease (1,2). Even in patients with localized disease who undergo resection, treatment failure occurs in approximately two out of three patients in the form of local or systemic progression of disease (3,4). In combination with improved local and systemic control via multiagent chemotherapy regimens, recent advances in surgical techniques such as improvements in vascular reconstructions and arterial divestment have increased surgical candidacy in patients with locally advanced pancreatic cancer (LAPC) (5-9). The current treatment approach for patients with LAPC now entails induction chemotherapy followed by surgical resection if deemed appropriate (10). However, there remains considerable variability in adherence to these guidelines (11-15). Determining surgical candidacy such that a patient derives maximal benefit from resection remains a challenge (16). This is primarily due to lack of reliable biomarkers to assess treatment response early on during induction therapy to guide treatment decision making.

Carbohydrate antigen 19-9 (CA19-9) is the most frequently used prognostic and monitoring biomarker for assessment of disease in pancreatic cancer. Except in CA19-9 non-producers (approximately 15–20% of the patients), CA19-9 levels at diagnosis and their dynamic changes are often used to inform treatment decisions (17). In this noteworthy nationwide effort, Seelen et al. define a minimal (≥40%) and optimal (≥60%) percent decrease in CA19-9 survival cut-off after 2 months of induction therapy (13). The authors demonstrate that these cut-offs are robust predictors of patient prognostication. Moreover, CA19-9 response may serve as a surrogate biomarker for favorable tumor biology and treatment response, hence informing optimal candidacy for surgical selection. Indeed, they demonstrate that in CA19-9 producers, this cut-off was associated with survival, in addition to surgical resection, SBRT, and duration of induction therapy. Similarly, in a study on LAPC after induction treatment with FOLFIRINOX, at the Heidelberg University Hospital, a 60% reduction in CA19-9 was identified as the optimal cut-off and yielded a positive predictive value for resectability of 83% (18). Furthermore, a post-treatment level of <91.8 U/mL was predictive of resectability and survival. Interestingly, patients above the cut-off did not benefit from resection compared to exploration only in terms of overall survival (18).

While a sufficient decrease and low post-induction treatment levels seem convincing in informing treatment decisions, the role of pre-treatment CA19-9 remains controversial. While having an important prognostic value, pretreatment CA19-9 levels do not necessarily predict resectability in LAPC (9,18). Seelen et al. address this important clinical question via a sub-analysis of patients with pre-treatment levels of >500 and <500 U/mL with significantly worse outcomes in inadequate responders with high pre-treatment levels. The optimal decrease of CA19-9 was only independently associated with an improved survival in patients with <500 U/mL pre-treatment levels and therefore questions the applicability of this threshold in patients with higher baseline levels. Further research, such as creating a composite score combining these values, may be necessary to increase applicability to patients with high pretreatment levels. Second, further research is necessary to inform treatment decisions in patients that fail to meet these cut-offs for optimal treatment response. Alva-Ruiz et al. have shown promising results for change in regimen in patients with unsuccessful induction treatment (19). However, high-level evidence for the decision on prolonging treatment with the same regimen versus switching the regimen versus surgery, to date, is lacking (20,21). Third, it is unlikely that CA19-9 as a sole biomarker can predict surgical candidacy with high accuracy. Currently, large efforts are being undertaken in employing liquid biopsies to harness ctDNA and circulating tumor cells as biomarkers of systemic disease and treatment response (22). Multianalyte tests could help determine the presence and extent of systemic disease and therefore define optimal surgical candidates for surgery as the most effective local treatment.

To date, evidence suggests that using CA19-9 dynamics with a cut-off of ≥60% reduction is the best data we have for treatment decision making after 2 months of induction chemotherapy in clinical practice. We would like to congratulate the authors on conducting a robust nationwide analysis to address this important question in the management of LAPC. This study adds to the growing evidence that CA19-9 dynamics can add value in patient prognostication and determining surgical candidacy in LAPC and hence improve survival.

Acknowledgments

Funding: I.F.R. is supported by the Swiss National Science Foundation (SNSF) (grant number 217684).

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-23-477/coif). The 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.

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