This retrospective analysis of patients with initially unresectable mPDAC treated at a single center in Taiwan provides key insights into the potential role of conversion surgery following systemic chemotherapy. Specifically, we identified four independent factors associated with recurrence after conversion surgery: male sex, tumor location in the pancreatic head or uncinate process, SD by RECIST criteria (as compared to partial response), and higher tumor regression grade. This finding contribute to the growing body of evidence supporting the use of conversion surgery in appropriately selected mPDAC patients, while also highlighting clinical and pathological features that may predict postoperative recurrence.

Pancreatic cancer is one of the most aggressive malignancies, and the survival rate is low, in part, because early signs and symptoms are non-specific and the disease is usually diagnosed at an advanced stage (Garajova et al. 2023; Hank & Strobel 2019). Surgery followed by chemotherapy is the standard treatment for pancreatic cancer that is considered resectable at diagnosis, and there are no high-risk factors (Garajova et al. 2023). In the past, treatment options for unresectable pancreatic cancer were limited, with systemic chemotherapy primarily used for palliation rather than for potential downstaging. However, with the advent of more effective chemotherapy regimens, select patients may experience significant tumor regression, potentially allowing for conversion surgery. However, this approach remains investigational and is not yet the standard of care (Garajova et al. 2023; Hank & Strobel 2019; Klaiber & Hackert 2019; Y. N. Lee et al. 2024).

A recently published meta-analysis reported that conversion surgery significantly improved survival (HR 0.55) in patients with initially unresectable pancreatic cancer who had a favorable response to chemotherapy (Zhou et al. 2022). The two most common chemotherapy regimens for unresectable pancreatic cancer are FOLFIRINOX or gemcitabine plus nab-paclitaxel (Ide et al.). Ide et al. (Ide et al.) recently reviewed the records of 318 patients with unresectable pancreatic cancer initially treated with one of the aforementioned chemotherapy regimens. OS was significantly longer in patients who received conversion surgery than in those who did not (median 33 vs. 11 months; a HR 0.32). The median survival after conversion surgery was 44 months in patients with initially locally advanced disease and 21 months in patients with metastasis at diagnosis. Notably, factors that were associated with the opportunity for conversion surgery were locally advanced disease, no liver metastasis, CA19-9 ≤ 37, and an adequate response to chemotherapy (Ide et al. 2023).

In a study published in 2024, Higashi et al. (2024) examined predictors for attaining the requirements for conversion surgery in patients with unresectable PDAC. The analysis showed that total protein (HR 2.81), neutrophil-to-lymphocyte ratio (HR 0.53), and lymphocyte-to-monocyte ratio (HR 1.28) were significantly associated with conversion surgery. These findings emphasize the emerging role of conversion surgery and the importance of related biomarkers and clinical indicators.

In our study, conversion surgery was considered only for patients with no new metastases, radiologically stable or improved metastatic lesions sustained for at least six months, and a primary tumor downstaged to a resectable state with the potential for R0 resection. By contrast, the Heidelberg group (Hank et al. 2023) applied more flexible criteria, selecting patients based on RECIST-defined radiological response and concurrent declines in CA19-9 and CEA, and typically proceeding to surgery after six cycles of chemotherapy, often within 5–9 months of diagnosis. Thus, our approach was more conservative, while theirs relied on integrated radiological and biological response to guide earlier surgical intervention. Future research are warranted to directly compare different selection criteria to determine their relative impact on outcomes.

Our analysis identified several key prognostic factors for patients undergoing conversion surgery. Other studies also examined conversion surgery outcomes and prognostic factors influencing post-surgical survival. For example, Satoi et al. (2020) reported that patients who received conversion surgery based on clinical response to chemotherapy and decreased CA19-9 level had a median survival time of 36 months. The multivariate analysis indicated that a decreased CA19-9 level was a predictor of resectability, OS, and disease-free survival (DFS). Yanagimoto et al. (Yanagimoto et al. 2020) reported that the median survival time and 5-year survival of patients who received conversion surgery were 37 months and 34%, compared to 9 months and 1% for patients who did not have surgery. Notably, lymph node metastasis, positive washing cytology, large tumor size (> 35 mm), and no postoperative adjuvant chemotherapy were statistically significant predictors of early recurrence, and the site of pancreatic lesion and administration of postoperative adjuvant chemotherapy were statistically significant prognostic factors for OS. In another study that included 638 patients, the median OS of patients with conversion surgery, resectable cancer, borderline resectable, unresectable locally advanced, and unresectable and distant metastases was 74 months, 33 months, 23 months, 16 months, and 9 months, respectively. The multivariate analysis indicated that the presence or absence of chemoradiotherapy and a RECIST PR or CR of the primary tumor were statistically significant prognostic factors for OS in patients who received conversion surgery (Mataki et al. 2021). In another recent study, Hank et al. (2023) reported that in patients with a complete pathological response of metastasis, the OS was 26 months, compared to 8 months in patients who did not have surgery. As seen in other studies, CA19-9 level was an independent prognostic factor for all patients in the study.

Other studies have also reported similar findings. Notably, studies reported that a decrease in CA19-9 level was a positive prognostic factor (Igarashi et al. 2023; Lee et al. 2023; Li et al. 2023). In a recent study that included 67 patients with unresectable pancreatic cancer, Li et al. (2023) reported that R0 resection and a decrease in the levels of tumor markers after conversion surgery were the most important prognostic factors for PFS. Lee et al. (Lee et al. 2023) reported that a CA19-9 level > 200 U/ml after neoadjuvant chemotherapy was an independent factor for early recurrence after conversion surgery (HR 7.2). Igarashi et al. (2023) retrospectively analyzed the records of 144 patients with unresectable locally advanced PDAC. In patients who received induction gemcitabine and nab-paclitaxel followed by additional chemoradiation therapy, the multivariate analysis revealed CA19-9 normalization prior to surgery (HR 0.23) and a prognostic nutritional index ≥ 42 (HR 0.05) were independent prognostic factors for prolonged survival.

Overall, the identification of prognostic factors in this study contributes to the growing body of literature on the treatment of PDAC. These findings may help guide the implementation of tailored postoperative or adjuvant therapies aimed at reducing recurrence risk and improving long-term outcomes.

The strengths of this study include its focus on a patient population with unresectable mPDAC undergoing conversion surgery, which is a relatively underexplored topic of research. The data collection was comprehensive, including clinical, pathological, and outcome data, allowing for a detailed analysis of factors influencing survival and recurrence. Despite these strengths, the study has several limitations that should be considered. First, the retrospective design introduces inherent biases, particularly related to patient selection. The single-center nature of the study might limit the generalizability of the findings to other settings or populations due to differences in treatment protocols and patient demographics. Furthermore, the small sample size, especially for patients who underwent conversion surgery, may affect the statistical power to detect significant differences and interactions between various factors. Another limitation is the lack of molecular or genetic data, which could provide deeper insights into the biological behavior of tumors and possibly explain some of the observed variations in treatment response and survival outcomes.