Unraveling the oligometastatic phenotype and its association with pancreatic cancer survival.
Authors: Karalis John D , Elamir Ahmed , Murimwa Gilbert Zvikomborero , Enrico Sebastian , Balasubramanian Kishore , Wachsmann Megan , Chi Zhikai , Aguilera Todd Anthony , Polanco Patricio , Ligorio Matteo 
Published: January 2022

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Background: Stage IV pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis with a reported five-year survival of 2%. While treated as a monolithic population, a subset of stage IV patients exhibit a superior response to chemotherapy. In fact, anecdotal studies have shown that a well-selected subset of patients with oligometastatic disease of the liver and/or lung may benefit from more aggressive locoregional therapies. However, the definitions of oligometastatic disease utilized are arbitrary and exhibit a high degree of inter-study variation. In this study, we aim to advance a data-based definition of oligometastatic disease to support novel therapeutic approaches. Methods: Our institutional cancer registry was queried to identify consecutive patients diagnosed with pathologically confirmed stage IV PDAC (2015-2019). Pre-treatment cross-sectional imaging was reviewed and up to 10 liver and/or lung metastases were quantified while > 10 metastases was considered innumerable. Metastases to the peritoneum, bone, non-regional lymph nodes and other distant metastatic sites were recorded. A multivariable Cox regression model was used to assess the association of the number of isolated liver and/or lung metastases with overall survival (OS). Using time-dependent receiver operative characteristic (t-ROC) curves, we evaluated all of the subjects with isolated liver/lung metastasis for each cut-off (1-10) to identify the threshold most capable of predicting OS. Kaplan-Meier curves were used to visualize the patient survival function and the log-rank test was applied to test the statistical significance. Results: 183 patients with complete pre-treatment cross-sectional imaging available for review were included in this retrospective study. Amongst them, only 167 patients had complete treatment records and were included in the final multivariable analysis. 43% (72/167) of patients were treated with FOLFIRINOX, 38% (63/167) with gemcitabine/nab-paclitaxel, and 19% (32/167) elected best supportive care. Patients with ≤5 isolated liver/lung metastases had improved OS compared to patients with > 5 liver/lung metastases and/or other sites of distant metastasis (HR 0.48, 95% CI: 0.32, 0.76; p = 0.001). t-ROC analysis showed that a cut-off of ≤5 isolated liver/lung metastases was most predictive of survival at 12 (AUC 0.77) and 18 months (AUC 0.78) after diagnosis. Median OS of patients with ≤5 liver and/or lung metastases (n = 32) and > 5 liver/lung metastases and/or additional sites of metastasis (n = 135) was 13.7 vs. 5.8 months, respectively (p = 0.0004). Conclusions: In this study, we propose an anatomically-based definition of oligometastatic disease for stage IV PDAC patients. Our data showed that patients with ≤5 isolated liver/lung metastases have a more favorable prognosis and may benefit from early consideration of multimodal therapy intensification.