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Chapter 6112paclitaxel plus gemcitabine as the first-line treatment for patients with metastatic or recurrent pancreatic cancer compared to modified FOLFIRINOX or S-IROX (S1 in combination with irinotecan and oxaliplatin) based on the primary endpoint, a median OS of 17.1 months with nab-paclitaxel plus gemcitabine, 14.0 months with modified FOLFIRINOX (HR 1.31), and 13.6 with S-IROX (HR 1.35). The study was terminated for futility since the predictive probability for achieving superiority at the final analysis was 0.73% for modified FOLFIRINOX and 0.48% the S-IROX. Grade 3%u20134 non-hematological toxicity (anorexia) rates were higher for modified FOLFIRINOX (23.3%) and S-IROX (27.5%) compared to nab-paclitaxel plus gemcitabine (5.0%). These results are markedly different compared to the PRODIGE-4 and MPACT trials and also to a previous Dutch nationwide cohort study (20). Peer reviewed publication of this trial is awaited to provide a better understanding of the factors contributing to the observed differences in toxicity profiles and treatment outcomes. FOLFIRINOX is the most commonly used first-line systemic treatment for patients with metastatic PDAC in the Netherlands (20). In the PRODIGE-4 trial, the median number of treatment cycles of first-line FOLFIRINOX administered was 10, with a range from 1 to 47 cycles (13). In daily clinical practice, the maximum number of cycles is commonly limited to 12 cycles in patients with stable disease or response followed by a chemotherapy interruption to reduce toxicity. Reintroduction of FOLFIRINOX can be considered when signs of disease progression occur after a 4-6 months treatment free interval since the last FOLFIRINOX administration. This approach is not supported by clinical studies. In chapter 3 we describe a retrospective nationwide cohort study focusing on patients with advanced PDAC (not eligible for curative treatment) who were treated with FOLFIRINOX reintroduction after a therapy-free interval of 3 months or more following first-line palliative FOLFIRINOX. Data of the Netherlands Cancer Registry (NCR) were used for this cohort study. Out of the total 1381 patients who received first-line FOLFIRINOX, 119 were treated with FOLFIRINOX reintroduction after a therapy-free interval of 3 months or more. A favorable median OS of 23 months from diagnosis and 8.3 months from reintroduction of FOLFIRINOX with a median therapy-free interval of 7 months between first-line and FOLFIRINOX reintroduction was seen after FOLFIRINOX reintroduction. To our knowledge this is the first study that focuses on reintroduction of FOLFIRINOX after a treatment interruption following initial palliative FOLFIRINOX. Several studies explored a maintenance approach following induction chemotherapy with FOLFIRINOX or nab-paclitaxel plus gemcitabine. Maintenance therapy with 5FU, FOLFOX, or FOLFIRI after induction chemotherapy with FOLFIRINOX seems to be effective in patients with metastatic PDAC. (15-18). For patients with a known germline BRCA1/2