Platinum-based chemotherapy in locally advanced or metastatic pancreatic ductal adenocarcinoma

$\bf Background:$ Different therapeutic options are available for the treatment of advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). Platinum-based multi-agent chemotherapy regimens, such as FOLFIRINOX, are important elements in the multidisciplinary management of PDAC. $\bf Summary:$ At least one third of patients with metastatic PDAC are eligible for treatment with FOLFIRINOX. Eligibility criteria include good performance status and the absence of relevant comorbidities. However, chemotherapies can potentially be associated with serious adverse events, such as diarrhea or polyneuropathies. Here, we review relevant data from first-line, second-line, and maintenance therapy trials as well as real-world data. In addition, we address the management of possible adverse events. $\textbf {Key Messages:}$ (1) Selection of a suitable treatment regime depends on patient performance status, comorbidities, and anticipated toxicity. (2) FOLFIRINOX is an appropriate treatment for patients up to 75 years of age with an ECOG PS of 0 or 1, without relevant comorbidities, normal or nearly normal bilirubin levels, and no significantly reduced DPD activity. (3) In particular, patients with germline $textit {BRCA1/2 (gBRCA1/2)}$ or $\it PALB2$ mutations may benefit from first-line platinum-containing therapy. (4) Early and comprehensive testing of the patient’s mutational status could support the first-line treatment decision-making

Dihydropyrimidine dehydrogenase testing prior to treatment with 5-Fluorouracil, Capecitabine, and Tegafur

$\bf Background:$ 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2–1.0%. $\bf Summary:$ Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. $\bf Key Messages:$ (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring

Microsatellite instability (MSI-H) is associated with a high immunoscore but not with PD-L1 expression or increased survival in patients (pts.) with metastatic colorectal cancer (mCRC) treated with oxaliplatin (ox) and fluoropyrimidine (FP) with and without bevacizumab (bev)

$\bf Introduction$ In a retrospective analysis of two randomized phase III trials in mCRC patients treated first line with oxaliplatin, fluoropyrimidine with and without Bevacizumab (the AIO KRK 0207 and R091 trials) we evaluated the association of high microsatellite instability (MSI-H), immunoscore (IS) and PD-L1 expression in relation to overall survival (OS). $\bf Methods$ In total, 550 samples were analysed. Immunohistochemical analysis of the MMR proteins and additionally fragment length analysis was performed, molecular examinations via allele-discriminating PCR in combination with DNA sequencing. Furthermore PD-L1 and IS were assessed. $\bf Results$ MSI-H tumors were more frequent in right sided tumors (13.66% vs. 4.14%) and were correlated with mutant BRAF ($\it p$ = 0.0032), but not with KRAS nor NRAS mutations (MT). 3.1% samples were found to be PD-L1 positive, there was no correlation of PDL1 expression with MSI-H status, but in a subgroup analysis of MSI-H tumors the percentage of PD-L1 positive tumors was higher than in MSS tumors (9.75% vs. 2.55%). 8.5% of samples showed a positive IS, MSI-H was associated with a high IS. The mean IS of the pooled population was 0.57 (SD 0.97), while the IS of MSI-H tumors was significantly higher (mean of 2.4; SD 1.4; $\it p$ =< 0.0001). $\bf Discussion$ Regarding OS in correlation with MSI-H, PD-L1 and IS status we did not find a significant difference. However, PD-L1 positive mCRC tended to exhibit a longer OS compared to PD-L1 negative cancers (28.9 vs. 22.1 months)