Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

IMPORTANCE: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. OBJECTIVE: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. DESIGN, SETTING, AND PARTICIPANTS: A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. INTERVENTIONS: Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin. MAIN OUTCOMES AND MEASURES: The primary outcome was progression-free survival (PFS) of 80% at 6 months. RESULTS: For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). CONCLUSIONS AND RELEVANCE: Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.

Brain Metastases in Pancreatic Ductal Adenocarcinoma: Assessment of Molecular Genotype-Phenotype Features-An Entity With an Increasing Incidence?

PURPOSE: To assess clinical characteristics of patients with metastatic pancreas ductal adenocarcinoma (PDAC) and brain metastases (BM), and to assess somatic and germ-line molecular profiles where performed. PATIENTS AND METHODS: Patients with PDAC and BM between January 1990 and January 2016 were identified. Molecular characteristics of somatic and germ-line testing where performed in the subset of patients who had provided informed consent. Somatic alterations were assessed by either MSK-IMPACT testing (>340 key cancer genes) or Sequenom testing (8-gene panel). Overall survival was calculated from date of diagnosis to either date of last follow-up or death. Survival after BM was calculated from date of diagnosis of BM by radiology or pathology to either date of last follow-up or death. RESULTS: From a total of 5824 patients with PDAC identified from January 2000 to January 2016, twenty-five patients (0.4%) had BM. Median age at PDAC diagnosis was 58 years. Median time to the development of BM from initial PDAC diagnosis was 17 months (range, 0-79 months). Median overall survival after BM diagnosis was 1.5 months (range, 1-31 months). Overall survival for patients who had craniotomy (n = 4) was 11 months (range, 1-31 months), with 2 long-term survivors at 21 and 31 months, respectively. Four patients had leptomeningeal disease. Six of 25 patients had germ-line testing, and 3 had BRCA mutations (2 BRCA1 and 1 BRCA2). Somatic profiling identified KRAS mutations in 100% (4 G12D, 2 G12V, and 1 Q61K). CONCLUSION: BM from PDAC is a rare event. We identified a speculative association of germ-line BRCA1/2 alterations with BM in PDAC, which requires corroboration. Survival after BM development is poor; prolonged survival occurred in selected patients via a multidisciplinary approach.

Incidence, Management, and Implications of Visceral Thrombosis in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Visceral or splanchnic thrombosis is defined as thrombi within the hepatoportal venous system, including portal (PV), mesenteric (MV), and splenic vein (SV), as well as thrombi in renal or gonadal veins. There are limited data to evaluate the prognostic significance, incidence, and clinical management of visceral thromboses in patients with pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We conducted an analysis of 95 patients treated at Memorial Sloan Kettering Cancer Center with PDAC who had a visceral thrombosis. RESULTS: A total of 153 visceral thromboses (VsT) were identified in 95 patients (n = 51, 54% woman). A total of 36 patients (37%) had locally advanced disease, and n = 59 (62%) had metastatic disease. Systemic therapies received included FOLFIRINOX (n = 57, 60%) and GC/PTX (n = 27, 28%). All VsT events were incidentally detected. Overall survival of cohort was 12.3 months (range, 10.2-14.4 months). Visceral thrombosis incidence in the cohort was as follows: portal vein (PV) (45%), MV (26%), SV (17%), and gonadal veins (8%). Time to develop first VsT was 4.3 months (range, 3-5.6 months), and time to death from VsT development was 1.87 months (range, 0.8-2.8 months). Forty-five patients (47%) developed a second VsT. Sixty percent had a Khorana risk score of > 3. Thirty-nine patients (41%) were treated with short-term anticoagulation (AC) (< 1 month) (low-molecular-weight heparin, n = 34). Forty-five patients (47%) were treated with long-term AC (> 1 month) (low-molecular-weight heparin, n = 32; 23 were transitioned to an oral anticoagulant). Twenty-two patients (23%) were not treated with AC. Eight patients (8%) had a bleeding complication from AC. Portal vein thrombosis had the shortest overall survival at 3.6 months (range, 2.3-4.8 months). CONCLUSION: In PDAC, VsT can frequently present as an incidental finding on routine abdominal imaging. The most common location is PV, followed by MV and SV. We observed that AC is underutilized in this setting despite a low bleeding complication rate. PV was associated with the least overall survival of the VsT. Future large prospective studies should explore the role of AC and value in this setting.