Duodenal ischemia and upper GI bleeding are dose-limiting toxicities of 24-h continuous intra-arterial pancreatic perfusion of gemcitabine following vascular isolation of the pancreatic head: early results from the Regional Chemotherapy in Locally Advanced Pancreatic Cancer (RECLAP) study

Abstract

Background: Regional chemotherapy is used successfully in the treatment of both primary and secondary malignancies, in particular of the peritoneal surface and the liver, and is currently explored as an attractive approach for patients with locally advanced pancreatic ductal adenocarcinoma. To establish the feasibility and toxicity of regional intra-arterial gemcitabine delivered as a 24-h continuous infusion to the pancreas as a novel treatment option for patients with locally advanced PDAC a phase I clinical trial was conducted.

Methods: Between April 2011 and September 2013 six patients with biopsy confirmed, borderline or unresectable pancreatic adenocarcinoma, and having received at least one line of systemic chemotherapy, underwent vascular redistribution of the inflow to the head of the pancreas by arterial coil embolization followed by perfusion catheter placement within the splenic artery. Patients were treated with increasing doses of gemcitabine administered by continuous splenic arterial infusion over 24 h with inter-patient and intra-patient dose escalation scheme. The primary endpoint was toxicity of the intra-arterial gemcitabine regimen and to establish the maximum tolerated dose.

Results: Catheter placement and gemcitabine infusion was successful in all patients enrolled to date (n = 6). Four out of six patients experienced catheter tip migration requiring replacement or revision. Patients received a median of four doses of 24-h gemcitabine infusion. Two patients developed grade 3 and 4 duodenal ischemia and upper gastrointestinal bleeding. Median overall survival was 15.3 months and median time to progression was 3 months. Three patients (50 %, n = 3/6) progressed systemically. Two patients had stable disease >4 months following treatment and underwent pancreaticoduodenectomy.

Conclusions: While technically feasible to treat locally advanced pancreatic ductal adenocarcinoma, prolonged regional pancreatic perfusion with gemcitabine following pancreatic arterial redistribution carries a high risk for gastrointestinal toxicity. Shorter infusion schedules with frequent on treatment evaluations should be considered for future clinical trials.

Figure 1

Re-vascularization protocol of the head of the pancreas of patients enrolled onto the RECLAP trial: hemodynamic changes following peri-pancreatic arterial collateral embolization and catheter placement prior to selective regional chemotherapy administration. A) Celiac arteriogram showing gastroduodenal artery (GDA), proper hepatic artery (PH), and splenic artery (SA) prior to vascular redistribution. B–C) Arteriogram of gastroduodenal artery (arrows) prior to embolization (B) and following coil embolization (C, arrows). D–E) Arteriogram of inferior pancreatoduodenal artery (arrows) prior to embolization and following coil embolization.

Figure 2

Post-embolization arterial phase cone beam CT images of the pancreas and port placement. A) Arterial phase cone beam CT images following injection of the splenic artery catheter with contrast. Pancreatic glandular enhancement (arrows) and splenic enhancement. B/C) Femoral and subclavian arterial port and infusion catheter placement. In cases where celiac encasement or tortuosity precluded advancement of the catheter into the splenic artery, splenic artery access for the perfusion catheter was achieved via left subclavian artery catheterization. A left infraclavicular subcutaneous pocket was created for the Celsite port (C).

Figure 3

Upper gastrointestinal bleeding related to duodenal ischemia was observed in two patients resulting in dose limiting grade 3 toxicities. A) Upper endoscopy of patient 4 shows duodenal enteritis in D1 36 hours following continuous infusion of super-selective gemcitabine at 115mg/m2. B) Several ulcerative lesions were covered with bile-tinged fibrin (arrows). C) Areas of ischemia in the duodenal mucosae (arrows) D) Active bleeding in the periampullary region (arrows).

Figure 4

Two patients with PDAC had stable disease. A/B) Representative computed topography images of patient 2 prior to regional infusion of gemcitabine (A) and following eight cycles of intra-arterial pancreatic gemcitabine infusion. C–E) 3D reconstructed tumor measurement images of patient 2 at the beginning of treatment (C), two months (D), and four months (E) after starting treatment after having received eight cycles of increasing intra-arterial gemcitabine infusions. The patient had an 8% reduction in tumor volume during treatment and was taken to the operating room where a pancreaticoduodenectomy with R0 resection was performed.

Figure 5

Neovessel formation four months after vascular redistribution following embolization of peripancreatic arterial collaterals to the pancreatic head and start of gemcitabine perfusions. A) Celiac angiogram demonstrating splenic artery and pancreatic branches prior to hemodynamic change B) Celiac angiogram with neovessel formation (black arrows) four months after hemodynamic change and eight cycles of gemcitabine.