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

• Published in: Investigational new drugs 2015-02, Vol.33 (1), p.109-118
• Main Authors: Beane, Joal D., Griffin, Kayla F., Levy, Elliot B., Pandalai, Prakash, Wood, Bradford, Abi-Jaoudeh, Nadine, Beresnev, Tatiana, Shutack, Yvonne, Webb, Carole C., Avital, Itzhak, Rudloff, Udo
• Format: Article
• Language: English
• Subjects: Aged; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - therapeutic use; Cancer therapies; Carcinoma, Pancreatic Ductal - drug therapy; Catheterization; Catheters; Chemotherapy; Clinical outcomes; Cytotoxicity; Deoxycytidine - administration & dosage; Deoxycytidine - adverse effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Drug dosages; Duodenal Diseases - chemically induced; Duodenum - blood supply; Duodenum - drug effects; Embolization; Female; Gastroenterology; Gastrointestinal Hemorrhage - chemically induced; Humans; Ischemia; Ischemia - chemically induced; Liver; Male; Maximum Tolerated Dose; Medical prognosis; Medicine; Medicine & Public Health; Metastasis; Middle Aged; Oncology; Pancreas - blood supply; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Patients; Perfusion; Pharmaceutical sciences; Pharmacology/Toxicology; Phase I Studies; Radiation therapy; Response rates; Splenic Artery; Studies; Surgery; Surgical outcomes; Toxicity; Treatment Outcome
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-014-0157-7

Summary 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.