Treatment of inoperable pancreatic carcinoma using a cell-based local chemotherapy: results of a phase I/II clinical trial.
BACKGROUND
The use of ifosfamide for conventional chemotherapy of pancreatic tumors is limited by systemic toxicity caused, in part, by its activation by liver-specific cytochrome enzymes and the subsequent systemic distribution of metabolites. Activation at the tumor site, on the other hand, should reduce systemic toxicity and provide more effective local therapeutic concentrations. The results of a phase I/II open, single-arm clinical trial of local intratumor activation of ifosfamide are presented.


METHODS
Treatment involved angiographic implantation of encapsulated allogeneic cells, genetically modified to overexpress the enzyme cytochrome P-450 2B1, into the vasculature leading to the tumor. The cells are protected from immune rejection and locally activate systemically administered ifosfamide to antitumor metabolites.


RESULTS
Of the 14 patients treated, 4 showed tumor regression and the other 10 patients showed stable disease, i.e., no further tumor growth. The median survival of the patient cohort was twice that of the control group. The 1-year survival was 36%, i.e., threefold that of the control group (twice that reported for gemcitabine). As far as clinical benefit was concerned, 4 of the 13 evaluable patients reported improvements in pain assessment at the last observation, with 6 remaining unchanged (4 of these experienced no pain) and 3 patients experiencing slightly greater pain. Using a worst case scenario, 50% experienced a clinical benefit, which rose to 71% of patients if a best case scenario was applied. The best predictor of clinical benefit was lack of pain, whereas significant weight loss possibly predicts a poor clinical benefit.


CONCLUSIONS
The data obtained from this phase I/II clinical trial are promising and suggest that further clinical trials are warranted.
Salmons
Brian
B
Austrianova GmbH, Veterinaerplatz 1, A-1210 Vienna, Austria.
Löhr
Matthias
M
Günzburg
Walter H
WH
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000627:therapeutic use*; D017690:Cell Transplantation; D019362:Cytochrome P-450 CYP2B1 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D015870:Gene Expression / Q000235:genetics; D005818:Genetic Engineering; D015316:Genetic Therapy; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage* / Q000627:therapeutic use*; D036502:Infusions, Intralesional; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D011446:Prospective Studies; D015996:Survival Rate
D018906:Antineoplastic Agents, Alkylating; D019362:Cytochrome P-450 CYP2B1; D007069:Ifosfamide