Dr. Gary J. Becker Young Investigator Award: intraarterial adenovirus for metastatic gastrointestinal cancer: activity, radiographic response, and survival.
OBJECTIVE
To determine the antitumoral activity and radiographic response pattern of intraarterial administration of a selective replication-competent adenovirus in patients with hepatic metastases from gastrointestinal carcinomas.


METHODS
Thirty-five patients were treated, seven in the dose-escalation phase and 28 at high doses. Inclusion criteria allowed mild laboratory value and performance status abnormalities and as much as 50% replacement of hepatic volume by tumor. An attenuated adenovirus that selectively replicates in p53-deficient cells (Onyx-015) was administered by hepatic arterial infusion at doses as high as 2 x 10(12) particles for two cycles. Subsequent cycles (maximum of eight total) were administered in combination with intravenous 5-fluorouracil (5-FU) and leucovorin.


RESULTS
Tumor responses were demonstrated in combination with chemotherapy, even in 5-FU-resistant patients. The 15 patients who responded radiographically showed a pattern of acute tumor enlargement despite normalization of laboratory and clinical parameters, followed by very slow regression of tumor size. Radiographic response did not correlate with p53 status. Median survival of radiographic responders (475 days) was significantly longer than that of nonresponders (143 days).


CONCLUSIONS
Hepatic arterial infusion of the replication-selective adenovirus Onyx-015 in combination with chemotherapy resulted in tumor regressions in select patients, including some in whom previous chemotherapy had failed. A biphasic radiographic response pattern was demonstrated. The mechanism of action appears to be more complex than that seen in vitro.
Sze
Daniel Y
DY
Division of Cardiovascular and Interventional Radiology, Stanford University Medical Center, Stanford, CA 94305-5642, USA. dansze@stanford.edu
Freeman
Scott M
SM
Slonim
Suzanne M
SM
Samuels
Shaun L
SL
Andrews
James C
JC
Hicks
Marshall
M
Ahrar
Kamran
K
Gupta
Sanjay
S
Reid
Tony R
TR
D000256:Adenoviridae; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005770:Gastrointestinal Neoplasms / Q000473:pathology*; D015316:Genetic Therapy; D006801:Humans; D007261:Infusions, Intra-Arterial; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011859:Radiography; D016896:Treatment Outcome; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000627:therapeutic use; D014765:Viral Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*
D014613:Vaccines, Attenuated; D014765:Viral Vaccines; C464532:dl1520; D002955:Leucovorin; D005472:Fluorouracil