Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial.
BACKGROUND
To determine the response rate of trastuzumab and irinotecan in HER-2/neu overexpressing advanced colorectal cancer (CRC), determine the frequency of HER-2/neu expression in CRC, and evaluate the pharmacokinetics of trastuzumab in a phase II study.


METHODS
Patients were screened for HER-2/neu by immunohistochemistry (DAKO HercepTest). Prior chemotherapy was limited to one regimen. Trastuzumab was administered weekly (loading dose of 4 mg/kg i.v. and 2 mg/kg thereafter). Irinotecan 125 mg/m2, i.v. was administered weekly for 4 weeks with a 2-week rest period.


RESULTS
HER-2/neu overexpression was detected in 11 of 138 (8.0%) of screened tumors (2+ in 5 and 3+ in 6 patients). Nine patients were entered in the study; 6 had received prior chemotherapy. Partial responses were seen in 5 of 7 evaluable patients. Grade 3-4 toxicities in 31 cycles of therapy included diarrhea (19%), nausea (10%), and vomiting (6%). Leukopenia occurred in 6%, and congestive heart failure and acute renal failure (secondary to diarrhea and dehydration) were seen in 3% of cycles. The study was prematurely closed due to low accrual.


CONCLUSIONS
The low overexpression rate of HER-2/neu (8.0%) in advanced CRC limits the potential for further investigation of regimens involving trastuzumab, despite evidence suggestive of activity. Irinotecan did not alter the pharmacokinetic disposition of trastuzumab.
Ramanathan
Ramesh K
RK
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15232, USA. ramanathanrk@msx.upmc.edu
Hwang
Jimmy J
JJ
Zamboni
William C
WC
Sinicrope
Frank A
FA
Safran
Howard
H
Wong
Michael K
MK
Earle
Martin
M
Brufsky
Adam
A
Evans
Terry
T
Troetschel
Monica
M
Walko
Christine
C
Day
Roger
R
Chen
Helen X
HX
Finkelstein
Sydney
S
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002166:Camptothecin; D000077146:Irinotecan; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab