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Conrad Notes
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D.J. Slamon, MD, PhD, University of California-Los Angeles School of Medicine, found antibodies to the human epidermal growth factor receptor (HER-2) additive in treating breast cancer patients. Combined use of HER-2 antibodies (H) with cyclophosphamide/doxorubicin or paclitaxel improved time to disease progression (TTP) by 4 months and overall response rate (RR) by 26%. Of concern is the more frequent occurrence of grade 3/4 cardiomyopathy with combined therapy. This well-controlled, multicenter trial in 469 high-risk women provides a rationale for future combination studies.
Introduction to Phase III trial Slamon et al correlated relapse and poor survival in primary human breast cancers showing amplified HER-2/neu oncogenes (Science 1987;235; 177). The 189 sampled patients had a positive rate of 28%. Two or more copies of the tumor deoxyribonucleic acid (DNA) shortened median survival based on the Kaplan-Meier method (Science 1989;244:707). The results of these studies led to preparation and purification of rhu Mab HER2 antibodies (H) for clinical evaluation.

Baselga et al conducted a Phase II study in women with metastatic disease including overexpressed HER-2 (J Clin Oncol 1996;14:737). Five of 43 evaluable patients showed remissions (1 complete and 4 partial) after an iv loading dose of 250 mg H plus 100 mg weekly for 10 weeks. Toxicity in 46 recipients after 768 administrations included moderate fever and chills (5/46), pain at tumor site (2/46), diarrhea (2/46), and nausea/ vomiting (1/46). One patient reported severe pain at the tumor site.

Controlled trial methodology Eligible cancer patients had to have HER-2 overexpression using immunohistochemistry, a Karnofsky normal function score of 60 or more, no prior stage 4 chemotherapy, and measurable disease. The 469 patients entering the multicenter trial were assigned randomly to take chemotherapy alone or combined with HER-2 antibodies. Among the measured response variables were: TTP as determined by an independent evaluation group, RR, duration of response, 1-year survival, quality of life (QoL), and adverse drug events (ADEs).

The patients received one of two chemotherapy regimens every 3 weeks for six cycles with or without added antibodies (H):

  • A - Cyclophosphamide (600 mg/msq) and doxorubicin (60 mg/msq) or epirubicin (75 mg/msq)
  • B - Paclitaxel (175 mg/msq) if previously treated with doxorubicin
  • H - Loading dose of 4 mg/kg followed by 2 mg/kg weekly
Overall, the treatment assignments were:
Slamon chart
Results of treatment at 12 months Slamon reported statistically significant improvement comparing test and control patients:
  • Overall RR increased to 62% vs 36% with chemotherapy alone (p<0.01)
  • TTP moved to a median of 8.6 mo from a control of 5.5 mo (p<0.01)
The quality of life in antibody recipients showed an improvement trend by the European Organization for Research and Treatment of Cancer (EORTC) Questionnaire QLQ-C30. Duration of response and 1-year survival rate also favored H-combined therapy, without reaching statistical significance (p>0.05).
Adverse drug events in H-treated women Preliminary analyses show leukopenia and anemia occurred more frequently in H-treated patients. More women also developed grade 3/4 cardiomyopathy, 20% vs 3%, but responded favorably to ACE inhibitors, diuretics, or an occasional inotrope, according to Slamon. Combining chemotherapy with H monoclonal antibodies was well tolerated according to this double-blind, multicenter, multinational trial in 469 evaluable patients.

Eugene A. Conrad

Presented at the American Society of Clinical Oncology (ASCO) Meeting, May 16-19, 1998
Copyright © 1998 Conrad Group Inc. All Rights Reserved
Eugene A. Conrad, PhD, MPH / ISSN 1078-2230 / June 1998
Send Comments to: ConradNote@aol.com

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