L-phenylalanine mustard (L-PAM) in the management of primary breast cancer:An update of earlier findings and a comparison with those utilizing L-PAM plus 5-fluorouracil (5-FU)

Abstract

In 1972, a prospective, randomized, multi-institutional, cooperative clinical trial was begun to evaluate the efficacy of prolonged 1-phenylalanine mustard (L-PAM) administration following operation in lengthening the disease free interval of patients with primary breast cancer. That protocol using a single agent was the first of a series directed toward evaluating successively more complex chemotherapeutic regimens in an attempt to define subsets of patients which might be responsive to less therapy than others. When it was observed that L-PAM prolonged the disease free interval, particularly of premenopausal patients, findings were reported and a new evaluation comparing L-PAM with L-PAM plus 5-fluorouracil (5-FU) was begun. Upon completion of patient accrual in that protocol, an additional trial comparing L-PAM and 5-FU with L-PAM, 5-FU and Methotrexate was implemented. The present report updates findings from the initial study and presents those from the second. It compares results across the first two protocols as well as between groups within a protocol. While insufficient time has elapsed for determining the ultimate worth of the modalities employed, findings from the second protocol confirm those previously reported indicating that L-PAM lengthens the disease free interval following mastectomy. The combination of L-PAM with 5-FU resulted in a reduction of treatment failure at 12 months which is as good or better than that observed with L-PAM in the first protocol lending further credibility to the earlier findings. While at the end of the first year following mastectomy there was alomst a 50% reduction in treatment failures in patients aged 50 or over (post-menopausal), by 18 months the reduction was 23% and at two years, based on small numbers of patients, only 5%. Examination of results from the first protocol (placebo vs L-PAM) after two years reveals a most highly significant effect of L-PAM in pre-menopausal women with one to three positive nodes. There is an 89% reduction of treatment failures. A similar but less striking effect is noted for those under 50 with ≥four positive nodes. In older patients in both nodal categories, the early observed effect for L-PAM has decreased with time. Inter-protocol comparisons relative to survival are premature. At two years survival in L-PAM patients is 36% greater than in those receiving placebo. It is somewhat better in every subgroup for those receiving L-PAM. Information relative to the effect of these agents on patient toxicity and loco-regional treatment failures is presented. All of the findings stress the urgency for obtaining results on subsets of patients rather than on a population as a whole and they lend support to the thesis that since breast cancer is an eponym to describe a heterogeneous group of tumors residing in a heterogeneous group of women, it is unlikely that uniformly qualitative and quantitative systemic regimens of therapy will be required for every patient.

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Affiliated Institutions

• University of Pittsburgh US

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