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Publications (7)75.22 Total impact

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    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.
    Cancer 06/2006; 39(6):2883 - 2903. · 5.20 Impact Factor
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    ABSTRACT: During the 1970s, information obtained from animal tumor models and from patients with a spectrum of solid tumors indicated the worth of a variety of immunostimulating agents. These findings provided a biological and clinical rationale for conducting randomized trials to evaluate the worth of those agents. Consequently, in May 1977 the National Surgical Adjuvant Breast and Bowel Project (NSABP) implemented a randomized trial to determine whether Corynebacterium parvum (C. parvum, CP) plus chemotherapy would be more effective than chemotherapy alone in prolonging the disease-free survival (DFS) and survival (S) of patients with primary operable breast cancer and positive axillary nodes. The results of that trial through 8 years of follow-up fail to indicate that treatment with CP used in conjunction with 1-phenylalanine mustard (L-PAM) plus 5-fluorouracil (PF) results in a better DFS and S than that observed after chemotherapy alone. Use of the immunomodulator has instead resulted in a poorer, but not statistically significant, outcome. Despite adjustments made to account for any imbalance in distribution of prognostic factors between the two treatment groups and despite considering treatment compliance as a factor, the unfavorable outcome persisted. A high incidence of fever and chills was associated with the administration of CP. The administration of hydrocortisone before each CP treatment reduced the frequency of those and other systemic effects. The failure to demonstrate a benefit from CP is in keeping with the failure of other nonspecific stimulating agents to contribute to the creation of a new paradigm for the treatment of breast cancer.
    Cancer 06/2006; 66(2):220 - 227. · 5.20 Impact Factor
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    ABSTRACT: In 1971 we began a randomized trial to compare alternative local and regional treatments of breast cancer, all of which employ breast removal. Life-table estimates were obtained for 1665 women enrolled in the study for a mean of 126 months. There were no significant differences among three groups of patients with clinically negative axillary nodes, with respect to disease-free survival, distant-disease--free survival, or overall survival (about 57 per cent) at 10 years. The patients were treated by radical mastectomy, total ("simple") mastectomy without axillary dissection but with regional irradiation, or total mastectomy without irradiation plus axillary dissection only if nodes were subsequently positive. Similarly, no differences were observed between patients with clinically positive nodes treated by radical mastectomy or by total mastectomy without axillary dissection but with regional irradiation. Survival at 10 years was about 38 per cent in both groups. Our findings indicate that the location of a breast tumor does not influence the prognosis and that irradiation of internal mammary nodes in patients with inner-quadrant lesions does not improve survival. The data also demonstrate that the results obtained at five years accurately predict the outcome at 10 years. We conclude that the variations of local and regional treatment used in this study are not important in determining survival of patients with breast cancer.
    New England Journal of Medicine 04/1985; 312(11):674-81. · 54.42 Impact Factor
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    ABSTRACT: The current findings completely affirm the validity of our original observations indicating the appropriateness of grouping primary breast cancer patients into those with negative, 1 to 3, or greater than or equal to 4 positive nodes. Results, however, reveal that there is a risk in combining all patients with greater than or equal to 4 positive nodes into a single group. Since there was a 25% greater disease-free survival and an 18% greater survival in those with 4 to 6 than in those with greater than or equal to 13 positive axillary nodes, such a unification may provide misleading information regarding patient prognosis, as well as the worth of a therapeutic regimen when compared with another from a putatively similar patient population. Of particular interest were findings relating the conditional probability, i.e., the hazard rate, of a treatment failure or death each year during the 5-year period following operation to nodal involvement with tumor. Whereas the hazard rate for those with negative, or 1 to 3 positive nodes, was relatively low and constant, in those with greater than or equal to 4 positive nodes the risk in the early years was much greater, but by the fifth year it was similar to that occurring when 1-3 nodes were involved, and not much different from negative node patients. The same pattern existed whether 4 to 6 or greater than or equal to 13 nodes were positive. When the current findings are considered relative to other factors with predictive import, it is concluded that nodal status still remains the primary prognostic discriminant.
    Cancer 12/1983; 52(9):1551-7. · 5.20 Impact Factor
  • International advances in surgical oncology 02/1982; 5:65-90.
  • Cancer 07/1977; 39(6 Suppl):2883-903. · 5.20 Impact Factor
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    ABSTRACT: Since 1972, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has carried out a series of clinical trials evaluating the worth of adjuvant chemotherapy in the management of patients with primary breast cancer. This report provides information concerning (a) protocol compliance relative to drug administration and (b) acute toxicity encountered by patients in three separate trials who were given one-, two- or three-drug chemotherapy within 1 month of operation. The findings are derived from 1548 women who received 20,765 courses of chemotherapy, the most extensively documented experience yet reported. They indicate that despite the large number of physicians and the heterogeneity of the institutions participating, large cooperative efforts can be accomplished with credibility. Only 13 (0.8%) of the women failed to complete all courses of therapy for reasons directly related to nonprotocol compliance by physicians. Only 4.3% failed to complete therapy for miscellaneous reasons other than toxicity, treatment failure, occurrence of a second primary, or death unrelated to tumor. While almost all patients experienced toxic reactions during the therapy, only 3%--4% of recipients of melphalan (L-PAM; P) and 4%--5% of recipients of L-PAM + 5-FU(F)(PF) failed to complete 2 years of therapy because of toxicity. Of those patients receiving PF + methotrexate (MTX; M) (PMF), 15% did not finish their treatment for that reason. While there was little difference in hematologic and nonhematologic toxicity between those patients receiving P or PF, and such toxicity was generally acceptable to both patients and physicians, the addition of MTX (PMF) resulted in greater toxicity (vomiting, stomatitis, and alopecia) which was less readily accepted. Tolerance of any of these regimens was unrelated to patient age, despite the belief that older women are less tolerant of chemotherapy. The earlier toxicity occurred, the greater was the number of subsequent courses associated with toxicity, and the lower was the total amount of drug received. The extent of the toxicity produced by the NSABP regimens and the end results obtained with them, must be compared with the end results and toxicity obtained by other regimens before making a choice of the adjuvant therapy to be used.
    Cancer treatment reports 65(5-6):363-76.