Harvey J. Lerner

Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer

In 1976 we began a randomized trial to evaluate breast conservation by a segmental mastectomy in the treatment of Stage I and II breast tumors less than or equal to 4 cm in size. The operation removes only sufficient tissue to ensure that margins of resected specimens are free of tumor. Women were randomly assigned to total mastectomy, segmental mastectomy alone, or segmental mastectomy followed by breast irradiation. All patients had axillary dissections, and patients with positive nodes received chemotherapy. Life-table estimates based on data from 1843 women indicated that treatment by segmental mastectomy, with or without breast irradiation, resulted in disease-free, distant-disease-free, and overall survival at five years that was no worse than that after total breast removal. In fact, disease-free survival after segmental mastectomy plus radiation was better than disease-free survival after total mastectomy (P = 0.04), and overall survival after segmental mastectomy, with or without radiation, was better than overall survival after total mastectomy (P = 0.07, and 0.06, respectively). A total of 92.3 per cent of women treated with radiation remained free of breast tumor at five years, as compared with 72.1 per cent of those receiving no radiation (P less than 0.001). Among patients with positive nodes 97.9 per cent of women treated with radiation and 63.8 per cent of those receiving no radiation remained tumor-free (P less than 0.001), although both groups received chemotherapy. We conclude that segmental mastectomy, followed by breast irradiation in all patients and adjuvant chemotherapy in women with positive nodes, is appropriate therapy for Stage I and II breast tumors less than or equal to 4 cm, provided that margins of resected specimens are free of tumor.

Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update.

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 ≫4 positive nodes. Results, however, reveal that there is a risk in combining all patients with ≫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 ≫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 ≫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 ≫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.

L-Phenylalanine Mustard (L-PAM) in the Management of Primary Breast Cancer

Abstract Prolonged L-phenylalanine mustard (L-PAM) administration as an adjuvant to mastectomy in the management of patients with primary breast cancer and pathologically positive axillary nodes was evaluated by a prospective, randomized, clinical trial. Treatment failures occurred in 22 per cent of 108 patients receiving placebo and 9.7 per cent of 103 women given L-PAM (p = 0.01). A statistically significant difference (p = 0.02) existed in favor of L-PAM relative to disease-free interval. In premenopausal women, the difference with respect to disease-free interval of treated and control groups was highly significant (p = 0.008). A treatment failure occurred in 30 per cent of premenopausal patients receiving placebo and 3 per cent of those treated with L-PAM (p = 0.008). Whereas a similar trend was observed in postmenopausal patients, the difference is not statistically significant. Thus, L-PAM has been demonstrated to be effective in the treatment of women with primary breast cancer, particularly those...

Treatment of Primary Breast Cancer with Chemotherapy and Tamoxifen

We studied the possibility that the addition of tamoxifen to L-phenylalanine mustard combined with 5-fluorouracil enhances the benefit from the latter two drugs that has been observed in women with primary breast cancer and positive axillary nodes. Recurrence of disease was reduced at two years in patients given the three-drug regimen whose tumor estrogen-receptor levels were greater than or equal to 10 fmol. Among patients greater than or equal to 50 years old treatment failure was significantly reduced (P less than 0.001): by 51 per cent in those with one to three positive nodes and by 64 per cent in those with four or more. Higher receptor levels were associated with a greater probability of disease-free survival. Patients less than or equal to 49 years old were less responsive: those with one to three positive nodes received no benefit from tamoxifen at any receptor level, whereas those with four or more appeared to have reduced treatment failure associated with higher receptor levels. This adjuvant chemotherapy is not indicated in patients less than or equal to 49 years old whose tumor receptor levels are below 10 fmol; there is a suggestion of benefit in patients greater than or equal to 50 years old whose levels are low.

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)

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.

Malignant mesothelioma. The eastern cooperative oncology group (ECOG) experience

The Eastern Cooperative Oncology Group has conducted a retrospective review of their experience of 96 patients with a tissue diagnosis of malignant mesothelioma treated between 1972 and 1980 on four separate sarcoma chemotherapy protocols. Thirty‐two of the 96 patients were diagnosed and treated in South Africa. There were 75 males and 21 females with an age range of 27 to 78 with a median of 58.1 years. All, except for 28 patients, had some form of prior therapy. The median time from the onset of symptoms to diagnosis was 12 weeks; from the diagnosis to randomization was 15.1 weeks. Only 12 of the 96 patients demonstrated an objective regression. The responses were 7/51 on Adriamycin with 2 complete responses (complete responses—38 weeks and 52 weeks), 2/24 on Adriamycin combinations, 2/7 on cycloleucine, 1/3 on bleomycin, and 0/10 on non‐Adriamycin combinations. Only 1/28 responded to a cross‐over therapy (Adriamycin). The median survival from the start of protocol chemotherapy was 7.4 months and 7.5 months for Adriamycin treated patients. The median survival for responders was 29.9 months, compared to 6.3 months for nonresponders. The median survival for this entire series from the time of first symptoms was 15.2 months. The median survival for the 7 patients with abdominal mesothelioma was 12 weeks. There was a slight improvement in survival for the South Africans as compared to the Americans. Malignant mesothelioma in this series, was a rapidly lethal, nonresponsive disease whose treatment will require new therapies. Cancer 52:1981‐1985, 1983.

A randomized prospective comparison of methotrexate with a combination of methotrexate, bleomycin, and cisplatin in head and neck cancer

Combination chemotherapy with methotrexate, bleomycin, and cis‐diamminedichloroplatinum (II) was compared to weekly therapy with methotrexate alone in a randomized prospective trial in 163 patients with recurrent or metastatic squamous cancer of the mucous membranes of the head and neck. The combination produced responses in 48% compared to 35% for methotrexate alone, with 16% complete remissions versus 8%, respectively. The difference in overall and complete remission rates is significant (P = 0.04) using a one‐sided binary regression test. Median time to disease progression among responders was 5.8 months for the combination and 5 months for methotrexate, and median survival was 5.6 months in each group. Toxicity was similar in the two groups. Ambulatory patients, those without fixed neck nodes and those without distant metastases, responded more often. Poor performance status, distant metastases, history of heavy smoking, and adjacent organ invasion by the primary tumor were associated with shorter survival, as were weight loss, the presence of tumor in the neck, and heavy alcohol consumption. The addition of bleomycin and cisplatin to methotrexate produces more remissions, and especially complete remissions, but has not made a major impact on the course of far‐advanced head and neck cancer.

Survival of patients at pennsylvania hospital with hepatic metastases from carcinoma of the colon and rectum

SummaryA retrospective study of 58 patients with hepatic metastases from carcinoma of the colon at the time of initial operation revealed a median survival of 178 days from the time of operation. No chemotherapeutic agents were administered to any of the patients.

Mitomycin‐C, methotrexate, bleomycin and cis‐diamminedichloroplatinum II in the chemotherapy of advanced squamous cancer of the head and neck

Thirty‐four patients with advanced squamous cancer of the head and neck were treated with an outpatient regimen combining mitomycin‐C, cis‐diamminedichloroplatinum (II), methotrexate and bleomycin. Five had complete remissions and 15 partial remissions, for an overall response rate of 59%. Responses were noted in 11 of 13 patients (85%) with disease above the clavicles without prior irradiation. Median duration of partial remission was four months. Response rate was independent of age, performance status, presence of distant metastases and primary site. Hematologic toxicity was substantially more severe with this program than had been observed in a prior study using the same regimen without mitomycin‐C. Since neither complete nor partial response rates, nor response durations improved with the addition of mitomycin, we conclude that it adds little to the efficacy of the other three agents.

Concomitant hydroxyurea and irradiation: Clinical experience with 100 patients with advanced head and neck cancer at Pennsylvania Hospital☆☆☆

One hundred outpatients with proved advanced epidermoid carcinoma of the head and neck underwent complete treatment with concomitant hydroxyurea and irradiation therapy. Seventy-three patients exhibited complete regression of the tumor. All patients became candidates for operation after completion of combination therapy, although not all patients accepted surgery.