Paul P. Carbone

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-Related Myelodysplasia and Acute Leukemia in Non-Hodgkin's Lymphoma Patients

PURPOSE Standard therapies for non-Hodgkins lymphoma (NHL) are associated with an increased risk of developing treatment-related myelodysplastic syndrome or acute myelogenous leukemia (tMDS/AML). However, there is considerable debate over the incidence or risk of tMDS/AML in NHL patients treated with any particular modality and the factors that contribute to malignant transformation. DESIGN Conclusions were based on thorough analysis of data reported in the peer-reviewed literature and careful examination of the statistical methodology and methods for identifying cases of tMDS/AML. Unless noted, data are reported only for NHL patients, excluding Hodgkins disease patients. RESULTS Despite differences in methods used to identify cases and to estimate the cumulative incidence over time (actuarial v cumulative calculations), up to 10% of NHL patients treated with either conventional-dose chemotherapy or high-dose therapy and autologous stem-cell transplantation may develop tMDS/AML within 10 years of primary therapy. Kaplan-Meier estimates of the actuarial incidence, which are based on censoring of patients who died without developing tMDS/AML, can lead to artificially high estimates with large confidence intervals at later time points. Although there is much debate about the cause(s) of tMDS/AML, there is compelling evidence that alkylating agents, certain other leukemogenic agents, and total-body irradiation (TBI) cause chromosomal damage that can lead to tMDS/AML. CONCLUSION Limiting exposure to alkylating agents and eliminating TBI from transplantation conditioning regimens may reduce the relative risk of tMDS/AML.

Chemotherapy studies in primary liver cancer: a prospective randomized clinical trial.

One hundred and sixty‐eight patients with unresectable primary liver cancer were prospectively studied by members of the Eastern Cooperative Oncology Group. These patients were randomized to receive treatment with oral 5‐Fluorouracil (5‐Fu), oral 5‐Fu plus Streptozotocin, oral 5‐Fu plus MethylCCNU or Adriamycin. The single agent treatments (oral 5‐Fu and Adriamycin) were associated with less gastrointestinal toxicity than were the oral 5‐Fu treatment combinations. A total of 15 partial responses were reported. Adriamycin appears to be the most active agent and responsible for 9 of the 15 responses. No response was seen in any of the 48 patients randomized to oral 5‐Fu alone. The survival associated with oral 5‐Fu alone was significantly shorter than the survival time associated with the remaining 3 treatment programs among both North American and South African patients. A multivariate model of survival was formulated. Covariates of prognostic significance were treatment, initial performance status and sex. South African black patients had a shorter survival time than North American black patients. Excluding oral 5‐Fu from consideration, prognostic variables appeared to dominate any differences between the remaining treatments under study. Cancer 42:2149–2156, 1978.

Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5‐fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients. An eastern cooperative oncology group trial

The current trial was designed to assess whether the addition of prednisone or prednisone + tamoxifen would enhance the therapeutic effectiveness of 1 year of adjuvant CMF therapy. Premenopausal women with ipsilateral axillary node‐positive breast carcinoma and known estrogen receptor (ER) status were randomized to receive 1 year of postoperative treatment with 12 28‐day cycles of cyclophosphamide, methotrexate, 5‐fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus tamoxifen (CMFPT). There were 553 analyzed cases with 188 receiving CMF, 183 CMFP, and 182 CMFPT. The overall time to relapse (TTR) and survival comparisons between the regimens are not statistically different at a median follow‐up time of 7.7 years. The major subgroups currently with a suggestive TTR difference are > 3N+ (CMFPT > CMF,P = 0.07) and estrogen receptor‐negative (ER‐) > 3N+ (CMFPT > CMF, P = 0.03). Patients receiving CMFPT appeared to have a superior survival to CMF in the ER‐ >3N+ cohort (P = 0.02). The following patient characteristics were associated with a significantly longer TTR: decreasing nodal involvement or tumor size, positive ER status, age ≧ 40 years, and decreasing obesity. The favorable effects of decreasing nodal involvement, positive ER status, age 40 years or greater, and decreasing obesity carried over to survival. Development of amenorrhea was also significantly associated with improved survival (P = 0.001). Toxicity was increased by the addition of prednisone to CMF and by the addition of tamoxifen to CMFP. Overall relapse patterns were similar among the three regimens. The results of the current trial do not currently suggest an overall therapeutic benefit for adding prednisone or only 1 year of tamoxifen to CMF adjuvant treatment.

Six-year results of the Eastern Cooperative Oncology Group trial of observation versus CMFP versus CMFPT in postmenopausal patients with node-positive breast cancer.

The Eastern Cooperative Oncology Group (ECOG) trial of adjuvant cyclophosphamide, methotrexate, fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen (CMFPT) for 1 year compared with observation alone in 265 postmenopausal patients with node-positive breast cancer is reported with 74 months median follow-up. Overall relapse-free survival tended to favor CMFPT (P = .08), but no survival differences existed between any treatment group. The addition of tamoxifen to CMFP led to slightly (but not significantly) better relapse-free status in all subgroups analyzed. Subgroup analysis based on stratification variables showed significant benefit from CMFP (+/- T) only in estrogen receptor (ER)-negative patients with respect to disease-free status (P = .0003), but not survival (P = .54). Relapse-free status was actually worse for CMFP-treated patients with ER-positive tumors, but not significantly so (P = .15). By multivariate analysis other significant risk factors for relapse-free status were primary tumor size, number of nodes pathologically involved, and the number of nodes examined. ER status was prognostic only for the observation group with the benefit from chemotherapy on ER-negative patients obliterating this difference in treated patients. Survival was affected by the number of involved nodes, tumor size, presence of tumor necrosis, and patient obesity. Analysis of toxicity showed elevation of liver enzymes during the first year to be more common in the observation group compared with those patients receiving adjuvant treatment and to be associated with early recurrence. Toxicity from adjuvant treatment persisted beyond termination of therapy in 53% of patients, but was usually mild and self-limited. We conclude CMFPT offers relapse-free survival benefit in ER-negative patients, but the value of chemotherapy in ER-positive postmenopausal, node-positive patients must be questioned.

Adjuvant CMFP versus CMFP plus tamoxifen versus observation alone in postmenopausal, node-positive breast cancer patients: three-year results of an Eastern Cooperative Oncology Group study.

After mastectomy, 265 postmenopausal patients with node-positive breast cancer were stratified according to pathologic nodal status and estrogen-receptor (ER) status and randomized to receive either 12 cycles of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP), or CMFP plus tamoxifen (CMFPT), or observation alone. Patients entered the study between March 1978 and July 1981. Cox regression analysis indicated that, compared to observation alone, chemotherapy (CMFP and CMFPT groups combined) led to a significant reduction in relapses by the end of the first year of study in every examined prognostic subgroup. However, after the first year the relapse-free survival curves of all treatment groups tended to merge, so that by three years 52% of the observation group and 51% of the chemotherapy groups remained disease free. Chemotherapy continued to show a significantly superior relapse-free survival rate for three years only in the subgroup of patients with ER-negative tumors (the subgroup with the largest relapse-free survival advantage at one year). The addition of tamoxifen produced no benefit or harm in any prognostic subcategory examined. ER status was prognostically important for predicting early relapse only in those patients not receiving chemotherapy, due to the greater effectiveness of this chemotherapy to prevent early relapse in the ER-negative subgroup. Treatment has had no early effect on survival. As breast cancer continues to recur even after ten or more years, later relapse patterns may alter these results.

The eastern cooperative oncology group experience with cyclophosphamide, adriamycin, and 5‐fluorouracil (CAF) in patients with metastatic breast cancer

Data on 162 women (90 premenopausal and 72 postmenopausal) with metastatic breast cancer randomized to receive cyclophosphamide, Adriamycin (doxorubicin) and 5‐fluorouracil (CAF) on two Eastern Cooperative Oncology Group (ECOG) protocols were analyzed. Twenty‐three percent had complete remission; 39% had partial remission; 28% had no change; and 3% had disease progression. Of those patients in whom receptors were known, response rates were 65% for estrogen (ER)‐receptor positive and 70% for ER‐negative patients. The median duration of response was 11.4 months. The median survival time from the start of CAF was 20.2 months. The response rate, time to treatment failure (TTF), and median survival time were superior in the premenopausal women. These differences ceased, however, to be statistically significant in logistic models. Factors significantly associated with longer TTF and longer survival were as follows: one or two organs with metastases (TTF, P < 0.0001; survival, P < 0.0001); dominant site other than soft tissue (TTF, P < 0.0001; survival, P = 0.05); and an initial good performance status (TTF, P = 0.007; survival, P = 0.02). Patients with ER‐positive disease had a significantly longer median survival time (P = 0.003).

Comparison of intensive versus moderate chemotherapy of lymphocytic lymphomas. A progress report

In an Eastern Cooperative Oncology Group trial, Cytoxan‐prednisone (CP) Induction was compared to BCNU‐prednisone (BP) in 273 patients with lymphocytic lymphoma. Response rates were comparable, with 21% achieving complete response and 40%, partial response. Patients with a nodular pattern responded better. Maintenance phase comparing cyclic intensive therapy (BCVP) with intermittent chlorambucil revealed the superiority of BCVP as demonstrated by improvement of the quality of response and somewhat longer remissions. The value of the Rappaport classification in the evaluation of lymphoma chemotherapy results is discussed. It is suggested that NHL be separated into “favorable” and “unfavorable” groups, based on the presence or absence of nodularity and treatment schedules devised accordingly.

Combination chemotherapy of the malignant lymphomas. A Controlled clinical trial

The Eastern Cooperative Oncology Group has studied 113 patients with generalized progressive malignant lymphomas in a randomized clinical trial. Pathologic diagnosis was subclassified by cell type and nodal pattern by The Pathology Panel for Lymphoma Clinical Trials. Patients were randomly assigned treatment with either cyclophosphamide (C), vincristine (O), and prednisone (P) (COP) or CO without prednisone. Initial treatment was given for 8 weeks and further randomization of responders to observation or additional chemotherapy was carried out. A significant difference in complete remission rate between treatments was shown: with COP, 43%, and with CO, 17%, indicating an important role for prednisone in inducing CR. COP was also associated with longer remission durations and improved survival. Complete remission following initial chemotherapy is also associated with longer duration of disease‐free time and survival. The initial pathologic cell types and nodal pattern also strongly influence survival. Extended “maintainence” CO treatment improved disease‐free remission duration, but not survival.

Chemotherapy of advanced measurable colon and rectal carcinoma with oral 5-fluorouracil, alone or in combination with cyclophosphamide or 6-thioguanine, with intravenous 5-fluorouracil or beta-2'-deoxythioguanosine or with oral 3(4-methyl-cyclohexyl)-1(2-chlorethyl)-1-nitrosourea: a Phase II-III study of the Eastern Cooperative Oncology Group (EST 4273).

In a randomized multi‐institutional trial of the Eastern Cooperative Oncology Group, 316 patients with advanced measurable colorectal adenocarcinoma were treated with a weekly schedule of 5‐fluorouracil given orally and intravenously with oral 5‐fluorouracil in combination with cyclophosphamide or 6‐thioguanine, or with oral Methyl CCNU administered once every eight weeks. On failure or progression, 133 protocol patients crossed‐over to a secondary therapy, while 116 other patients previously treated with 5‐fluorouracil off protocol were randomized to treatment with Methyl CCNU or B‐2′‐deoxythio‐guanosine. Response rates among patients who had received no prior chemotherapy were 18% to oral 5‐FU, 15% to intravenous 5‐FU and to MeCCNU, 12% to 5‐FU and 6‐thioguanine and 5% to cyclophosphamide and 5‐FU, with little activity (3% response rate) in crossover or previously treated patients. Treatment with 5‐FU, particularly oral 5‐FU was associated with the least drug‐related toxicity. Hematologic toxicity was greatest with Methyl CCNU, but was no more frequent in previously treated than in untreated patients. A tendency toward cumulative bone marrow depression was noted. 5‐FU was effective only in ambulatory patients, whereas responses among non‐ambulatory patients were seen only in the group treated with Methyl‐CCNU. Cancer 42:2538–2545, 1978.