Frank J. Cummings

Locoregional Failure 10 Years After Mastectomy and Adjuvant Chemotherapy With or Without Tamoxifen Without Irradiation: Experience of the Eastern Cooperative Oncology Group

PURPOSE To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure (LRF) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation. PATIENTS AND METHODS The study population consisted of 2,016 patients entered onto four randomized trials conducted by the Eastern Cooperative Oncology Group. The median follow-up time for patients without recurrence was 12.1 years (range, 0.07 to 19.1 years). RESULTS A total of 1,099 patients (55%) experienced disease recurrence. The first sites of failure were as follows: isolated LRF, 254 (13%); LRF with simultaneous distant failure (DF), 166 (8%); and distant only, 679 (34%). The risk of LRF with or without simultaneous DF at 10 years was 12.9% in patients with one to three positive nodes and 28.7% for patients with four or more positive nodes. Multivariate analysis showed that increasing tumor size, increasing numbers of involved nodes, negative estrogen receptor protein status, and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF. CONCLUSION LRF after mastectomy is a substantial clinical problem, despite the use of chemotherapy with or without tamoxifen. Prospective randomized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens.

Adjuvant tamoxifen versus placebo in elderly women with node-positive breast cancer: long-term follow-up and causes of death.

PURPOSE This study analyzes the long-term results and causes of death in elderly women with node-positive breast cancer who participated in a double-blind adjuvant trial that compared tamoxifen with placebo to determine the benefit of 2 years of treatment. PATIENTS AND METHODS One hundred eighty-one women 65 to 84 years old were given 20 mg of tamoxifen or placebo daily for 2 years after stratification by estrogen receptor status, tumor size, and degree of lymph node involvement. Approximately 30% of patients were older than 70 years and 20% were older than 75 years. Eighty-five percent were estrogen receptor-positive. Median follow-up was 10 years. RESULTS Among the 168 eligible patients, there have been 98 recurrences (59 placebo v 39 tamoxifen), with reduced distant and bone-only first sites in patients treated with tamoxifen. Median time to failure was 4.4 years for placebo versus 7.4 years for tamoxifen (log-rank P = .001). A similar number of new nonbreast cancers occurred in each arm (seven placebo v six tamoxifen), but a reduced number of opposite-breast cancers (five placebo v one tamoxifen) was noted. Overall, there were 102 deaths (57 placebo v 45 tamoxifen). Median survivals were 8.0 years with placebo and 8.5 years with tamoxifen (log-rank P = .063); 50% of the tamoxifen patients and 33% of the placebo patients are still alive. Sixty-one percent of the deaths were reported to have been caused by breast cancer recurrence, 4% by other cancers, and 22% by the sequelae of non-cancer-related illness, with equal distributions for cardiovascular and cerebrovascular disease. There was no increase in the number of endometrial or other types of cancer, or thrombotic or orthopedic complications in this older group. CONCLUSION Tamoxifen currently is the treatment of choice for elderly women with breast cancer. It extends the time to treatment failure by 3 years and reduces the number of recurrences, deaths, distant and bone-only first recurrences, and second breast cancers.

Combination Chemotherapy Compared to Tamoxifen as Initial Therapy for Stage IV Breast Cancer in Elderly Women

In a randomized crossover study, 181 patients over the age of 65 with recurrent breast cancer received either tamoxifen or cyclophosphamide, methotrexate, and fluorouracil (CMF). After progression on tamoxifen, a hormone withdrawal period was required. Because of altered pharmacokinetics with aging, creatinine clearance was used in calculating the dose of CMF. Response rates were 45% on tamoxifen and 38% on CMF, with median durations of 10.4 and 7.9 months, respectively. Survival rates tended to favor tamoxifen as the initial treatment even in estrogen-receptor-negative patients. Additional disease control with hormone withdrawal occurred in 23% of patients, and this benefit was highly correlated with prior hormone response. We conclude that initiation of hormone therapy rather than CMF chemotherapy is justified in almost all situations in elderly patients, and combination chemotherapy, is safe and useful after hormone failure if modified on the basis of renal dysfunction.

Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment.

PURPOSE To investigate the value of maintenance treatment for patients with metastatic breast cancer whose disease is in complete remission (CR). PATIENTS AND METHODS One hundred ninety-five women (141 eligible) whose disease was in CR or in CR except for bone metastases following six cycles (6 months) of doxorubicin-containing induction treatment were randomized to receive cyclophosphamide, methotrexate, fluorouracil, prednisone, tamoxifen, and halotestin [CMF(P)TH] or observation. In a previous pilot study, patients in CR after 24 months of induction treatment were randomized to continue chemotherapy for 4 more years or stop chemotherapy. RESULTS Among patients randomized to CMF(P)TH, life-threatening toxicity included leukopenia in 3%, thrombocytopenia in 3%, cardiac in 2%, and diabetes in 1%. The median time to relapse from randomization was 18.7 months on CMF(P)TH and only 7.8 months on observation (P < .0001). The median time to death was 32.2 months on CMF(P)TH and 28.7 months on observation (P=.74). Similar results were seen in the pilot study (median time to relapse, 12.6 and 6.4 months; median survival, 37.7 and 24.2 months; study too small for statistical significance). Maintenance treatment was always the most significant covariate in time-to-relapse models. CONCLUSION There is definite toxicity associated with CMF(P)TH maintenance treatment. When CR was obtained on induction, maintenance treatment with CMF(P)TH was never significant in survival models. However, maintenance treatment was always the most significant covariate in the time-to-relapse models, which motivates its consideration for appropriately informed patients.

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.

Adjuvant tamoxifen treatment of elderly women with stage II breast cancer. A double-blind comparison with placebo.

One hundred seventy elderly women with stage II breast cancer, stratified on the basis of the number of positive axillary nodes and estrogen receptor status, were randomly assigned to receive tamoxifen or placebo for 24 months in a prospective, double-blind, adjuvant trial. The median age was 71 years with a range from 65 to 84 years. The overall percentage of patients disease-free at 4 years was 76% for those given tamoxifen and 52% for those given placebo (p = 0.0004). Benefit was seen in all subgroups of patients treated with tamoxifen. Two years of tamoxifen therapy represents an effective postoperative adjuvant treatment for elderly women with stage II breast cancer, resulting in improved time to relapse, statistically fewer distant first recurrences, and minimal toxicity. No improvement in overall survival has been seen yet.

Hormonal treatment for metastatic breast cancer. An eastern cooperative oncology group phase III trial comparing aminoglutethimide to tamoxifen

Background. Tamoxifen and aminoglutethimide are two hormone therapies reported to be effective palliative approaches for patients with metastatic breast cancer. The current trial was designed to evaluate their relative therapeutic effectiveness.

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.

Ten-year follow-up study of premenopausal women with metastatic breast cancer: an Eastern Cooperative Oncology Group study.

PURPOSE To investigate the long-term survival of premenopausal women with previously untreated first recurrence or metastases of breast cancer entered on Eastern Cooperative Oncology Group (ECOG) study 2177 (EST 2177), which completed accrual in June 1983. MATERIALS AND METHODS One hundred forty-seven premenopausal women with metastatic breast cancer were entered onto the study. Eighty-nine patients with estrogen receptor (ER)-positive and ER-unknown disease were randomized to receive cyclophosphamide (CTX), doxorubicin (ADR), and fluorouracil (FU) (CAF) or surgical oophorectomy plus CAF (O+CAF). Fifty-eight patients with known ER-negative disease were treated with CAF. Survival time was measured from the time of study entry. Randomization was stratified by performance status (PS), dominant metastatic site, and ER status. RESULTS One hundred thirty patients were eligible. The median survival time of randomized patients was 35 months (90% confidence interval, 28.9 to 54.3), with 28% alive at 5 years. The overall median survival duration, including ER-negative patients, was 30 months. There was no significant difference in survival time between the randomized treatments (median, 42 months for O+CAF and 30 months for CAF). In models of survival time, age > or = 45 years and last menstruation within 1 month were associated with significantly longer survival (P < .004 for each). There were also three significant interactions with treatment (even after correction for multiple comparisons): age (P = .00009; O+CAF associated with longer survival in patients < 45 years, CAF associated with longer survival in patients > 45 years), PS (P = .002; O+CAF associated with consistently better survival in PS O patients), and disease-free interval (DFI). CONCLUSION Long-term follow-up data of premenopausal women with metastatic breast cancer show a longer than expected median survival time at 2.5 years overall and close to 5 years for patients treated with O+CAF who were ER-positive or had a good PS.

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.