Ann H. Korzun

Combination chemotherapy with mastectomy or radiotherapy for stage III breast carcinoma: a Cancer and Leukemia Group B study.

One hundred thirteen evaluable patients with previously untreated stage III breast carcinoma were treated with three monthly cycles of cyclophosphamide (CYC), doxorubicin (DOX), 5-fluorouracil (5-FU), vincristine (VCR), and prednisone (PRED) (CAFVP). Subsequently, 91 (81%) were deemed operable. Patients were then randomized to receive surgery or radiotherapy (RT) to determine which of these modalities afforded better local tumor control. All patients also received 2 additional years of CAFVP in a further attempt to eradicate local disease and systemic micrometastases. Forty-one of the randomized patients have relapsed. Approximately half of the initial relapses in each arm were local. The overall duration of disease control was similar following either modality, with a median of 29.2 months for surgery patients and 24.4 months for RT patients. Similarly, there was no major difference in survival related to randomized treatment with an overall median of 39 months (median follow-up 37 months). Pre- or perimenopausal status and inflammatory disease were associated with shorter disease control and survival. Treatment was generally well tolerated and toxicity was acceptable. This study demonstrates that prolonged control of stage III breast carcinoma can be achieved with combined modality therapy in which cytotoxic chemotherapy precedes and follows treatment directly primarily at the breast tumor, using either surgery or RT. Nevertheless, new regimens must be designed if significant advances that may lead to the cure of this disease are to be achieved.

Arterial Thrombosis Associated with Adjuvant Chemotherapy for Breast Carcinoma: A Cancer and Leukemia Group B Study

PURPOSE Multiagent chemotherapy and chemohormonal therapy for breast cancer are associated with an increased risk for venous thromboembolic complications. We observed instances of arterial thrombosis in two studies of breast cancer involving multiagent chemotherapy for stages II and III disease. Our purpose in this study was to determine the incidence of this complication and whether it appeared to be related to the chemotherapy or was a random event. PATIENTS AND METHODS Episodes of arterial thrombotic events were identified from record reviews of 1,014 assessable patients with breast cancer entered on two Cancer and Leukemia Group B protocols. Details of the kind of arterial event, when it occurred, the outcome, and the occurrence of metastases were analyzed. RESULTS Thirteen (1.3%) patients had an arterial thrombosis: six (5.3%) of 113 patients with stage III disease and seven (0.8%) of 901 patients with stage II disease. Four of these patients had a peripheral arterial thrombosis and nine had strokes (four were fatal). All these events occurred while the patients were receiving adjuvant chemotherapy. Only one additional arterial event (a stroke approximately four years later) has occurred in this patient group after chemotherapy was completed. CONCLUSION Arterial thrombosis is also associated with multiagent chemotherapy in patients with breast cancer. The mechanism is unknown.

Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. Cancer and Leukemia Group B.

Three combination chemotherapy regimens each with or without the methanol-extracted residue of bacillus Calmette-Guérin (BCG) (MER) were compared for efficacy. After stratification for disease-free interval and dominant sites of disease, patients were randomized to either CMF (cyclophosphamide [CYC], 100 mg/m2 orally, days 1 through 14; methotrexate [MTX], 40 mg intravenously [IV], days 1 and 8; 5-fluorouracil [5-FU], 500 mg/m2 IV, days 1 and 8), or CAF (CYC, 100 mg/m2 orally, days 1 through 14; doxorubicin [DOX], 25 mg/m2 IV, days 1 and 8; 5-FU, 500 mg/m2 IV, days 1 and 8), or CAFVP (CAF as above plus vincristine [VCR], 1.0 mg/m2 IV, days 1 and 8; and prednisone [PRED], 40 mg/m2 orally, days 1 through 14). Nonspecific immunotherapy with MER was administered in five sites at 100 micrograms or at the lowest tenfold dilution that produced a 1-cm indurated lesion. A total of 432 patients were entered, but 37 were disqualified, leaving 395 evaluable for treatment results and toxicities. One hundred thirty-five evaluable patients were randomized to chemoimmunotherapy until October 28, 1978. One hundred twenty-six evaluable patients were randomized to chemotherapy alone in the same time period. For the entire study, a total of 260 evaluable patients were randomized to chemotherapy. Chemoimmunotherapy patients were compared with the initial 126 chemotherapy patients. Chemotherapy regimens were compared among all 260 patients. Patient characteristics were similar between regimens and between chemotherapy and chemoimmunotherapy treatment groups. For patients on chemotherapy plus MER, there was no significant differences between the regimens for response frequencies: 43%, 41%, and 32%, respectively for CMF, CAF, and CAFVP. The comparable chemotherapy alone group had 36%, 58%, and 63% response, respectively. The response rates, adjusted for chemotherapy regimen, were 52% and 38% (P = .02) for chemotherapy and chemoimmunotherapy, respectively. MER was associated with painful ulcers and fevers. Thus, MER produced toxicity without response or survival benefit and further randomization after October 28, 1978 was to chemotherapy alone. For 260 evaluable patients on chemotherapy alone, the complete (CR) and partial responses (PR) were 37%, 55%, and 58%, respectively for CMF, CAF, and CAFVP. These response rates for CAF and CAFVP were significantly better than CMF (P = .01 and P less than .01, respectively). These comparisons were consistent within subgroupings such as dominant sites of disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Diverse prognosis in metastatic breast cancer: Who should be offered alternative initial therapies?

In an attempt to clarify appropriate treatment options for women with stage IV breast cancer, we studied the survival experience of a large dataset of patients treated on Cancer and Leukemia Group B (CALGB) protocols. The study, restricted to women who had had no prior chemotherapy for metastatic disease, demonstrated a surprisingly poor prognosis, with an estimated median survival of 1.6 years and only 26% alive at 3 years. Analysis of prognostic factors permitted the identification of subsets with even shorter survival, such as women with estrogen receptor negative tumor in more than one metastatic site and prior adjuvant chemotherapy. We feel that an evaluation of intensive investigational treatment approaches, such as trials using autologous bone marrow transplantation, is justified for most stage IV breast cancer patients, in view of their poor prognosis.

Postsurgical adjuvant chemotherapy of stage II breast carcinoma with or without crossover to a non-cross-resistant regimen: a Cancer and Leukemia Group B study.

PURPOSE To compare two cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone (CMFVP) regimens with a doxorubicin-based regimen--vinblastine, doxorubicin, thiotepa, and Halotestin (Upjohn, Kalamazoo, MI) (VATH)--in patients with stage II node-positive breast carcinoma. METHODS Nine hundred forty-five women were treated with a 6-week induction course of CMFVP. They were then randomized to receive one of two consolidation CMFVP regimens: 6-week courses or 2-week courses. Following completion of CMFVP consolidation, patients were again randomized to either continue the CMFVP regimen or to receive six escalating doses of VATH. RESULTS Among all patients, with a median follow-up time of 11.5 years, there is no statistically significant difference in disease-free survival (DFS) between the two consolidation CMFVP regimens. VATH intensification treatment is statistically significantly superior to CMFVP in terms of DFS (P = .0040). For patients with one to three involved nodes, there is currently no significant difference between VATH and CMFVP; however, among those with four or more positive lymph nodes, there is a significant difference in favor of VATH (P = .0037). There is also improved overall survival with VATH (P = .043; median, > 14 years v 10 years). This difference is also statistically significant in patients with four or more involved lymph nodes, among postmenopausal patients, and among postmenopausal estrogen receptor-positive patients. CONCLUSION Chemotherapy with crossover to escalating doses of VATH following CMFVP was well tolerated and effective. Inauguration of VATH as a treatment intensification at the eighth month produced a major increase in relapse-free and overall survival. The observation that sensitivity to VATH is retained so long after mastectomy raises questions about the proper duration of adjuvant chemotherapy and lends support to further investigation of cross-over designs in future trials to postoperative adjuvant chemotherapy regimens.

Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081.

In a prospective, randomized trial Cancer and Leukemia Group B (CALGB) evaluated CAF chemotherapy (cyclophosphamide + doxorubicin + 5-fluorouracil [5-FU]) v CAF plus tamoxifen (TCAF) in advanced breast cancer. Patients were stratified by estrogen receptor (ER) status, dominant site of metastatic disease, menopausal status, and prior adjuvant therapy. Regardless of ER status or menopausal status, the addition of tamoxifen conferred no significant advantage in response rate, response duration, time to treatment failure (TTF) or survival over CAF alone. A secondary objective was to compare the response to CAF of ER positive (ER+) and ER negative (ER-) patients to determine if there was a differential response to cytotoxic chemotherapy. Response rates of ER+ and ER- patients to CAF were identical (56%), but the response duration, time to treatment failure, and survival of ER+ patients were significantly longer than ER- patients. This lack of differential response implies that chemotherapy and hormonal therapy may compete for the same pool of ER+ cells. It also suggests that chemotherapy kills breast cancer cells indiscriminately, regardless of ER status.

Responses to chemotherapy or chemohormonal therapy in advanced breast cancer patients treated previously with adjuvant chemotherapy: A subset analysis of CALGB study 8081†

The Cancer and Leukemia Group B (CALGB) evaluated the response to subsequent chemotherapy or chemohormonal therapy in 46 patients with advanced breast cancer treated previously with adjuvant chemotherapy that had been completed 6 months or more before protocol entry. The results were compared with 379 patients in the same study who had not received prior adjuvant chemotherapy. The patients were treated with cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and 5‐fluorouracil (CAF), with or without tamoxifen. There was no difference in response rate, response duration, time to treatment failure, or survival between patients who had received prior adjuvant chemotherapy and those who had not. The addition of tamoxifen to CAF failed to enhance response rates or response durations in all subgroups. Women who relapsed 6 months or more after completion of adjuvant chemotherapy did not have inherently drug‐resistant tumors. They responded to standard CAF chemotherapy with the same response rate and survival as patients untreated previously with chemotherapy.

Hyperglycemic Complications Associated with Adjuvant Chemotherapy of Breast Cancer A Cancer and Leukemia Group B (calgb) Study

Many adjuvant chemotherapy regimens used for breast cancer include prednisone, which has the potential to cause hyperglycemia. We reviewed the results of three CALGB studies employing prednisone as part of adjuvant therapy to determine the incidence and severity of hyperglycemic complications. All treatment regimens included cyclophosphamide, methotrexate or doxorubicin, 5-fluorouracil, and vincristine in addition to prednisone. Among 1,237 evaluable patients receiving a five-drug regimen including prednisone, there were 98 patients (7.9%) who experienced any degree of hyperglycemia. Thirty patients (2.4% overall; 30.6% of those having any hyperglycemia) had severe or life-threatening degrees of hyperglycemia, including two patients whose hyperglycemia contributed directly to death. We conclude that prednisone administration as part of adjuvant chemotherapy regimens in breast cancer produces an appreciable incidence of hyperglycemia. Serum glucose levels should be monitored during therapy to help prevent the occasional severe or life-threatening episode of hyperglycemia in these patients.

Cytosine arabinoside and cisplatin for advanced breast cancer. A phase II study of the cancer and leukemia group B

Forty‐four women with advanced breast cancer participated in a prospective clinical trial to evaluate the efficacy and toxicity of a regimen consisting of cytosine arabinoside and cisplatin. All patients had previously received chemotherapy. Three patients (7%) responded to therapy with response durations of 153, 160, and 441 days. The median time to disease progression and median survival time in all 44 patients were 2.3 and 5 months, respectively. This regimen had significant toxicity, with most patients experiencing severe or life‐threatening hematologic, renal, or infectious complications. This regimen cannot be recommended for previously treated patients with advanced breast cancer.

A Feasibility Study of Intensive CAF as Outpatient Adjuvant Therapy for Stage II Breast Cancer in a Cooperative Group: CALGB 8443

In preparation for a national Phase III study of dose and dose intensity in the treatment of node-positive, Stage II adenocarcinoma of the female breast, CALGB instituted a pilot study of intensive intravenous outpatient CAF (cyclophosphamide, Adriamycin, 5-fluorouracil) for four months. This study was designed to give full doses of drugs without dose reduction for hematologic toxicity. In order to evaluate the feasibility of physician and patient compliance with a potentially toxic therapy, a multi-institution pilot study was performed. This protocol demonstrated that a cooperative group could deliver toxic drug doses to outpatients with a median of 98% of cyclophosphamide, 97% of Adriamycin (doxorubicin), and 91% of 5-fluorouracil administered on schedule. Major side effects, as expected, were leukopenia, nausea, and vomiting. Disease-free survival is at least equivalent to that observed in previous studies.