G. Bonadonna

Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes.

To improve current adjuvant results in high-risk breast cancer, in February 1982 we activated a prospective randomized trial using both intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) and Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy) involving patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. The objective of the study was to assess the effectiveness of four courses of Adriamycin followed by eight courses of CMF versus two courses of CMF alternated with one course of Adriamycin for a total of 12 courses. All drug courses were recycled every 3 weeks. Rather than temporarily reducing doses in the event of myelosuppression on the planned day of treatment, drug administration was delayed for 1 to 2 weeks. At a median follow-up of 59 months, treatment outcome was significantly superior for patients who received Adriamycin followed by CMF (Adriamycin----CMF) than for those given alternating regimens (CMF/Adriamycin). The 5-year relapse-free survival was superior post-Adriamycin----CMF (61%) compared with post-CMF/Adriamycin administration (38%; P = .001). The corresponding figures for the 5-year total survival were 78% and 62%, respectively (P = .005). The benefit of Adriamycin----CMF was observed in all patient subsets. Treatment was fairly well tolerated, and we documented only one case of fatal congestive heart failure in a patient who received postoperative irradiation to the left breast in addition to Adriamycin. Present findings indicate that in women with extensive nodal involvement, Adriamycin----CMF yielded superior results compared with CMF/Adriamycin.

Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes.

In the attempt to improve current adjuvant results in patients with one to three positive axillary lymph nodes, in November 1981 we activated a prospective randomized study to assess the effectiveness of intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) for 12 courses versus CMF for eight courses followed by Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) for four courses. The 5-year results were evaluated in a total of 486 patients entered into the study up to December 1987. CMF chemotherapy was delivered IV for a total of 12 courses when given alone and for eight courses when followed by four courses of Adriamycin. All drugs were recycled every 3 weeks. Rather than temporarily reducing doses, drug administration was delayed for 1 to 2 weeks in the face of myelosuppression on the planned day of treatment. After a median follow-up of 61 months, no significant differences were evident between the treatment groups in terms of relapse-free (CMF 74% v CMF followed by Adriamycin 72%) and total survival (CMF 89% v CMF followed by Adriamycin 86%). Drug treatments were fairly well tolerated and devoid of life-threatening toxicity. Present results, which were not influenced by menopausal status, indicate that Adriamycin given after CMF failed to improve treatment outcome over CMF alone. However, the role of Adriamycin in an adjuvant setting remains to be further clarified. Considering the good 5-year results achieved in this study at the expense of minimal toxicity, full-dose CMF remains, at present, the adjuvant chemotherapy of choice for patients with one to three positive nodes.

Cell kinetics as a prognostic indicator in node-negative breast cancer

The consistency of the prognostic role of cell kinetics (evaluated as the [3H]thymidine labeling index, LI) over a period of years has been assessed in 354 patients with resectable node-negative breast cancer subjected only to Halsted or modified radical mastectomy. The risk of disease recurrence and death was proportional to LI values and the pattern was superimposable, regardless of menopausal status, in the two consecutive case series entered in this retrospective study. In particular, tumors with high LI (greater than 2.8%) had a higher 6-year probability (41% vs. 25%, P less than 0.0001) of manifesting local-regional and distant metastases and of dying (19% vs. 5%, P = 0.0005) as compared to tumors with low LI. In tumors with high LI the risk of relapse within the first 2 years from mastectomy was twofold compared to that of tumors with low LI. Multiple regression analysis showed that LI also retained its prognostic significance in both relapse-free and overall survival when tumor size and estrogen receptor status were considered. The present findings confirm that LI can substantially contribute to the selection of high risk node-negative patients who could be candidates for adjuvant chemotherapy.

Comparison of different trials of adjuvant chemotherapy in stage II breast cancer using a natural history data base.

Prognostic factors and treatment were analyzed for 2,578 patients to assess the impact of various forms of adjuvant chemotherapy on the natural history of operable stage II (node-positive) breast cancer. The outcome after surgery alone (or with radiotherapy) was determined in 1,014 patients in the natural history data base (NHDB). Adjuvant chemotherapy consisted of L-phenylalanine mustard (L-PAM; 130 patients); cyclophosphamide, methotrexate, and 5-fluoro-uracil (CMF; 645 patients); doxorubicin and cyclophosphamide (AC; 241 patients); CMF plus vincristine and prednisone (CMFVP; 263 patients); and 5-fluorouracil plus AC (FAC; 285 patients). L-PAM had minimal effect on relapse-free survival (RFS) compared to the NHDB, but all combination chemotherapy programs significantly improved RFS and survival compared to the NHDB. In women with 1–3 positive nodes, all combination chemotherapy programs produced similar results. In women with 4–9 positive nodes, the FAC regimen appeared to be associated with superior RFS compared to other programs, but all were superior to the NHDB. In women with 10 or more positive nodes, FAC was the only regimen associated with improved RFS. The use of a NHDB and known pretreatment characteristics, such as nodal status and tumor size, permits comparison of patients at similar risk of recurrence of breast cancer who have received adjuvant chemotherapy and provides leads for evaluation in future prospective clinical trials.

Development and use of a natural history data base of breast cancer studies

Pretreatment information, type of treatment, and longitudinal follow-up on 1,971 patients with operable breast cancer were used to establish a breast cancer natural history data base (NHDB). Data were available for 957 patients with stage I (node-negative) breast cancer and 1,014 stage II (node-positive) patients. In women with negative nodes, information was available on 759 patients treated at the Milan National Cancer Institute and 188 patients treated at the Royal Marsden Hospital. After adjustment for differences in the distribution of patient prognostic factors, relapse-free survival and overall survival were not significantly different. Of the 1,014 node-positive patients, 540 were treated at the Milan National Cancer Institute, 258 at the Royal Marsden, and 216 at the M. D. Anderson Hospital. Relapse-free survival and overall survival did not significantly differ between Milan patients and those treated at the Royal Marsden Hospital. However, M. D. Anderson Hospital patients did have significantly better relapse-free and overall survival. In each institution, outcome was consistently most dependent on the number of involved axillary lymph nodes and tumor size. Also, similar patterns of survival were observed for each of the institutions. The development of an NHDB can be of value in the identification and evaluation of consistency of prognostic factors, permitting improved comparisons between clinical trials. The development of such a natural history data base (NHDB) provides a reference for assessing the impact of different adjuvant chemotherapy programs, and aids in the design of new protocols.

3H-thymidine-labeling index as a prognostic indicator in node-positive breast cancer.

The prognostic relevance of 3H-thymidine-labeling index (3H-TdR-LI) was retrospectively evaluated in 523 women with resectable node-positive breast cancer given adjuvant combination chemotherapy consisting of cyclophosphamide, methotrexate, and fluorouracil (CMF) +/- Adriamycin (doxorubicin; Farmitalia, Carlo Ezba, Italy). The 5-year relapse-free survival (RFS) and overall survival (OS) rates were significantly higher for patients with slowly proliferating tumors (3H-TdR-LI less than or equal to 2.8%) compared with rapidly proliferating tumors (RFS, 66% v 50%, P = .0007; OS, 85% v 73%, P = .0012). In the analysis of RFS, 3H-TdR-LI provided prognostic information independent of axillary node involvement, tumor size, and estrogen receptor (ER) status, with an estimated lower hazard ratio compared with the degree of nodal involvement, but equivalent to that of the other indicators. Conversely, nodal involvement was found to interact with 3H-TdR-LI and receptors on survival. Present findings confirm that tumor cell kinetics represents a prognostic indicator also in an adjuvant situation. 3H-TdR-LI can substantially contribute to a more precise definition of high-risk patients within subsets having the traditionally favorable prognostic characteristics.

Estrogen-receptor status and response to chemotherapy in early and advanced breast cancer

SummaryThe value of estrogen receptor (ER) status in the prediction of tumor response to combination chemotherapy was retrospectively analyzed in breast cancer patients selected for prospective controlled trials of chemotherapy (85 with advanced disease and 256 with operable tumors). All patients were previously untreated with either chemotherapy or endocrine therapy, and in all instances drug therapy was applied at the time of primary treatment. The ER status was considered positive in 54% of women with advanced disease and in 70% of women with operable breast tumor and positive axillary nodes, respectively. About 12% of patients were considered to have borderline ER. The response to drug therapy (complete plus partial remission in advanced breast cancer and 3-year relapse-free survival after mastectomy, respectively) was not significantly different between ER+ and ER—tumors. The comparative results of ER+ vs ER—patients were similar whether the cutoff point for ER+ tumors was >5 or >10 fmol/mg cytosol protein. The present results indicate that in advanced and early breast cancer combination chemotherapy is effective regardless of ER status. Therefore, in the presence of ER+ tumors there is no reason to delay the early administration of effective chemotherapy. This is particularly true both in the presence of rapidly progressing metastatic disease and in the adjuvant setting.

Combined sequential approach in locally advanced breast cancer

BACKGROUND The interaction between primary and adjuvant chemotherapy is a crucial point in the treatment of locally advanced breast cancer. OBJECTIVE To evaluate the therapeutic efficacy of a sequential treatment with primary anthracyclines and adjuvant CMF in this patient subset. DESIGN Prospective cohort study. PATIENTS Eighty-eight breast cancer patients, stage T3b-T4 abc, N0-2, M0. RESULTS From February 1991 to July 1994, 88 consecutive patients with locally advanced breast cancer were treated at the Istituto Nazionale Tumori, Milano, with full-dose doxorubicin (75 mg/m2) or epirubicin (120 mg/m2) for three cycles followed by surgery, adjuvant chemotherapy with i.v. CMF for six cycles and local radiotherapy +/- Tamoxifen. A high rate of objective responses (70%), but a low incidence of pathologic complete remission (2%), were observed following primary treatment with single-agent anthracyclines. Frequency of responses was not associated with tumor estrogen or progesterone receptors status, Mib-1 or grading. In 28 patients (32%) conservative surgery could be performed. At a median follow-up of 52 months, relapse free survival and overall survival are 52% and 62%, respectively. A multivariate analysis demonstrated a significant favorable prognosis in patients with limited nodal involvement at surgery and negative Mib-1 values. This drug sequence failed to significantly ameliorate the long term results in this unfavorable patient subset and more effective drug regimens and innovative therapeutic strategies are needed.

Long-Term Sequelae from Adjuvant Chemotherapy

It has been estimated that 5000000 Americans living in 1987 have had cancer at some time during their lives, and that 3000000 have survived 5 years or longer, largely because of improvement in early detection techniques and the use of intensive multimodal therapies [1]. As far as operable breast cancer is concerned, the updated international overview [2] (reprinted in part in this volume) has recently confirmed that adjuvant systemic treatments can effectively reduce the 10-year risk of new disease manifestations and mortality. While worthwhile in human terms, this improvement seems moderate in size especially when findings from various chemotherapy protocols, different for drugs, doses, and intensity of treatment, are combined to produce an “average” result. It is thus important to investigate types and severity of long-term and late effects to assess the cost-benefit ratio of these treatments.

Salvage Treatments in Relapsing Resectable Breast Cancer

There is convincing evidence that the natural history of resectable breast cancer can be perturbed by adjuvant medical intervention. In fact, a highly significant reduction in the recurrence rate has been documented, which was reflected in a highly significant reduction in the odds of death following adjuvant chemotherapy, especially in premenopausal women (Bonadonna and Valagussa 1988; Consensus Conference 1985; Henderson 1987). Nonetheless, despite improvements in primary treatments, a considerable proportion of women who receive adjuvant therapy subsequently develop recurrent disease. The proper management of these patients, can present a therapeutic problem. In fact, the prognostic variables at the time of first treatment failure can be considerably different as far as disease-free interval, the anatomical extent of recurrence, patient performance status, menopausal and steroid-receptor status are concerned. Limited case series have been reported so far in medical literature (Bitran et al. 1983; Buzdar et al. 1981; Chlebowsky et al. 1981; Morris et al. 1985; Wendt et al. 1980), and all concerned women who relapsed after adjuvant chemotherapy. The conclusions about the efficacy of salvage therapy have been somewhat contradictory; controversies also exist about whether previous adjuvant therapy, especially chemotherapy, could adversely affect survival after recurrence (Brincker et al. 1987).