Sequential Adriamycin and CMF in Metastatic Breast Cancer

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1 Sequential Adriamycin and CMF in Metastatic Breast Cancer M. ZAMBETTI, A. GIACOBONE, M. TERENZIANI, P. ZUCCHINELLI, R. DEMICHELI, S. BIASI, P. PIOTTI, C. BARTOLI, P. VALAGUSSA, G. BONADONNA Istituto Nazionale Tumori, Milano, Italy Key Words. Breast cancer Sequential chemotherapy Adriamycin CMF ABSTRACT Purpose. To evaluate the clinical activity of a sequential treatment with Adriamycin followed by CMF (cyclophosphamide, methotrexate, fluorouracil) and the relative therapeutic contribution of the two drug regimens given at full conventional doses in metastatic breast cancer. Patients and Methods. From August 1990 to February 1993, 44 patients with advanced breast cancer previously untreated with chemotherapy entered the study. Treatment consisted of the intravenous administration of Adriamycin (75 mg/m 2 on day 1 every three weeks) for four cycles followed by intravenous CMF (cyclophosphamide, 600 mg/m 2 ; methotrexate, 40 mg/m 2 ; fluorouracil 600 mg/m 2 ) on days 1 and 8 every four weeks for four total courses. Results. In 41 evaluable patients, four cycles of fulldose Adriamycin were able to achieve an overall response INTRODUCTION The introduction of Adriamycin in various drug combinations for the treatment of metastatic breast cancer was able to achieve objective responses in 60%-70% of patients. Overall, complete remission rates never exceeded 20% and objective responses lasted between 8 and 10 months [1]. However, none of the conventional chemotherapy regimens proved to be clearly superior to the others, and the investigators focused on treatment dose intensity, suggesting that it could be a major determinant for patient response and survival [2]. Recently, the 10-year results from a prospective adjuvant study carried out at the Istituto Nazionale Tumori of Milano in women with operable breast cancer and more than three positive axillary nodes documented the superiority of the sequential administration of Adriamycin followed by CMF over the alternating delivery of the same drug regimens or of other conventional combinations [3]. We postulated that the sequential administration of the two drug regimens, coupled with the intensity of the anthracycline, which was delivered rate of 75%, including 17% complete remissions. Four cycles of CMF administered after Adriamycin were able to increase tumor response in 64% of evaluable cases. At the end of the sequential treatment program, 78% of 41 patients achieved an objective remission and in 30% of them a clinical complete response was documented. Main side effects, i.e., leukopenia and gastrointestinal disturbances, were moderate and short-lasting. One patient died because of acute myocardial infarction. Conclusion. In untreated metastatic breast cancer patients, the sequential administration of Adriamycin and CMF is highly effective at the expense of a moderate toxicity profile that allows high-dose intensity of both drug regimens. CMF treatment after upfront Adriamycin is able to exert a further therapeutic advantage. The Oncologist 1997;2: at the full dose of 75 mg/m 2 every three weeks for four cycles, accounted for this outcome. Nonetheless, in the adjuvant setting it is impossible to separately evaluate the relative efficacy of each drug regimen. In the attempt to assess the relative contribution of the two regimens, we activated a nonrandomized trial in patients with metastatic breast cancer not previously subjected to chemotherapy. PATIENTS AND METHODS Patient Selection Patients who entered this study were required to meet the following criteria: histologically proven invasive breast carcinoma; disease extent measurable either by physical examination, x-rays, computed tomography, or nuclear magnetic resonance; no prior chemotherapy; no medical contraindications for the administration of the planned drugs. Patients with central nervous system localizations or with bone lesions as the only site of metastasis were considered Correspondence: M. Zambetti, M.D., Divisione Oncologia Medica A, Istituto Nazionale Tumori Via Venezian 1, Milano, Italy. Telephone: ; Fax: Accepted for publication June 4, AlphaMed Press /97/$5.00/0 The Oncologist 1997;2:

2 Zambetti, Giacobone, Terenziani et al. 224 ineligible. Hematologic and blood chemistry levels within normal limits were mandatory unless the pathologic values were clearly related to the disease extent. Drug Administration and Dose Modification The treatment program consisted of Adriamycin delivered i.v. at the dose of 75 mg/m 2 every three weeks for four cycles and followed by CMF (cyclophosphamide, 600 mg/m 2 ; methotrexate, 40 mg/m 2 ; fluorouracil, 600 mg/m 2, on days 1 and 8) given i.v. every four weeks for four cycles. Treatment was always delivered in the outpatient clinic. According to the criteria conventionally adopted in the adjuvant setting, a delay of one week was considered in the presence of white blood cell count <3,400/mm 3, and platelet count <100,000/mm 3 on the planned day of treatment administration. Dose reduction was performed only if hematological toxicity persisted for more than two weeks. All patients received antiemetic support with granisetron or tropisetron plus dexamethasone. Response Assessment Pretreatment evaluation included physical examination, blood chemistry, and cardiac evaluation with electrocardiographic record. Radiological staging consisted of chest x-ray, bone scan with skeletal survey in the presence of scintigraphic positivity, echography of the abdomen and pelvis, and mammography whenever indicated. The peripheral blood cell count was repeated before every treatment cycle, while renal and liver function tests as well as cardiac evaluation were planned after the last dose of Adriamycin and after the completion of the entire treatment program. The therapeutic activity of the two drug regimens was evaluated by monthly physical examination and by the comparison of radiographic pathologic findings performed after the last dose of Adriamycin and at the completion of the treatment program unless required more frequently because of individual situations. In particular, the disease extent after Adriamycin represented the baseline evaluation for assessing CMF clinical efficacy. Patients requiring major procedures (i.e., laparoscopy or bone marrow biopsy) were assessed only at the end of the entire treatment program. A complete response (CR) was defined as the complete disappearance of all clinical and radiological signs of disease. A partial response (PR) was defined as >50% reduction in the product of the two largest diameters of measurable disease with no progression in any site. In patients with multiple lesions including bone metastases, a radiographic or scintigraphic stabilization of osseous lesions for at least six months was required to qualify for a partial remission. Freedom from progression and overall survival were computed from the first dose of Adriamycin using the product-limit method [4]. Table 1. Patient characteristics Evaluable patients 44 Median age (range) 56 (37-76) Menopause Pre- 21 (48%) Post- 23 ER status Positive 24/32 (75%) Negative 8/32 Metastatic breast cancer at diagnosis 32 (73%) Recurrent breast cancer* 12 Previous hormonal therapy 6 (14%) *Median disease-free interval from surgery: 28.5 months *(range: 6-131). ER = estrogen receptors. Patient Characteristics From August 1990 to February 1993, a total of 44 evaluable consecutive patients entered this prospective nonrandomized study. Table 1 outlines the main characteristics. Thirty-two patients presented with metastatic breast cancer at diagnosis, whereas the remaining 12 women had a median disease-free interval of 28.5 months (range: 6-131) from surgery. The majority of patients had a Karnofsky performance status of 90. In 11 cases, a single disease localization was documented, while in the remaining 33 patients, multiple lesions were detected. Visceral metastases were documented in 18 patients (41%), some of whom presented with multiple sites (lung, 6; pleura, 3; liver, 5; ovaries-peritoneum, 6; others, 6); bone involvement was documented in 18 cases (41%) (lytic, 3; mixed, 5; osteoblastic, 4; positive bone scan, 6) and 35 patients (79%) presented with soft tissue metastases (breast and axillary nodes, 25; supraclavicular nodes, 23; chest wall, 4; others, 7). RESULTS Therapeutic Efficacy The relative therapeutic role of the two drug regimens could be assessed in all but three patients who were evaluated only at the end of the entire program since they required a major procedure (laparoscopy or bone marrow biopsy). After four cycles of Adriamycin, 31 of 41 evaluable patients (76%) achieved an objective tumor response, including seven (17%) complete remissions. Two patients progressed while on therapy and in the remaining eight cases a minor response or disease stabilization was demonstrated. As far as assessment of the therapeutic activity of CMF was concerned, only 33 of 41 cases presented with measurable disease at the beginning of treatment. In fact, seven patients continued to maintain the complete remission achieved with

3 225 First-Line Chemotherapy in Metastatic Breast Cancer Table 2. Relative therapeutic activity of Adriamycin followed by CMF (41 patients) After ADM After CMF Total Prior n % n response to ADM n % CR CR 7, PR 4, NR PR 15 PR 15 PR PR 3, NR NR NR PRO PR 1, NR 2, PRO ADM = adriamycin; CR = complete response; NR = no response; PR = partial response; PRO = progressive disease. One PR with ADM unevaluable for CMF efficacy (see text). Adriamycin, while one woman with partial response died because of myocardial infarction after the first cycle of CMF. CMF was able to induce a complete remission in four partial responders as well as in a patient with stable disease after Adriamycin (Table 2). In addition, one woman who showed only minimal response after the anthracycline achieved PR with CMF, whereas further tumor shrinkage was documented in 15 of the remaining 19 partial responders. At the end of the entire sequential treatment, 12 complete and 20 PR were documented in the 41 women evaluable for the separate analysis of the two drug regimens. One additional complete remission was achieved in the remaining three patients; therefore the response rate of the sequential regimen was 75%. The frequency of CR was greater in the presence of a single disease site (56%) than in patients with multiple lesions (22%). In particular, complete remission was documented in five patients presenting with supraclavicular node involvement alone, in three patients with locally advanced breast cancer and adenopathies, and in five women with visceral involvement, whereas we failed to document complete bone recalcification. Table 3 shows the response rate according to sites of metastatic disease and also stresses the high incidence of remission in visceral localizations. Sixty-four percent of symptomatic patients experienced a complete relief of their symptoms. Table 3. Response rate according to sites of metastatic disease (data are in numbers) Sites Pts CR PR SD PRO NE Soft tissues Viscera Bone CR = complete remission; NE = not evaluable; PR = partial response; PRO = progressive disease; Pts = patients; SD = stable disease. At the end of the planned treatment, 38 patients received additional systemic treatment (chemotherapy: 6; hormonal therapy: 32) which was selected according to estrogen receptor status and/or dominant sites of disease. Figure 1 displays the overall freedom from progression and survival for the entire case series of 44 women. At four years from starting Adriamycin, 61% of the patients were still alive and the median time to progression was 16 months. At the time of present analysis, only 4 of 13 complete responders showed new disease manifestations as compared with 18 of 20 partial responders. As far as total survival is concerned, 12 of 13 complete responders were still alive as compared with 46% of partial responders. Percent Survival FFP Years Figure 1. Freedom from progression (FFP) and overall survival for the entire case series.

4 Zambetti, Giacobone, Terenziani et al. 226 Table 4. Treatment compliance Adriamycin No. % Evaluable cycles 174 Treatment delay Dose reduction CMF Day 1 Evaluable cycles 165 Treatment delay Dose reduction Day 8 Evaluable cycles 161 Treatment delay Dose reduction Toxicity Sequential Adriamycin and CMF therapy was completed in all patients according to the planned program. A total of 500 chemotherapy doses was administered. Treatment delay or dose reductions due to myelosuppression were documented in 11% of cycles (56 of 500). Hematological toxicity was more frequently observed on day 8 of CMF (Table 4) and consisted mainly of leukopenia. A platelet count below 100,000/mm 3 was never recorded. One patient died because of acute myocardial infarction after the first CMF cycle. She had no history of risk factors for cardiac disease and her cardiac tests before and after Adriamycin treatment were within normal values. Another woman, with aspecific abnormalities of ST-T waves at baseline electrocardiogram, developed transient and asymptomatic signs of ischemic heart disease four months after completion of the treatment program. During Adriamycin treatment, gastrointestinal disturbances of grade 3 were recorded in 9% of patients and grade 2 mucositis occurred in 9% of cases. The corresponding figures for CMF were 2% and 11%, respectively. Five patients experienced grade 2 transient increase in liver enzymes during CMF administration. Three patients developed non-neutropenic febrile episodes, which, however, never required hospital admission. At the end of the sequential treatment, iatrogenic amenorrhea occurred in 77% of premenopausal women. DISCUSSION Present data confirm the therapeutic activity of the sequential administration of Adriamycin and CMF and indicate that, in measurable metastatic breast cancer, both Adriamycin and CMF contributed to tumor shrinkage. After four cycles of the anthracycline, the observed response rate was 75%. As a consequence of subsequent CMF, four partial responders and one minor responder obtained complete remission, shifting the complete remission rate from 17% to 29%. In addition, we documented further shrinkage of metastatic lesions in 16 other patients. Some considerations on the therapeutic activity of CMF following an Adriamycin-containing regimen may be drawn from one of our oldest studies in metastatic breast cancer [5]. One hundred and ten patients were randomly allocated to receive treatment with CMF or Adriamycin and vincristine (AV). In the AV regimen, eight total courses were planned and treatment was then switched to CMF because of the potential risk of cardiac toxicity after a planned cumulative dose of 480 mg/m 2 of the anthracycline. Additional treatment with CMF after AV almost doubled the number of complete remissions (CR: 8% to 15%), all of which were obtained in responsive patients. In addition, crossover treatment with CMF after progressive disease on AV resulted in a response rate of 35%. Similar results were observed by Tormey et al. [6], who reported a 35% response rate (including 9% complete remissions) in patients crossed over to CMF after failure on AV. These two studies, as well as the present one, confirm that, at least on clinical grounds, Adriamycin and CMF can be considered as non-cross-resistant regimens. The results documented in the present study also confirm that, in patients with measurable metastatic breast cancer, the reported increased relapse-free and overall survival in the adjuvant treatment of high-risk operable breast cancer [3] may not be entirely ascribed to Adriamycin alone and that the inclusion of CMF into a sequential treatment approach is able to obtain additional therapeutic advantage. However, it is important to point out that, considering the fact that 38 patients received additional systemic treatment, the longterm results should not be interpreted as exclusively obtained by the presented chemotherapeutic regimen. Admittedly, conventional regimens with Adriamycin concomitantly combined with cyclophosphamide ± fluorouracil (AC, FAC) are able to induce therapeutic results similar to those reported after our sequential approach [6-12]. In particular, the M.D. Anderson investigators [7] documented a response rate of 75%, including 17% of complete remissions after the FAC combination. This Adriamycincontaining regimen was delivered up to a cumulative dose of 450 mg/m 2 for the anthracycline, and nine cases (6%) of congestive heart failure were reported. The clear-cut relationship between Adriamycin dose and toxicity is well-known, in particular at the cardiac level, with a reported significant reduction in left ventricular ejection fraction in up to 61% of patients treated with a mean dose of 495 mg/m 2 [10]. In our sequential regimen, four cycles of Adriamycin given for a cumulative planned dose of 300 mg/m 2 were able to achieve a response rate similar to the one reported by investigators from M.D. Anderson and were associated with a very low incidence of cardiac toxicity. The subsequent addition of

5 227 First-Line Chemotherapy in Metastatic Breast Cancer CMF was able to double the rate of CR. For these reasons, we believe the sequential administration of Adriamycin and CMF has an important role in the treatment of breast cancer patients with metastatic disease and warrants the assessment of its efficacy in a prospective randomized study in comparison with a more conventional regimen. In the last few years, the introduction of paclitaxel and docetaxel offered a substantial therapeutic advantage in the treatment of metastatic breast cancer patients. In particular, the association of these drugs with Adriamycin in the frontline treatment showed an increase in the overall response rate up to 95%, including 40% complete responders [13-16]. Because of the risk of cardiac toxicity, the administration of this drug association cannot be prolonged beyond four to six cycles. In this perspective, the availability of a non-crossresistant regimen is warranted for patients needing a more prolonged treatment. REFERENCES 1 Henderson IC. Chemotherapy for metastatic disease. In: Harris JR, Hellman S, Henderson IC et al., eds. Breast Disease (Ed. 2). Philadelphia, PA: Lippincott, 1991: Hryniuk WM, Bush M. The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 1984;2: Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten year results. JAMA 1995;273: Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958;53: Brambilla C, De Lena M, Rossi A et al. Response and survival in advanced breast cancer after two non-cross resistant combinations. Br Med J 1976;1: Tormey DC, Gelman R, Band PR et al. Comparison of induction chemotherapies for metastatic breast cancer. An ECOG Cooperative Oncology Group Trial. Cancer 1982;50: Hortobagyi GN, Gutterman TU, Blumenschein GR et al. Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer 1979;43: Jones SE, Durie BGM, Salmon SE. Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer 1975;36: Focan C, Adrien JM, Closon MT et al. Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial. J Clin Oncol 1993,11: Jones RB, Holland JF, Bhardwaj S et al. A Phase I-II study of intensive-dose Adriamycin for advanced breast cancer. J Clin Oncol 1987;5: Henderson IC, Gelman R, Canellos GP et al. Prolonged diseasefree survival in advanced breast cancer treated with Super CMF adriamycin: an alternating regimen employing high-dose methotrexate with citrovorum factor rescue. Cancer Treat Rep 1981;65: Caimo-Pereira J, Costa O, Henriques E et al. Advanced breast carcinoma: a comparison of two dose levels of Adriamycin. Proc Am Soc Clin Oncol 1986;5: Gianni L, Munzone E, Capri G et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 1995;13: Seidman AD. The emerging role of paclitaxel in breast cancer therapy. Clin Cancer Res 1995;1: Trudeau ME, Eisenhauer E, Lofters W et al. Phase II study of taxotere as first line chemotherapy for metastatic breast cancer. A National Cancer Institute of Canada Clinical trials group study. Proc Am Soc Clin Oncol 1993;12: Seidman AD, Hudis C, Crown JPA et al. Phase II evaluation of taxotere as initial chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 1993;12:52.

Copyright, 1995, by the Massachusetts Medical Society

Copyright, 1995, by the Massachusetts Medical Society Copyright, 99, by the Massachusetts Medical Society Volume 332 APRIL 6, 99 Number ADJUVANT CYCLOPHOSPHAMIDE, METHOTREXATE, AND FLUOROURACIL IN NODE- POSITIVE BREAST CANCER The Results of Years of Follow-up