Mitoxantrone, fluorouracil, and L-folinic acid in anthracycline-pretreated metastatic breast cancer patients

In this phase II trial we have evaluatedthe activity and toxicity of a combination regimencontaining mitoxantrone, L-leucovorin, and fluorouracil in patients withadvanced breast cancer pretreated with anthracyclines. Forty-six patientswere included into the study; they received atotal of 227 cycles of chemotherapy. Median agewas 63 years (range 34–78), median performance statuswas 80 (range 60–100). Visceral metastases were presentin 37 patients, 6 patients had bone involvementonly, while 3 patients had soft tissue/lymph nodedisease. Median number of previous chemotherapy regimens foradvanced disease was 2 (range 1–3). Ten patientshad anthracycline primary resistance (progressive disease during treatment).Twenty-three patients received mitoxantrone 12 mg/sqm day 1;fluorouracil 370 mg/sqm and L-folinic acid 100 mg/sqmdays 1–3 administered every three weeks. Another groupof 23 patients were treated with the sameregimen using a prolonged 5FU/L-FA schedule (5 days).Two complete responses and 6 partial responses wererecorded with the 3-day schedule; 7 partial responsesin the 5-day schedule (overall response rate 32.6%,95% C.I. 19–46%). Two partial responses were observedin patients with anthracycline primary resistance. Median responseduration was 9 months (range 3–16). Hematologic toxicitywas mild: grade 3–4 leukopenia was recorded in5 patients, grade 3–4 thrombocytopenia in 3 patients.Grade III–IV stomatitis and diarrhea was recorded in4 and 5 patients respectively (all receiving the5-day 5-FU/L-FA schedule). Cardiac toxicity was observed intwo cases. This regimen proved active in advancedbreast cancer following anthracycline-containing chemotherapy, and the 3-dayschedule could be offered to such patients withacceptable toxicity.     

米托蒽醌、氟尿嘧啶与亚叶酸钙联合治疗有转移的乳腺癌41例

目的：观察米托蒽醌（Ｍｉｔｏｘａｎｔｒｏｎｅ，ＭＩＴ）、氟尿嘧啶（Ｆｌｕｏｒｏｕｒａｃｉｌ，５－ＦＵ），亚叶酸钙（Ｌｅｕｃｏｖｏｒｉｎ，ＣＦ?治疗有转移的乳腺癌的疗效。方法：采用ＭＴＴ、５－ＦＵ与ＣＦ联合治疗有转移的乳腺癌４１例，２６例初治，１５例复治，雌激素受体（ＥＲ）阳性１９例，采用ＭＩＴ１２ｍｇ／ｍ＾２静脉推注，第１天；５－ＦＵ３２０ｍｇ／ｍ＾２静脉滴注，ｄＩ－５，ＣＦ５０ｍｇ／ｍ＾２静脉推注，与５－ＦＵ一起开始用，间隔１２ｈ一次，连续５天，每３周重复。结果：完全缓解（ＣＲ）１１例，部分缓解（ＰＲ）１９例，总有效率７３．２％，中位缓解期１７月，中位生存期２３月，本方案主要毒性为骨髓抑制，白细胞下降占８５．４％，其中Ⅲ、Ⅳ度为１９．５％，口腔炎发生率９．８％，局部静脉炎发生率１２．２％。结论：该方案治疗转移     

Mitoxantrone, fluorouracil, and high-dose leucovorin: an effective, well-tolerated regimen for metastatic breast cancer

Between September 1988 and August 1990, we treated 35 women with metastatic breast cancer with a novel regimen containing mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin. This regimen was designed to take full advantage of the favorable toxicity profiles of these agents while maintaining a high level of activity. All patients had received previous chemotherapy (adjuvant only, 15 patients; at least one metastatic regimen, 20 patients). Seven patients had received previous doxorubicin, but none within 6 months of study entry. Of 31 assessable patients, 20 (65%) had objective responses (two complete, 18 partial), with a median response duration of 6 months (range, 3 to 16+ months). Four patients with bone metastases (abnormal bone scan only) and pain were not considered assessable by strict response criteria; two of these patients had sustained symptomatic relief for 6 and 8 months, respectively. Myelosuppression was the most frequent toxicity but was mild in most patients; only four hospitalizations for fever and neutropenia were required (2% of courses). No severe thrombocytopenia occurred and no RBC transfusions were required. Alopecia, mucositis, and nausea/vomiting were uncommon and were not severe in any patient. The combination of mitoxantrone, 5-FU, and high-dose leucovorin is well tolerated and active as a first- or second-line treatment for metastatic breast cancer. Comparison with other standard regimens for breast cancer is indicated.     

A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma

Three hundred thirty-one women with metastatic breast cancer were randomized to receive combination chemotherapy with either cyclophosphamide, Novantrone (mitoxantrone; Lederle Laboratories, Wayne, NJ), and fluorouracil (CNF) or cyclophosphamide, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and fluorouracil (CAF). Patients could not have had prior chemotherapy, although adjuvant chemotherapy was acceptable. Initial doses were 500 mg/m2 of cyclophosphamide and 500 mg/m2 of fluorouracil with either 10 mg/m2 of mitoxantrone or 50 mg/m2 of doxorubicin, administered intravenously (IV) on day 1 and repeated every 3 weeks. There were no statistically significant differences in pretreatment or prior therapy characteristics between the groups. For patients assigned to the CNF and CAF groups, respectively, 25 (18%) were premenopausal, 39 (40%) were estrogen receptor (ER) negative, 39 (38%) had a disease-free interval less than 1 year, and 24 (26%) had received prior adjuvant chemotherapy. All patients were compared for response rate, duration of response, time to progression or death, time to treatment failure (TTF), and survival. None of these parameters were statistically significant favoring one regimen over the other. The response rate (complete [CR] and partial response [PR]) was 29% for the CNF group (95% confidence interval of 22% to 37%) and 37% for the CAF group (95% confidence interval of 29% to 45%). The median response duration and TTF were 171 days and 125 days for the CNF group and 254 days and 147 days for the CAF group, respectively. The median survival times for the CNF group and the CAF group were 377 and 385 days, respectively. The major dose-limiting toxicity for both regimens was leukopenia, manifested as granulocytopenia. The incidence of stomatitis/mucositis was 10% in the CNF group and 19% in the CAF group. Alopecia occurred in 49% of CNF patients (severely for 4%) and in 86% of CAF patients (severely for 39%). Nausea/vomiting occurred in 80% of CNF patients and in 81% of CAF patients; the degree of severity was also comparable. There was significantly less cardiotoxicity observed in the CNF group compared with the CAF group. Although CNF is somewhat less effective in overall response rate, survival curves are identical. CNF can be offered to patients who reject anthracycline-containing regimens because of fear of alopecia.     

Phase II trial of liposome-encapsulated doxorubicin, cyclophosphamide, and fluorouracil as first-line therapy in patients with metastatic breast cancer.

PURPOSE: To determine the efficacy and safety profile, including the risk for cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil (5-FU), and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one women were registered in this phase II study. All patients had measurable disease and no previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3 weeks. Serial cardiac monitoring, including endomyocardial biopsies, was performed. RESULTS: The overall response rate was 73% (95% confidence interval, 57% to 86%). The median duration of response was 11.2 months, the median time to treatment failure was 8.1 months, and the median overall survival duration was 19.4 months. The median number of cycles per patient was 10. The median cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three patients (7%) were withdrawn from the study due to protocol-defined cardiac toxicity, two because of a decrease in left ventricular ejection fraction to < or = 40%, and one because her endomyocardial biopsy result was grade 1.5. One patient had congestive heart failure that was probably nonanthracycline related. CONCLUSION: This chemotherapy regimen, including TLC D-99, was highly active against MBC and associated with low cardiac toxicity despite high cumulative doses of doxorubicin.     

Phase III trial of cyclophosphamide, epirubicin, fluorouracil (CEF) versus cyclophosphamide, mitoxantrone, fluorouracil (CNF) in women with metastatic breast cancer

Background: The mitoxantrone combination CNF and the epirubicin combination CEF have shown similar activity and less toxicity than the standard CAF combination in metastatic breast cancer (MBC). A prospective randomised study was started to compare safety and activity between CEF and CNF administered using a classical chemotherapeutic schedule in MBC.Patients and methods: From December 1987 to June 1993, 151 patients were randomised to receive cyclophosphamide (C) 100mgm^–2 p.o. days 1–14, fluorouracil (F) 500mgm^–2 i.v. days 1 and 8, and epirubicin (E) 30mgm^–2 i.v. days 1 and 8, or mitoxantrone (N) 6 mgm^–2 i.v. days 1 and 8, every 4 weeks. Seventythree patients were eligible for CEF and 72 for CNF.Results: Objective responses were observed in 61.6 of the CEF group and 44.4 in CNF group (p=0.004). The median duration of response was 64 weeks in CEF and 50 weeks in CNF group (p=0.02) and median time to progression was 51 and 33 weeks, respectively (p=0.0004). At the time of analysis, all except six patients (one in CNF and five in CEF) had died and the median survival time in the CEF group was longer than in CNF (74.4 weeks vs 51.4 weeks; log-rank ² test p=0.015). CNF produced more hematologic toxicity than CEF (WHO scale; grades 2–4): leucopenia 84% vs 68% (p=0.03) and trombocytopenia 17% vs 4.5% (p=0.01); CEF caused more grade 2 and 3 alopecia: 93% vs 70% (p=0.00 1).Conclusion: The combination CEF using this schedule and dosage in metastatic breast cancer is more effective with less toxicity than CNF, except for alopecia, and was associated with longer survival.     

Sequential cyclic combined hormonal therapy for metastatic breast cancer

Thirty postmenopausal patients who had evaluable estrogen receptor-positive or unknown metastatic breast cancer were treated with cyclic sequential combined hormonal therapy consisting of 50 micrograms of ethinylestradiol orally daily for 7 days followed by 400 mg of medroxyprogesterone acetate orally daily for 21 days, followed in turn by 7 days of rest. Cyclic administration was continued until progressive disease was detected. Patients who had had one previous chemotherapy regimen were included, but 63% of patients were previously untreated. Six patients achieved complete remission and 11, a partial remission, for an overall response rate of 57%. Median remission duration was 22 months; median time to disease progression for all 30 patients was 8 months. Toxicity consisted of cyclic vaginal bleeding, hot flashes, weight gain, irritability, and fluid retention. This cyclic, sequential hormonal regimen was effective and well tolerated.     

Mitoxantrone and paclitaxel combination chemotherapy in metastatic breast cancer

This study evaluated mitoxantrone and paclitaxel combination chemotherapy in the treatment of patients with metastatic breast cancer. Thirty-seven patients who had developed progressive disease after prior chemotherapy were treated with mitoxantrone (14 mg/m²) and paclitaxel (150 mg/m²) every 21 days for a maximum of six cycles. The most frequent grade 3 or 4 nonhematological toxicities were fever and nausea. Grade 4 neutropenia occurred in 71% of patients. Cardiotoxicity occurred in 2 patients, both of whom had previously received doxorubicin. Objective response was achieved in 35% of patients (5% complete response and 30% partial response) and 41% had stable disease. Median time to disease progression and median survival were 6 and 12 months, respectively. The percent of patients with an objective response was not different for those who had received prior doxorubicin or had chemotherapy in the preceding 6 months. This regimen appears to be effective and well tolerated as salvage therapy and merits further evaluation.     

Second line hormonal therapy with aminoglutethimide in metastatic breast cancer

One hundred and twenty patients with metastatic breast cancer, whose disease progressed on hormonal therapy with tamoxifen, were treated with aminoglutethimide. The overall response rate was 34% and the median duration of response 9.5 months. Response to aminoglutethimide was achieved in all metastatic sites except lung and brain. Even 25% of patients who had failed to respond to prior tamoxifen did respond objectively to aminoglutethimide. The actuarial survival for all patients at 30 months was 22%. Although initial toxicity was high (70%), side effects of aminoglutethimide were transient, and treatment had to be discontinued in only four patients. The results of this trial confirm that aminoglutethimide is an effective treatment in metastatic breast cancer.     

FAC (fluorouracil, doxorubicin, cyclophosphamide) as second line chemotherapy in patients with metastatic breast cancer progressing under FEC (fluorouracil, epirubicin, cyclophosphamide) chemotherapy

Background: The cross-over resistance between different anthracyclinesin breast carcinoma has not been largely evaluated in clinicaltrials. Patients and methods: Nineteen patients with metastatic breastcancer who had failed prior first line FEC chemotherapy (fluorouracil500 mg/m², epirubicin 50 mg/m² cyclophosphamide 500 mg/m², every4 weeks) were treated with a combination of fluorouracil 500mg/m², doxorubicin 50 mg/ m² and cyclophosphamide 500 mg/m²every 4 weeks (FAC). Results: Five patients achieved partial responses, ranging induration from 5 to 8 months. The main toxicity was cardiac,with congestive heart failure documented in five patients. Conclusion: The findings indicate an absence of cross-resistanceof doxorubicin in some epirubicin-resistant patients. breast cancer, anthracyclines, cross-resistance     

Mitoxantrone as second-line single agent in metastatic breast cancer

Mitoxantrone (MIX), a member of the anthraquinone chemical class, was found to be a potential anticancer agent. It has a similar spectrum of activity as Adriamycin in experimental and human tumors. Thirty-five female patients with metastatic breast cancer, refractory to previous chemotherapy, were treated between 1986 and 1987 with MIX (14 mg/m2 i.v. every 3 weeks); patients with diffuse bone metastases or heavily pretreated patients received 10-12 mg/m2 MIX. All patients were evaluable for response and toxicity. Two patients achieved complete response and 4 partial response, giving an overall response rate of 17%. Median time of response was 5.5 months. The drug was well tolerated. Objective response was obtained mostly in patients with a performance status (Karnofsky scale) of more than 70%, and in those who received more than 12 mg/m2 MIX per course. One patient developed cardiomyopathy, another an acute myocardial infarction, and 3 patients had pathological changes on echocardiography or multigated nuclear angiography. Hematological and gastrointestinal toxicity was tolerable. We found MIX to be a potentially effective second-line treatment with mild toxicity in patients with metastatic breast cancer.     

Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan

Background

To compare the cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and the anthracycline-containing regimen cyclophosphamide, epirubicin, and fluorouracil (CEF) to evaluate the efficacy and safety of the latter.

Methods

A total of 294 patients with axillary node-positive primary breast cancer of STAGE I–IIIa were randomly assigned to either CEF [cyclophosphamide (CPA) 500 mg/m² i.v. days 1 and 8; epirubicin (EPI) 60 mg/m² i.v. day 1; and 5-fluorouracil (5-FU) 500 mg/m² i.v. days 1 and 8] or CMF [CPA 500 mg/m² i.v. days 1 and 8; methotrexate (MTX) 40 mg/m² i.v. days 1 and 8; and 5-FU 500 mg/m² i.v. days 1 and 8]. Both treatment regimens were comprised of six cycles at 4-week intervals. Tamoxifen (TAM) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years.

Results

The overall 5-year survival was 77.1% for CEF and 71.4% for CMF [p = 0.24; hazard ratio 0.79 (95% CI 0.50–1.24)], and the 5-year disease-free survival was 55.7% for CEF and 48.9% for CMF [p = 0.15; hazard ratio 0.80 (95% CI 0.57–1.12)]. Although the log-rank test did not show a significant difference, both overall and disease-free survivals were higher for CEF according to the point estimates. Adverse drug reactions (ADRs) occurred more frequently in CEF.

Conclusion

Whereas CEF had a good trend compare with CMF, it could not be proven statistically significant. The principal cause of the failure seems to be insufficient power, that is, the dose intensity (EPI: 60 mg/m²) set 10 years ago, when the trial began, was low, and the number of trial subjects was small because of the background of the times, which made the accumulation of cases extremely difficult. However, the trial should be considered to be meaningful, as it was the first, formally conducted controlled trial on chemotherapy in Japan.     

Mitoxantrone plus vinorelbine in pretreated patients with metastatic breast cancer

Vinorelbine and mitoxantrone have both been demonstrated to have significant antitumor activity in patients with breast cancer. The aim of this study was to evaluate the efficacy and safety of the combination as second or third line treatment in patients with metastatic breast cancer (MBC). Fifty-one previously treated patients with MBC were enrolled from October 2001 to May 2004 and 48 were eligible for evaluation. Median age was 59 years (range 33-82) and ECOG performance status was < or =2. Distant sites of metastasis were as follows: liver 64%, bone 49%, lung 36%, lymph nodes 6%, skin 4%, brain 2% and other sites 6%. All patients received vinorelbine 20 mg/m(2), D1+8 and mitoxantrone 10 mg/m(2) D8 every 21 days for 6 cycles. All eligible patients were analyzed for toxicity and response. Two patients (4%) achieved complete response and 12 (25.5%) partial response. The objective overall response rate was 29.5% (95% confidence interval [CI] 17 - 45), 9 (19%) patients had stable disease, 17 (36%) had progressive disease and 7 (15%) were non-evaluable. After a median follow up of 18 months, overall survival was 13 months (range 0.8 - 38+) and median time to disease progression was 5 months (range 1 - 32). A total of 280 cycles was delivered. The relative dose intensities of mitoxantrone and vinorelbine were 79% and 77%, respectively. Toxicities (grade III-IV) were as follows: leukopenia 18 (38%), neutropenia 21 (45%), thrombocytopenia 1 (2%), anemia 4 (8.5%), alopecia 2 (4%) and constipation 1 (2%). Febrile neutropenia was recorded in one patient. There were no treatment related deaths. The combination of mitoxantrone and vinorelbine is an effective regimen with manageable toxicity in pretreated patients with advanced breast cancer.     

Mitoxantrone plus gemcitabine in pretreated patients with metastatic breast cancer

Gemcitabine and mitoxantrone have both shown significant antitumor activity in patients with breast cancer. The aim of this study was to evaluate the efficacy and safety of this combination as second or third-line treatment in patients with metastatic breast cancer (MBC). Forty-six previously treated patients with MBC were enrolled from June 2000 to November 2002. Mean age was 56 years and ECOG performance status was < or =2. All patients received mitoxantrone 10 mg/m2, D8 and gemcitabine 1000 mg/m2, D1+8 every 21 days for 6 cycles. There were no complete responders. Objective response was observed in 12 patients (26%), 15 (33%) patients had stable disease, 15 (33%) had progressive disease and 4 (9%) were non-evaluable. At median follow-up of 27.8 months, overall survival was 13.3 months (range 0.6-33.8+) and the median time to disease progression (TTP) was 4.4 months (range 0.2-33.8). Toxicities (grade 3-4) were as follows: leukopenia 18 (39%), neutropenia 19 (41%), thrombocytopenia 4 (8.5%), anemia 6 (13%) and alopecia 1 (2%). Febrile neutropenia was recorded in 2 (4%) patients. There were no treatment related deaths. The authors conclude that the combination of mitoxantrone and gemcitabine is an effective regimen in pretreated patients with metastatic breast cancer. Toxicity was manageable.     

Dosage of capecitabine and cyclophosphamide combination therapy in patients with metastatic breast cancer

BACKGROUND: Capecitabine is a highly effective and well-tolerated treatment for metastatic breast cancer (MBC) and extends survival when combined with docetaxel. Capecitabine and cyclophosphamide are orally administered and have preclinical synergy and non-overlapping toxicities. PATIENTS AND METHODS: Sixteen pretreated MBC patients received escalating doses of oral capecitabine 628 to 829 mg/m2 twice daily (bid) plus oral cyclophosphamide 33 to 50 mg/m2 bid, on days 1 to 14 every 21 days. RESULTS: Among the ten patients receiving capecitabine/cyclophosphamide 829/33 mg/m2 bid on days 1 to 14, two experienced dose-limiting toxicities (DLT, treatment delay > 1 week due to grade 2 leukopenia). Because neither patient developed further grade > 1 toxicity and none of the patients experienced grade 3/4 toxicities or further DLTs, this dose level is the recommended regimen, producing partial responses in two of five evaluable patients. CONCLUSION: The recommended all oral capecitabine/cyclophosphamide combination regimen is well tolerated and active in MBC, and is being evaluated in a phase II study in anthracycline-pretreated MBC.     

Prediction of response to hormonal treatment in metastatic breast cancer

Prediction of outcome and individualization of therapeutic strategies are challenging problems in oncology. Predictive parameters for response to hormonal treatment include the expression of hormone receptor, the extent and location of metastatic spread, disease-free interval, patient age, response to prior hormonal therapy, grading, and more recently, some molecular markers like the expression of HER-2/neu. The use of conventional statistics for prediction of response to hormonal treatment is limited by non-linearities and complex interactions between predictive factors. Modern computational mathematical models like artificial neural networks, entropy-based inductive algorithms or chi(2) interaction detection algorithms can describe these interactions and generate classification models and decision structures. They can be used to predict the clinical outcome for individual patients. In contrast to conventional methods, the level of confidence for the predictions can reach 90% and more. This might be an important step towards further individualization of therapeutic strategies.     

A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer

This study was designed to assess the role of dosage of chemotherapy for treatment of metastatic breast cancer. One hundred thirty-three patients without prior chemotherapy for metastatic disease were randomly allocated to receive two different dose levels of cyclophosphamide (C), methotrexate (M), and fluorouracil (F), administered intravenously (IV) every 3 weeks. Patients were stratified by sites of disease (visceral, bone, or soft-tissue dominant) and by interval from primary surgery to first recurrence. Doses on the higher-dose arm were 600 mg/m2 (C,F) and 40 mg/m2 (M) with escalation if possible; doses on the lower-dose arm were 300 mg/m2 (C,F) and 20 mg/m2 (M) without escalation. Patients who failed to respond to lower-dose CMF were crossed over to the higher-dose arm. Patients randomized to the higher-dose arm had longer survival measured from initiation of chemotherapy (median survival, 15.6 months v 12.8 months, P = .026 by log-rank test), but the effect of dose was of borderline significance (P approximately 0.12) when adjusted for a chance imbalance between the two arms in the time from first relapse to randomization, using the Cox proportional hazards model. Response rates (International Union Against Cancer [UICC] criteria) for patients with measurable disease were higher-dose arm: 16/53 (30%) and lower-dose arm: 6/53 (11%), (P = .03). Only one of 37 patients responded on crossover from the lower- to the higher-dose arm. Patients experienced more vomiting, myelosuppression, conjunctivitis, and alopecia when receiving higher doses of chemotherapy. A series of 34 linear analogue self-assessment scales were used to make detailed quality of life assessments on a subset of 49 patients. These scales confirmed greater toxicity in the immediate posttreatment period, but also a trend to improvement in general health and some disease-related indices, in patients receiving higher-dose chemotherapy. This trial suggests that better palliation is achieved by using full-dose chemotherapy.