Phase II trial of fazarabine (ARA-AC,arabinosyl-5-azacytosine) in metastatic breast cancer

Fourteen consecutive female patients with metastatic breast cancer received a total of 31 courses of fazarabine at a dose of 2 mg/m²/hour×72 hours (48 mg/m²/day×3) as a continuous infusion. There were no responses seen, although one patient achieved stability of her disease for five courses. Because of encouragingin vitro results and the primarily hematologic dose-limiting toxicity, further study in combination with colony stimulating growth factors might be of interest.     

Phase I/II trial of dipyridamole, 5-fluorouracil,leukovorin, and mitoxantrone in metastatic breast cancer

Summary Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m² by mouth every 6 h (700 mg/m²/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m² was given intravenously immediately prior to 5-FU 375 mg/ m² intravenously on days 1–5. Mitoxantrone 6 mg/m² was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m² days 1–2, 5-FU 375 mg/m² days 1–2, mitoxantrone 6 mg/m² on day 2, and dipyridamole 175 mg/m² every 6 h on days 0–3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.     

First-line combination chemotherapy with mitoxantrone and cyclophosphamide in advanced breast cancer

Summary In this study, 30 evaluable patients with advanced carcinoma of the breast were treated with cyclophosphamide 600 mg/m² i.v. followed one day later with mitoxantrone (Novantrone®; dihydroxyanthracenedione) 16 mg/m² i.v. Drug treatment was repeated every 3–4 weeks, for a maximum of 12 cycles. The overall response rate was 43%; five of 30 patients (16%) attained a complete remission, and eight of 30 (27%) had a partial remission. Median response duration was 12+ months. The greater number of responses was seen in skin and soft tissues. Hematologic toxicity was limiting with 75% of patients experiencing substantial-severe leukopenia. Clinically evident heart failure developed in one patient; in three other patients there was minor-moderate alteration of cardiac function during mitoxantrone-cyclophosphamide therapy. Based on these data, it is believed that this regimen may provide significant long-lasting palliation in patients with advanced breast cancer.     

A randomized trial comparing mitoxantrone with doxorubicin in patients with stage IV breast cancer

Summary Mitoxantrone (Novantrone®; dihydroxyanthracenedione) is an anthraquinone previously shown to be active in human breast cancer. It appears to have less toxicity than doxorubicin. Results of this phase II–III randomized cross-over trial to determine the relative efficacy and toxicity of mitoxantrone in comparison to doxorubicin, are presented. Patients with measurable, recurrent breast cancer with limited prior chemotherapy with or without radiotherapy for metastatic disease, and who had not been exposed to prior doxorubicin, were randomized to receive either mitoxantrone or doxorubicin every three weeks with crossover on progression. Response rates, duration of remission, time to treatment failure, and drug toxicity, including cardiac toxicity evaluated with serial radionuclide angiocardiography, were evaluated. Differences in the response rates for the two groups were not statistically significant. Neither time to treatment failure nor duration of response are significantly different (p>0.05). With respect to toxicity, mitoxantrone treated patients consistently exhibited a lower incidence and less severe drug toxicity as compared to their doxorubicin-treated counterparts. Cardiac toxicity was carefully monitored and thus four patients on doxorubicin have had drug related congestive heart failure, as compared to none on mitoxantrone.In summary, mitoxantrone appears to be as active as doxorubicin in patients with stage IV breast cancer previously treated with chemotherapy; however, mitoxantrone causes significantly less nausea, vomiting, stomatitis and alopecia at doses which induce equal or greater myelosuppression than doxorubicin, and appears to be less cardiotoxic.     

A randomized trial of doxorubicin,mitoxantrone and bisantrene in advanced breast cancer (A South West Oncology Group Study)

Summary New agents with increased activity and/or reduced toxicity are needed for the treatment of advanced breast cancer. The anthracene derivatives mitoxantrone and bisantrene had significant activity and acceptable toxicity in phase II trials. In an ongoing phase III trial we have now randomized 150 patients with advanced breast cancer to either doxorubicin (60 mg/m²), mitoxantrone (14 mg/m²) or bisantrene (260 mg/m²) i.v. q 3 weeks with re-randomization for cross-over at the time of progression to determine the relative efficacy and toxicity of these three agents. To be eligible, patients must have had only one previous chemotherapy regimen. ER positive patients must have failed endocrine therapy. Patients with CHF or severe cardiac disease were ineligible. In this preliminary evaluation, 117 patients are evaluable for response and 110 for toxicity. Median age for all patients is 58 years (range 26–78). The majority (86%) are postmenopausal. Fifty-nine percent of the patients have visceral dominant disease. Estrogen receptor is positive in 37%, negative in 39% and unknown in 24% of patients. Median performance status (SWOG) is 1, range 0–2. Objective responses have been observed on each arm (doxorubicin 9/35, mitoxantrone 6/38, bisantrene 6/44). Thirty-two patients are evaluable for cross-over response (doxorubicin 2/13, mitoxantrone 1/11, bisantrene 0/8). The predominant toxicity is leukopenia with a nadir WBC count <2000 in 45% of all courses administered. Leukopenia is similar with the three drugs. Significant nausea, vomiting and alopecia are common with doxorubicin and uncommon with the other agents. Congestive heart failure has been observed in one patient (doxorubicin). Definitive conclusions regarding the efficacy and toxicity of these agents await the completion of this trial.This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA-22433, CA-04920, CA-03096, CA-12644, CA-14028, CA-37981, CA-16385, CA-13238, CA-04915, CA-22411, CA-27057, CA-37445, CA-35178, CA-35995, CA-28862, CA-03389, CA-20319, CA-35117, CA-03396, CA-35438, CA-12213, CA-21116, CA-04919, CA-12014 and CA-32102. Address for reprints: Southwest Oncology Group (SWOG-8203), Operations Office, 4450 Medical Drive, San Antonio, TX 78229, U.S.A.     

CAF—HD—MIX与CAF方案治疗晚期乳腺癌的疗效比较

目的：比较环磷酰胺（CTX）,阿霉素（ADM）,氟尿嘧啶（5FU）及大剂量氨甲碾呤（HD－MTX）组成的CAF－HD－MTX方囊与CTX,AMD及5FU组成的CAF方案治疗晚期乳腺癌的疗效,方法：90例期乳腺癌随机分成两组,每组均为45例,结果：CAF－HD－MTX组完全缓解率20．0％（9／45）,总有效率80．0％（36／45）,CAF组完全缓解率13．3％（6／45）,总有效率46．7％（21／45）,统计学分析,完全缓解率没有显著差异（P＞0．05）,总有效率有非常显著差异（P＜0．01）,主要毒副反应,其中CAF－HD－MTX组的肝功[损害及口腔炎较CAF组有明显差异（前者P＜0．01,后者P＜0．05）,而骨髓抑制及胃肠道反应两组均无显著差异（P＞0．05）,结论：CAF－HD－MTX方案治疗晚期乳腺癌有效率高,病人可耐受,可在临床上进一步观察使用。     

Mitoxantrone combined to vincristine,cyclophosphamide and fluorouracil in advanced breast cancer

Summary In our wide experience of treating advanced breast carcinoma with chemotherapy, the combination of doxorubicin (DOX), vincristine (VCR), cyclophosphamide (CPM) and fluorouracil (FU) gave a complete plus partial response rate of over 60%, with 100% alopecia and frequent cardiac toxicity depending on total dose.After the EORTC Clinical Screening Group phase II trial we have conducted an expected difference method comparative phase II trial using the combination DOX, VCR, CPM, FU and the combination of MTX (10mg/m²), VCR, CPM and FU on a population of 50 breast carcinoma patients similar to those taking part in the first study.The reasons for similarity of action will be presented and discussed.     

Phase I trial of adjuvant chemotherapy with cyclophosphamide,epirubicin and 5-fluorouracil (CEF) for stage II breast cancer

Summary Epirubicin is a new anthracycline with a potentially more favorable toxicity profile than the parent compound, doxorubicin. Accordingly, the feasibility and toxicity of 6 courses of adjuvant chemotherapy with cyclophosphamide (C), epirubicin (E), and 5-fluorouracil (F) were assessed in 10 patients with Stage 2 (node positive) breast cancer. Doses of C and F were 600 mg/m² and E was 75 mg/m². Moderate granulocytopenia (median count = 610/mm³) occurred on day 14 of the first 21 day treatment course and was the main toxicity encountered with treatment, although there were no episodes of granulocytopenic fever. Grade 3 or 4 vomiting occurred in 40% and significant alopecia in 30% of patients. Four patients experienced transient asymptomatic decreases in calculated radionuclide cardiac ejection fraction of 10% but no signs or symptoms of cardiac failure were observed. If epirubicin proves to be less cardiotoxic than doxorubicin, this combination would merit further evaluation as potential adjuvant therapy for early breast cancer.     

Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as first-line treatment of MBC

Two i.v. regimens, bendamustine, methotrexate and 5-fluorouracil (BMF) and cyclophosphamide, methotrexate and 5-fluorouracil (CMF) were compared as first-line therapy in a randomized, open, multicenter phase III trial including 364 patients with metastatic breast cancer (MBC). Bendamustine is an anti-neoplastic agent with alkylating, but also additional, so far unclear, mechanisms of action. We wanted to show the superiority of BMF over CMF in terms of time to progression (TTP) (primary endpoint), overall response, response duration, toxicity and quality of life (QoL). TTP was significantly longer in the BMF group (8.2 versus 6.7 months for CMF) (p=0.0071). The effect of BMF on TTP was more pronounced in the stratum 'prior adjuvant therapy, no visceral metastases' (p=0.034). Overall response rates and QoL did not significantly differ between the regimens. BMF caused more mucositis and leukopenias. Thus, bendamustine, when replacing cyclophosphamide in the CMF combination, can be expected to produce longer progression-free survival in first-line treatment of MBC.     

Adriamycin, vincristine, cyclophosphamide and 5-fluorouracil (AVCF) compared with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in premenopausal breast carcinoma. Personal results

Adjuvant treatment of breast cancer with AVCF gave significantly longer disease-free survival than CMF in the group of patients taken as a whole, in the subgroup with lymph node involvement and in the premenopausal subgroup. No significant difference was found regarding overall survival.     

多西他赛联合奥沙利铂和5-氟尿嘧啶方案治疗晚期胃癌41例

目的:观察多西他赛联合奥沙利铂和5-氟尿嘧啶(5-Fu)方案治疗晚期胃癌的近期疗效、毒副反应及生存状况。方法:收集2004-2010年我院41例晚期胃癌患者,多西他赛75 mg.m-2(d 1);奥沙利铂130 mg.m-2(d 2);5-Fu 400～500 mg.m-2.d-1,[d 2～d 5或持续泵入96 h(civ 96 h)],每21 d重复1次,至少2个周期。结果:总缓解率(ORR)为26.8%,疾病控制率(DCR)为78.0%。中位无进展生存期(PFS)为5.6个月(95%CI:3.52～7.6),中位总生存(OS)为12.3个月(95%CI:2.7～21.9)。1年生存率为46.3%(19/41);2年生存率为21.9%(9/41);3年生存率为7.3%(3/41)。常见的毒副反应为骨髓抑制(主要为白细胞及中性粒细胞减少)、胃肠道反应(恶心和呕吐)、腹泻和脱发等。结论:多西他赛联合奥沙利铂和5-FU方案治疗晚期胃癌疗效显著,毒副反应可耐受。化疗近期疗效是晚期胃癌PFS和OS的独立预后因素[危害比(HR):3.6;95%CI:1.8～7.3]。     

多烯紫杉醇联合顺铂治疗晚期乳腺癌疗效观察

目的:观察国产多烯紫杉醇(艾素)联合顺铂治疗晚期乳腺癌的疗效及毒副反应。方法:21例患者均有病理学诊断及可评价的客观指标。采用多烯紫杉醇35mg/m2,静脉滴注1h,第1天、第8天及第15天,顺铂(DDP)为30mg/m2静脉滴注,第2天、第3天及第4天,28d为1个周期,所有患者均至少接受2个周期的化疗。结果:完全缓解(CR)1例,部分缓解(PR)11例,总有效率57.14%。主要毒副反应为骨髓抑制和脱发。结论:多烯紫杉醇联合顺铂治疗晚期乳腺癌有效率较高,毒副反应较小,值得临床进一步研究。     

紫杉醇阿霉素治疗晚期乳腺癌疗效观察

目的 观察紫杉醇联合阿霉素（TA）治疗晚期乳腺癌的疗效和不良反应。方法 对54例晚期乳腺癌患者进行观察。结果 TA总有效率61．1％，主要不良反应有骨髓抑制、胃肠反应、脱发等。结论 紫彬醇联合阿霉素对晚期乳腺癌有较好的疗效和耐受性。     

Phase II trial with oral idarubicin in advanced breast cancer

Summary Idarubicin, a new analogue of daunorubicin, was administered to 27 patients with advanced breast cancer in a phase II trial. The drug was given orally at a dose of 30–35 mg/m² every 3 weeks. Twenty-two patients were evaluable for response. All evaluable patients were previously treated with one or more chemotherapeutic regimens, including an anthracycline in more than 50% of the cases. Partial remissions were obtained in 5 patients, for a response rate of 23%. The median duration of response was 191 days. Mild nausea and vomiting were common. Diarrhea, which occurred in less than 50% of the patients, was usually short-lived. Alopecia was generally minimal. Myelosuppression was the dose-limiting toxic effect. Leukopenia was frequently seen, with full recovery by day 28 in 81 % of the courses. Thrombocytopenia was less common than leukopenia. Four cases of grade 1 acute cardiac toxicity were recorded. This study suggests that idarubicin can induce regressions in advanced carcinoma of the breast, and justifies further studies in combination with other agents.     

Phase II trial of vinorelbine and trastuzumab in patients with HER2-positive metastatic breast cancer. A prospective, open label, non-controlled, multicenter phase II trial (to investigate efficacy and safety of this combination chemotherapy)

Summary  The purpose of this study was to evaluate the efficacy (progression free survival (PFS) and response rate) and safety of vinorelbine and trastuzumab combination chemotherapy in patients with HER2-overexpressing, metastatic breast cancer as a first line chemotherapy regimen. Patients with histologically confirmed, HER2-positive (immunohistochemistry (ICH) 3+, or 2+ and FISH+) metastatic breast cancer who had nor received prior vinorelbine or anti-HER2 therapy in the adjuvant setting, received at least eight weeks of vinorelbine i.v. (25 mg/g weekly) and trastuzumab (4 mg/kg on day 1 followed by 2 mg/kg weekly). Forty-one women from six participating centers were enrolled into the trial. The overall response rate, was 43.9% (18 of 41 patients), (CI 28–60.3%), 30% of patients were progression free after 1 year. Four patients reached complete remission, 14 partial remission and five had stable disease for at least 18 weeks. Six patients developed primary progression. 35 patients (85%) experienced progression after a median time of 235 days. Therapy was in general well-tolerated. There were two CTC grade 4 infusion syndromes and two patients experienced cardiotoxicity at least grade 2. This phase II trial of vinorelbine and trastuzumab demonstrated an effective and well-tolerated regimen with a favourable safety profile.     

艾愈胶囊联合CAF化疗方案治疗乳腺癌的临床研究

目的探讨艾愈胶囊联合CAF化疗方案治疗乳腺癌患者的临床疗效。方法选取2013—2015年宜昌市第二人民医院收治的女性乳腺癌患者89例,随机分为对照组(44例)和治疗组(45例)。对照组静脉推注注射用盐酸多柔比星60 mg/m2,注射用环磷酰胺600 mg/m2,静脉滴注氟脲嘧啶注射液500 mg/m2,第1、8天各1次,21 d为1个疗程。治疗组在对照组的基础上口服艾愈胶囊,3粒/次,3次/d,21 d为1个疗程。两组均连续治疗2个疗程。观察两组的临床疗效,同时比较两组治疗前后血清血管内皮生长因子(VEGF)、CA125、CA153和癌胚抗原(CEA)水平及不良反应情况。结果治疗后,对照组总有效率和稳定率分别为34.09%和56.82%,分别低于治疗组的57.78%和77.78%,两组比较差异有统计学意义(P0.05)。治疗后,两组血清VEGF、CA125、CA153和CEA水平均有一定程度降低,与治疗前相比差异有统计学意义(P0.05)。且治疗组上述指标水平显著低于对照组,两组比较差异具有统计学意义(P0.05)。治疗期间,对照组患者白细胞和血红蛋白减少发生率高于治疗组,两组比较差异具有统计学意义(P0.05)。结论艾愈胶囊联合CAF化疗方案可以更好控制乳腺癌患者的VEGF以及相关肿瘤标志物水平,取得更好治疗效果,具有一定的临床推广应用价值。     

CAF与CMF方案用于局部晚期乳腺癌新辅助化疗临床观察

目的比较CAF、CMF两组不同新辅助化疗方案治疗局部晚期乳腺癌的疗效及毒性反应。方法用CAF、CMF化疗方案治疗Ⅱ、Ⅲ期乳腺癌94例,3-4周为1个周期。所有患者完成2个周期新辅助化疗后评价疗效。结果 CAF组的总有效率为68．89％(31／45),其中完全缓解(CR)3例,部分缓解(PR)28倒;CMF组的总有效率为 46．94％(23／49),其中CR 0例,PR 23例,P<0.05。两组毒性反应比较:CAF组有较为严重的白细胞下降、胃肠道反应,两组相比有显著性差异,P<0．05。结论两组新辅助化疗方案对乳腺癌治疗均有效,毒性反应均可耐受。CAF组疗效及毒性反应均高于CMF组。     

Gemcitabine and mitoxantrone in metastatic breast cancer: A phase-I-study

Background: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. Patients and methods: Patients with metastatic breast cancer were treated with gemcitabine (1000–1400 mg/m²) on days 1, 8 and 15 and mitoxantrone (10–14 mg/m²) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. Results: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m² gemcitabine and 14 mg/m² mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m² based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. Conclusion: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m².     

Supporting Asian patients with metastatic breast cancer during ixabepilone therapy

Importance of the field: Ixabepilone is currently FDA-approved in metastatic breast cancer, and most patients in the registrational trials were Caucasian. Studies in Asian populations receiving other cytotoxic agents have revealed differential pharmacokinetics and clinical outcomes. As such, clinicians should understand the possible contributions of Asian ethnicity and culture to the clinical profile of ixabepilone.

Areas covered in this review: Studies in Asian patients receiving other chemotherapeutics reported altered toxicity profiles for myelosuppression, neurotoxicity and gastrointestinal symptoms. Encouragingly, the limited clinical data in Asian patients receiving ixabepilone suggest that efficacy and toxicity in these women resemble those reported in the ixabepilone registrational trials.

What the reader will gain: The reader will better understand how Asian genetics and culture may influence treatment outcomes and patient attitudes toward therapy and interaction with caregivers. Management of ixabepilone-related adverse events is also discussed with an emphasis on special considerations for Asian patients.

Take home message: Awareness of possible altered drug response in Asian patients will aid clinicians in monitoring for toxicity, recognizing the need for dose modification and educating patients. Sensitivity to cultural aspects that are unique to Asians may improve adherence, reporting of adverse events and trust among Asian patients receiving ixabepilone.     

Phase II study of ionidamine in patients with metastatic breast cancer

Summary The Eastern Cooperative Oncology Group conducted a phase II study of lonidamine in patients with metastatic breast cancer. The drug was given orally to a maximum daily dose of 340 mg/m². Forty-two patients were entered on study. One partial response was observed; there were no life-threatening toxicities. The results of this study are compared to two similar phase II trials.Other participating institutions include: Fox Chase Cancer Center, Philadelphia, PA (CA-18281); Medical College of Ohio, Toledo, OH; Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL (CA-25988), Evanston Hospital (CCOP), Evanston, IL.