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Mitomycin C and Capecitabine Combination (Mixe) in Heavily Pretreated Metastatic Breast Cancer Patients

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Mitomycin C and Capecitabine Combination (Mixe) in Heavily Pretreated Metastatic Breast Cancer Patients ANTICANCER RESEARCH 25: 4513-4518 (2005) Mitomycin C and Capecitabine Combination (MiXe) in Heavily Pretreated Metastatic Breast Cancer Patients. A Dose-finding Study ROBERTO MAISANO1, NICOLA CARISTI2, MARZIA MARE3, ANTONINO MAFODDA2, RITA CARBONI1, ERIKA MONTALTO2, MONICA IORFIDA2 and MARIO NARDI1 1Unità Operativa di Oncologia Medica, A.O. "Bianchi-Melacrino-Morelli" Reggio Calabria; 2Unità Operativa di Oncologia Medica, A.O.U. "G. Martino" Policlinico Messina; 3Divisione di Oncologia, Istituto Oncologico del Mediterraneo Viagrande Catania, Italy Abstract. Background: No standard chemotherapy has been number of patients with disease resistance to both agents. defined for metastatic breast cancer patients pretreated with Therefore, new therapeutic strategies are needed for these anthracyclines and taxanes. In preclinical studies, mitomycin patients, in which the major aims of treatment are to obtain C (MMC) and capecitabine showed a synergistic effect by up- disease control, symptom reduction and better quality of regulation of thymidine phosphorylase, and both drugs were life. Several drugs, alone or in combination, have been active against breast cancer with a lack of overlapping tested in this stage of disease, and response rates ranging toxicity, making their combination a well-tolerated regimen. from 0% to 62% have been reported in small phase II Patients and Methods: A dose-finding study was carried out studies or in retrospective analyses (1). in order to determine the maximum tolerable dose of MMC Capecitabine has become an important treatment option combined with fixed-dose capecitabine and to describe the for patients with metastatic breast cancer (MBC) that has dose-limiting toxicities. Results: Twenty-one patients were progressed following taxane therapy, and has shown promise enrolled, with metastatic breast cancer pretreated at least with in anthracycline-pretreated patients, as monotherapy and as a anthracyclines and taxanes (3 at dose level I, 15 at dose level component of combination regimens (2-6). Capecitabine is an II, 3 at dose level III). At dose level III (MMC 12 mg/m2 and oral fluoropyrimidine that undergoes conversion to its active capecitabine 1000 mg/m2 days 2-15) dose-limiting toxicities metabolite fluorouracil (5-FU) through a 3-step enzymatic were recorded in 2 patients (G4 thrombocytopenia, metabolic process (7). The final step of this process, the neutropenic fever, G4 neutropenia); dose level II (MMC 10 conversion of 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-FU, mg/m2 and capecitabine 1000 mg/m2 days 2-15) was requires thymidine phosphorylase (dThdPase), a potent extended for a better safety evaluation. No severe toxicity was tumor-associated angiogenesis factor. The higher expression noted at this dose level, and therefore this dose was of dThdPase in tumor tissue provides for preferential recommend for the phase II study. With regard to activity, 4 conversion of capecitabine in neoplastic tissues (8). Given the partial responses and 2 stable diseases (28%) were recorded. prominent role of dThdPase in the therapeutic index of Conclusion: Our data show that the combination is feasible, capecitabine-based treatment, it follows that maximizing well tolerated and active in this set of patients. dThdPase activity would result in an enhanced therapeutic index. Treatment of malignant tumors with various cytokines, Anthracyclines and taxanes are considered the most such as tumor necrosis factor alpha, interleukin-1 and effective drugs against breast cancer, but their early use in interferon gamma has been observed to produce increases in the treatment of these tumors has led to an increase in the intratumoral dThdPase activity and to enhance tumor sensitivity to 5'-DFUR in vitro and in vivo (9). In addition, paclitaxel (100 mg/kg), docetaxel (15 mg/kg) and mitomycin C (MMC) (5 mg/kg) have also been shown to increase the Correspondence to: Maisano Roberto, MD, Via Comunale Sperone Fortuna Residence, 98158 Messina Italy. Fax: +390965397106, e- levels of dThdPase in human colon cancer xenograft studies mail: [email protected] by 8-fold, 6.1-fold, and 7.7-fold, respectively (10). These cytotoxic agents are thought to up-regulate dThdPase through Key Words: Mitomycin, capecitabine, metastatic breast cancer. increases in tumor necrosis factor alpha levels. 0250-7005/2005 $2.00+.40 4513 ANTICANCER RESEARCH 25: 4513-4518 (2005) MMC has been a treatment option for MBC since the Table I. Patient characteristics. early 1980s (11). It belongs to the family of antitumor No. of patients antibiotics, and also works against hypoxic tumor cells (12). Its toxicity is comparable to that of other cytotoxic agents, Enrolled 21 consisting of neutropenia and thrombocytopenia. Chronic Age (years) toxicities, such as renal failure due to the development of Median 61 hemolytic uremic syndrome (HUS) or pulmonary toxicity, Range 42-77 ECOG Performance Status are infrequent but may be severe and, therefore, the upfront 04 use of MMC should be avoided. The combination of MMC 18 with 5-FU and folinic acid was used in MBC with interesting 28 results (13). On account of preclinical data, the mechanisms 31 of action and lack of overlapping toxicities of MMC and Prior chemotherapy Adjuvant 17 capecitabine, we conducted a dose-finding study of this Metastatic 21 combination in MBC previously treated with anthracyclines Anthracycline and taxane 21 and taxanes. The study was designed to determine the Vinorelbine 9 maximum tolerable dose (MTD) of MMC combined with 5-Fluorouracil bolus 9 fixed-dose capecitabine and to describe the dose-limiting Gemcitabine 3 Cisplatin 2 toxicities (DLTs) of the combination. 1 Line 4 2 Lines 12 Patients and Methods 3 Lines 3 4 Lines 2 Eligibility. Patients with cyto/histologically–confirmed MBC Site of metastases pretreated with anthracyclines and taxanes were eligible for this Liver 11 study. Bidimensionally measurable disease was not a prerequisite, Lung 10 but patients received a complete evaluation of their sites of disease Bone 10 and each measurable lesion was recorded. Eligibility criteria also Lymph nodes 4 included the following: (i) age ≥ 18 years; (ii) ECOG performance Skin 4 status of 0 to 3; (iii) a life expectancy ≥ 12 weeks; (iv) no major 1 Site 4 surgery, radiotherapy, or chemotherapy within 28 days of study 2 Sites 9 entry; (v) no prior MMC or capecitabine treatment; (vi) no 3 Sites 7 gastrointestinal disorder that might affect the absorption of 4 Sites 1 capecitabine; (vii) adequate hematopoietic WBC count ≥ 3,000/mm3, absolute neutrophil count (ANC) of ≥ 1,500/mm3, platelet count ≥100,000/mm3 and hemoglobin level of ≥ 9.0 g/dL; (viii) hepatic (total serum bilirubin level ≤ 1.5 times institutional upper normal limits [UNL], AST and ALT ≤ 3 times UNL) and that resulted in interruption of capecitabine for more than 3 days, renal (serum creatinine ≤ 1.5 times UNL or calculated creatinine or delay in the dose of MMC for more than a week; and (iv) clearance ≥ 60 mL/min) functions; (ix) no brain metastases, unless clinical inability (because of toxicity) to start the next cycle of the lesions had been previously irradiated and were stable and treatment within 2 weeks of the planned start date. The maximum- asymptomatic; (x) absence of organ allografts or serious tolerated dose level was defined as the highest MMC dose level uncontrolled infections; (xi) no known existing coagulopathy or which, when combined with capecitabine 2000 mg/m2 day, resulted requirement for therapeutic doses of coumarin-based anticoagulants; in DLT in less than 2 out of 6 new patients, during both their first and (xii) no history of severe reaction to fluoropyrimidine therapy. and second cycles of treatment. An observation period of 6 weeks Patients gave written informed consent before treatment. (2 cycles of chemotherapy) for the development of DLTs was required by the protocol. Treatment plan. Capecitabine was administered at the fixed dose of 2000 mg/m2/day in two equally divided oral doses of 1000 mg/m2 for Dosage modifications. A new course of treatment was to begin only 14 days starting on days 2 through 15 every 21 days. MMC was when the granulocyte count was ≥ 1,500/mm3 and the platelet planned to be administered at 4 escalating dose levels of 7 mg/m2 count was ≥ 100,000/mm3 and any other treatment-related (level 1); 10 mg/m2 (level 2); 12 mg/m2 (level 3) and 14 mg/m2 (level toxicities were ≤ grade 1; otherwise, treatment was withheld for 4) every 42 days by i.v. infusion. A minimum of 3 new patients were up to 1 week. If the toxicity had not resolved from grade 0 to 1 at to be treated at all tolerable dose levels. Intrasubject dose escalation the end of this period, the patient was withdrawn from the study was not permitted. Toxicities were graded according to the National unless clinical benefit had been documented, in which case a Cancer Institute Common Toxicity Criteria version 2.0 (NCI-CTC). treatment delay of up to 1 additional week to allow recovery was DLT was defined as one of the following: (i) an ANC less than permitted. Planned treatment with capecitabine within a cycle of 500/mm3 for more than 5 days, or associated with fever therapy was withheld in the presence of grade ≥ 2 non- (temperature ≥ 38.5ÆC); (ii) a platelet count less than 25,000/mm3; hematological (except isolated-hyperbilirubinemia or alopecia) or (iii) severe (≥ grade 3) non-hematological toxicity (except alopecia) grade ≥ 3 hematological toxicity. Treatment was resumed when 4514 Maisano et al: Mitomycin Capecitabine Combination Dose-finding Study Table II. Toxicity per dose level in cycles one and two according NCI-CTC. Dose Patients level Neutropenia Neutropenic fever Thrombocytopenia HFS Nausea/vomit Stomatitis/mucositis Diarrhea 1 2 3 4 1 2 3 4 1 2 3 1 2 3 4 1 2 3 4 1 2 3 4 131 1 1 1 2152 1 1 33111 1 2 Table III.
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