ANTICANCER RESEARCH 36: 419-426 (2016) Mitomycin C and Capecitabine (MiX Trial) for Therapy of Patients with Metastasized, Breast Cancer Pretreated with Anthracycline KATRIN ALMSTEDT1, PETER A. FASCHING1, ANTON SCHARL2, CLAUDIA RAUH1, BRIGITTE RACK3, ALEXANDER HEIN1, CAROLIN C. HACK1, CHRISTIAN M. BAYER1, SEBASTIAN M. JUD1, MICHAEL G. SCHRAUDER1, MATTHIAS W. BECKMANN1 and MICHAEL P. LUX1 1Department of Obstetrics and Gynaecology, University of Erlangen, Erlangen, Germany; 2Department of Gynecology and Obstetrics, St. Marien Hospital, Amberg, Germany; 3Department of Gynecology and Obstetrics, Ludwig Maximilian University, Munich, Germany Abstract. Background/Aim: The aim of this single-arm, (MBC) is still a challenge. The majority of patients with prospective, multicenter phase II trial (MiX) was to increase breast cancer receive an anthracycline-based regimen as first treatment options for women with metastatic breast cancer chemotherapy, in an adjuvant, neoadjuvant, or metastatic pretreated with anthracycline and taxane by evaluation of the setting. The development of drug resistance and impairment efficacy and toxicity of the combination of mitomycin C and of organ functions limits the choice of further cytotoxic capecitabine. Patients and Methods: From 03/2004 to drugs in the metastatic situation. Although many patients are 06/2007, a total of 39 patients were recruited and received willing to receive further anticancer therapy to counteract mitomycin C in combination with capecitabine. The primary tumor growth, they often request a less toxic but still end-point was to determinate the tumor response according effective therapy. At present taxanes (e.g. paclitaxel, to Response Evaluation Criteria in Solid Tumors and the rate docetaxel, nab-paclitaxel), eribulin, vinorelbine, 5- of toxicities (safety). The secondary study objective was the fluorouracil (5-FU infusion, capecitabine per os) and evaluation of the time to progression (i.e. efficacy). Results: mitomycin C are widely used for salvage therapy in patients The median time to progression was 9.3 months (95% with metastatic breast cancer (2-5). confidence interval=6.6-12.0 months) and the median Mitomycin C has a well-studied therapeutic activity in survival was 12.8 months (95% confidence interval=6.8-18.8 metastatic breast cancer (6) as a result of its lack of cross- months). Most treatment-related adverse events were mild to resistance with anthracyclines. Numerous studies presented moderate. Conclusion: Mitomycin C and capecitabine is a high response rates, especially in patients with prior good taxane-free option in patients with metastatic breast anthracycline-based therapies. As a monotherapy, mitomycin cancer previously treated with anthracycline. achieves response rates of 26-38% in chemotherapy-naïve patients, and in pretreated patients 15-25% (7). The duration Worldwide, breast cancer is the most common malignancy of remission is usually 3-4 months. among women, with an estimated incidence of 1,38 million, The advantages of capecitabine are its oral bioavailability, and is the leading cause of cancer-related deaths in women which is especially appreciated by patients in the palliative (1). Although significant progress has been achieved for the setting (8), its possibility to cross the blood–brain barrier for therapy of early breast cancer, metastatic breast cancer an effective option in the treatment of patients with metastases of the central nervous system (9), and its additive effect with other cytotoxic agents, such as mitomycin C, cyclophosphamide, paclitaxel and docetaxel (10), which can Correspondence to: Michael P. Lux, MD, University Breast-Center be attributed to the up-regulation of the key enzyme thymidine of Franconia, Department of Gynecology and Obstetrics, University phosphorylase in capecitabine metabolism. Several studies Hospital of Erlangen, CCC Erlangen-EMN, Universitaetsstr. 21-23, have demonstrated a well-tolerable side-effect profile of 91054 Erlangen, Germany. Tel: +49 91318533553, e-mail: capecitabine, while taxane-specific side-effects such as high- [email protected] grade neuropathy or neutropenia have not been reported (11). Key Words: Breast cancer, mitomycin C, capecitabine, metastasis, The aim of this single-arm, prospective, multicenter phase chemotherapy. II trial (MiX) was to analyze further taxane-free treatment 0250-7005/2016 $2.00+.40 419 ANTICANCER RESEARCH 36: 419-426 (2016) options for patients with metastatic breast cancer who had of study randomization and the date of progressive disease. Patients undergone at least one prior treatment including an who had no progressive disease were censored at the date of their anthracycline. last clinical visit. Overall survival (OS) was defined as the time interval from the date of study randomization to either the date of Patients and Methods death or the date of the last contact the patient was alive. Patients who were lost to follow-up within 28 days after the last therapy of a maximum of six cycles were censored at the last date they were Primary and secondary end-points. The primary end-point was to known to be alive. A patient who was alive 28 days after diagnosis determine the tumor response according to the Response Evaluation was censored at that date. The data are described using simple Criteria in Solid Tumors (RECIST) (12) and the rate of toxicities survival analyses. Survival rates were estimated using the (safety). The secondary study objective was the evaluation of the Kaplan–Meier product-limit method. time to progression (i.e. efficacy). The clinical cut-off point of the study was 28 days after the last therapy of a maximum of six cycles. Inclusion and exclusion criteria. Eligible patients were women with metastatic breast cancer with at least one measurable lesion according to RECIST. Patients were between 18 and 80 years of Results age, with a Karnofsky performance status of 70% or more. All patients had received a prior anthracycline-containing therapy in the curative or metastatic setting. Patients were required to have normal Demographic data and medical history. Data of 34 patients baseline laboratory results within certain limits. All included women were analyzed. Five patients were excluded due to protocol gave their informed consent for participation in this study. The study violations (no prior anthracycline-containing therapy). All was approved by the Ethics Committee of the Friedrich Alexander patients received at least one cycle of mitomycin C in University Erlangen-Nuremberg, Germany (no. 3026). combination with capecitabine. Assessed with the Karnofsky The main specific exclusion criteria were previous treatment with performance status, 21 patients (61.8%) had normal activity mitomycin C at any time, or with nitrosoureas or capecitabine within and 12 (35.3%) had reduced activity. The mean body mass six weeks prior to the study treatment, major surgery or radiotherapy 2 2 within four weeks before the start of therapy, inadequate recovery index was 27.5 kg/m (range=19.1-43.6 kg/m ). Patients’ from previous therapy, previous or concurrent malignancy (except demographic data are summarized in Table I. The median basal cell carcinoma of the skin, in situ cervical cancer or age at the time of the primary diagnosis of breast cancer was contralateral breast cancer), unstable health, mental illness, addiction, 47 years (range=30-68 years) and median age at the start of cardiovascular disease, myocardial infarction within the last 12 study treatment was 52 years (range=38-71 years). months, or a life expectancy of less than 3 months. The average interval between the first diagnosis of Study design and treatment. This was a single-arm prospective metastases (median age at diagnosis of metastases=51 years) multicenter phase II study. Patients were enrolled at four German and the start of treatment was 14.88 months (range=0-73 centers in Bavaria: the University Breast Center of Franconia at the months). Twenty-eight (82.4%) of the primary tumors were University Hospital of Erlangen; the Department of Gynecology and estrogen receptor-positive and twenty (60.6%) were Obstetrics at the Ludwig Maximilian University of Munich; the progesterone receptor-positive. Ten (41.7%) cases were Department of Gynecology and Obstetrics at the St. Marien Hospital found to have overexpression of human epidermal growth of Amberg; and an oncological practice in the city of Weiden. factor receptor 2, of which four patients (40.0%, two in the Patients received mitomycin C as an intravenous bolus of 8 mg/m2 on day 1, in combination with 2,000 mg/m2 capecitabine on days 1 curative and two in the metastatic setting) received a targeted to 14, of a 21-day cycle. The treatment was continued for a therapy with trastuzumab. Thirty patients (91.0%) had maximum of six cycles or until tumor progression within 18 weeks. undergone previous surgery, all of them in the curative setting. Three patients had no surgery at any time point. Study assessments. Tumor response was evaluated by RECIST after Twenty-two patients (64.7%) had received radiotherapy. the fourth and sixth cycle. The best overall response was evaluated. Twenty-four patients (70.6%) had multiple sites of Time to progression was defined as the interval between metastasis. The most common metastatic sites were the liver randomization and tumor progression, death or loss to follow up in (61.8%), bone (50%), lymph nodes (29.4%), skin (26.5%) patients with no evidence of disease progression. Safety was evaluated in all patients. Toxicities were graded 1 to and lung (26.5%). 5 in accordance with the National Cancer Institute of Common The patients’ medical histories are summarized in Table Toxicity Criteria, version 2.0 (13). If the study treatment had to be II. Thirty-one patients (91.2%) had received chemotherapy discontinued due to toxicities, patients were included in the follow- in the curative setting (29.4% neoadjuvant and 61.8% up. The duration of the follow-up was 18 months after the last adjuvant), 24 patients (70.6%) had received adjuvant therapy of a maximum of six cycles.