Abstract
Background/Aim: The aim of this single-arm, prospective, multicenter phase II trial (MiX) was to increase treatment options for women with metastatic breast cancer pretreated with anthracycline and taxane by evaluation of the efficacy and toxicity of the combination of mitomycin C and capecitabine. Patients and Methods: From 03/2004 to 06/2007, a total of 39 patients were recruited and received mitomycin C in combination with capecitabine. The primary end-point was to determinate the tumor response according to Response Evaluation Criteria in Solid Tumors and the rate of toxicities (safety). The secondary study objective was the evaluation of the time to progression (i.e. efficacy). Results: The median time to progression was 9.3 months (95% confidence interval=6.6-12.0 months) and the median survival was 12.8 months (95% confidence interval=6.8-18.8 months). Most treatment-related adverse events were mild to moderate. Conclusion: Mitomycin C and capecitabine is a good taxane-free option in patients with metastatic breast cancer previously treated with anthracycline.
Worldwide, breast cancer is the most common malignancy among women, with an estimated incidence of 1,38 million, and is the leading cause of cancer-related deaths in women (1). Although significant progress has been achieved for the therapy of early breast cancer, metastatic breast cancer (MBC) is still a challenge. The majority of patients with breast cancer receive an anthracycline-based regimen as first chemotherapy, in an adjuvant, neoadjuvant, or metastatic setting. The development of drug resistance and impairment of organ functions limits the choice of further cytotoxic drugs in the metastatic situation. Although many patients are willing to receive further anticancer therapy to counteract tumor growth, they often request a less toxic but still effective therapy. At present taxanes (e.g. paclitaxel, docetaxel, nab-paclitaxel), eribulin, vinorelbine, 5-fluorouracil (5-FU infusion, capecitabine per os) and mitomycin C are widely used for salvage therapy in patients with metastatic breast cancer (2-5).
Mitomycin C has a well-studied therapeutic activity in metastatic breast cancer (6) as a result of its lack of cross-resistance with anthracyclines. Numerous studies presented high response rates, especially in patients with prior anthracycline-based therapies. As a monotherapy, mitomycin achieves response rates of 26-38% in chemotherapy-naïve patients, and in pretreated patients 15-25% (7). The duration of remission is usually 3-4 months.
The advantages of capecitabine are its oral bioavailability, which is especially appreciated by patients in the palliative setting (8), its possibility to cross the blood–brain barrier for 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 be attributed to the up-regulation of the key enzyme thymidine phosphorylase in capecitabine metabolism. Several studies have demonstrated a well-tolerable side-effect profile of capecitabine, while taxane-specific side-effects such as high-grade neuropathy or neutropenia have not been reported (11).
The aim of this single-arm, prospective, multicenter phase II trial (MiX) was to analyze further taxane-free treatment options for patients with metastatic breast cancer who had undergone at least one prior treatment including an anthracycline.
Patients and Methods
Primary and secondary end-points. The primary end-point was to determine the tumor response according to the Response Evaluation Criteria in Solid Tumors (RECIST) (12) and the rate of toxicities (safety). The secondary study objective was the evaluation of the time to progression (i.e. efficacy).
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 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 baseline laboratory results within certain limits. All included women gave their informed consent for participation in this study. The study was approved by the Ethics Committee of the Friedrich Alexander University Erlangen-Nuremberg, Germany (no. 3026).
The main specific exclusion criteria were previous treatment with mitomycin C at any time, or with nitrosoureas or capecitabine within six weeks prior to the study treatment, major surgery or radiotherapy within four weeks before the start of therapy, inadequate recovery from previous therapy, previous or concurrent malignancy (except basal cell carcinoma of the skin, in situ cervical cancer or contralateral breast cancer), unstable health, mental illness, addiction, cardiovascular disease, myocardial infarction within the last 12 months, or a life expectancy of less than 3 months.
Study design and treatment. This was a single-arm prospective multicenter phase II study. Patients were enrolled at four German centers in Bavaria: the University Breast Center of Franconia at the University Hospital of Erlangen; the Department of Gynecology and Obstetrics at the Ludwig Maximilian University of Munich; the Department of Gynecology and Obstetrics at the St. Marien Hospital of Amberg; and an oncological practice in the city of Weiden. 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 to 14, of a 21-day cycle. The treatment was continued for a maximum of six cycles or until tumor progression within 18 weeks.
Study assessments. Tumor response was evaluated by RECIST after the fourth and sixth cycle. The best overall response was evaluated. Time to progression was defined as the interval between randomization and tumor progression, death or loss to follow up in patients with no evidence of disease progression.
Safety was evaluated in all patients. Toxicities were graded 1 to 5 in accordance with the National Cancer Institute of Common Toxicity Criteria, version 2.0 (13). If the study treatment had to be discontinued due to toxicities, patients were included in the follow-up. The duration of the follow-up was 18 months after the last therapy of a maximum of six cycles. Data were collected for life status (survival) and further therapies every 3 months.
Statistical analysis. All patients with a measurable lesion according to RECIST and who had received at least one cycle of therapy were included. Time to progression was defined as time between the date of study randomization and the date of progressive disease. Patients who had no progressive disease were censored at the date of their last clinical visit. Overall survival (OS) was defined as the time interval from the date of study randomization to either the date of 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 known to be alive. A patient who was alive 28 days after diagnosis was censored at that date. The data are described using simple survival analyses. Survival rates were estimated using the Kaplan–Meier product-limit method.
The clinical cut-off point of the study was 28 days after the last therapy of a maximum of six cycles.
Results
Demographic data and medical history. Data of 34 patients were analyzed. Five patients were excluded due to protocol violations (no prior anthracycline-containing therapy). All patients received at least one cycle of mitomycin C in combination with capecitabine. Assessed with the Karnofsky performance status, 21 patients (61.8%) had normal activity and 12 (35.3%) had reduced activity. The mean body mass index was 27.5 kg/m2 (range=19.1-43.6 kg/m2). Patients' demographic data are summarized in Table I. The median age at the time of the primary diagnosis of breast cancer was 47 years (range=30-68 years) and median age at the start of study treatment was 52 years (range=38-71 years).
The average interval between the first diagnosis of metastases (median age at diagnosis of metastases=51 years) and the start of treatment was 14.88 months (range=0-73 months). Twenty-eight (82.4%) of the primary tumors were estrogen receptor-positive and twenty (60.6%) were progesterone receptor-positive. Ten (41.7%) cases were found to have overexpression of human epidermal growth factor receptor 2, of which four patients (40.0%, two in the curative and two in the metastatic setting) received a targeted therapy with trastuzumab. Thirty patients (91.0%) had undergone previous surgery, all of them in the curative setting. Three patients had no surgery at any time point. Twenty-two patients (64.7%) had received radiotherapy. Twenty-four patients (70.6%) had multiple sites of metastasis. The most common metastatic sites were the liver (61.8%), bone (50%), lymph nodes (29.4%), skin (26.5%) and lung (26.5%).
The patients' medical histories are summarized in Table II. Thirty-one patients (91.2%) had received chemotherapy in the curative setting (29.4% neoadjuvant and 61.8% adjuvant), 24 patients (70.6%) had received adjuvant endocrine therapy. These patients had up to five courses of palliative chemotherapy and four courses of palliative endocrine therapy. Nine patients (26.5%) had simultaneously received bisphosphonate treatment due to bone metastasis. All analyzed patients had previously received an anthracycline-containing treatment (55.9% in the curative and 44.1% in the palliative setting); 76.5% had previously received a taxane-based treatment.
Demographic data of the study collective (n=34 patients).
Administration and safety. Patients received a total of 150 cycles of treatment, with a median of 5.0 cycles per patient (range of one to six). Extension of the interval was required in 16 cycles (10.7%). Dose reduction due to adverse events was else required in 15 cycles (10%).
A total of 18 patients (52.9%) discontinued therapy before completion of six cycles due to disease progression in eight cases (23.5%), including one death (2.9%). Nine patients (26.5%) discontinued to an adverse event and one patient (2.9%) because of general reduced condition caused by other disease. No treatment-related deaths occurred (Table III).
The most common treatment-related adverse events (grades 1-4) were myelotoxicity (leucopenia 79.4%, anemia 76.5%, neutropenia 67.7%, thrombocytopenia 64.7%), elevated transaminases (67.7%) and alkaline phosphatase (52.9%), nausea (64.7%), hand-foot syndrome (58.8%) and paraesthesia (58.8%). Most of the treatment-related adverse events were mild to moderate in intensity, and the only grade 3/4 adverse events occurring in more than 5% of patients were dyspnea (20.6%), diarrhea (5.9%), hand-foot syndrome (5.8%) and thrombocytopenia (5.9%) (Table IV).
Medical history of the study collective (n=34).
Efficacy. Response was evaluated in 34 patients. Objective response occurred in 13 patients (38.2%), with a complete response in three patients (8.8%) and partial response in 10 (29.4%) (Table V). Stable disease was achieved in a further 12 patients (35.3%). No tumor response or disease stabilization was observed in nine patients (26.5%), for two of whom no imaging data were available because their death occurred before imaging could be carried out. The median follow-up of the study population was 8.6 months (range=0.26-25.0 months). The Kaplan–Meier curves for time to progression and OS are presented in Figures 1 and 2. The median time to progression was 9.3 months (95% confidence interval=6.6-12.0 months) and the median survival was 12.8 months (95% confidence interval=6.8-18.8 months).
Administration and complications of treatment (n=34).
Discussion
Therapy of patients with metastatic breast cancer is still a challenge. Different options are available after previous treatment with anthracycline and taxane. This single arm prospective multicenter phase II study (MiX) presents impressive results regarding treatment response, OS and the safety profile for the combination of mitomycin C and capecitabine in anthracycline-pretreated patients with metastatic breast cancer. Due to the shift of anthracyclines and taxanes to (neo)adjuvant regimes, subsequent treatment regimens used in the metastatic setting have to be matched. A reinduction of these substances can be an option in spite of possible drug resistance but drug-specific side-effects, such as the cumulative cardiotoxicity of anthracyclines and increased rates of high-grade neuropathy, could be a limiting factor. A gold standard for the treatment of patients with metastatic breast cancer does not actually exist. Following the recommendation of the German Association of Gynecological Oncology (AGO Mamma) capecitabine, eribulin or vinorelbine are recommended after anthracycline-taxane-containing pretreatment (14). Another option is the use of (peg)-liposomal doxorubicin or nanoparticle albumin-bound paclitaxel (nab-paclitaxel)(15). Generally, the use of combination therapies, which are primarily more effective due to synergistic effects, and monotherapies with less side-effects, have to be weighed together with prognosis and aggressiveness of the disease, the tumor characteristics, age and co-morbidities, as well as patient's expectations and wishes (14).
The present study analyzed the efficacy of mitomycin C in combination with capecitabine as a taxane-free treatment option for patients with metastatic breast cancer who had undergone previous treatments including an anthracycline-based regime. The patients had prior treatments, on average approximately one (range of 0 to 5) palliative chemotherapy line and one (range of 0 to 4) endocrine therapy. Moreover, 70.6% of the patients had multiple metastases, including numerous visceral lesions. The objective response rate was 38.2%, and 73.5% including stable disease. All patients had previously received an anthracycline-containing therapy (55.9% in the curative and 44.1% in the palliative setting) and 76.5% had additionally received a taxane-based treatment. The median time to progression was 9.3 months and the median survival 12.8 months. These data are consistent with previously published data, when in the current literature the benefit for monotherapy with capecitabine is associated with a median progression-free time of 3.2 to 4.9 months and a median OS of 12.2 to 15.2 months in an anthracycline/taxane-pretreated collective (16-19) (Table VI). Regarding the combination of 5-FU and mitomycin, our group previously presented a time to progression of 6.9 months and an OS of 10.5 months (20). The same combination was investigated by Maisano et al. [progression-free (PFS)=8.0 months, OS=17.6 months)] (21). The efficacy of mitomycin was also demonstrated by the MRF scheme (mitomycin/folinic acid/5-FU) [PFS=8.0months, OS=10.5 months (22); PFS=4.5 months, OS=6.0 months (23)]. Likewise, the data of the present study indicate comparability with other recommended monotherapy or combination therapies in an anthracycline-pretreated metastatic setting such as gemcitabine plus vinorelbine vs. vinorelbine (PFS=6.0 vs. 4.0 months, p=0.0028; OS=15.9 vs. 16.4 months, p=0.8046) (24), docetaxel with capecitabine vs. docetaxel (PFS=6.1 vs. 4.2 months, p=0.0001; OS=14.5 vs. 11.5 months, p=0.0126) (25), paclitaxel plus gemcitabine vs. paclitaxel (PFS=6.14 vs. 3.98 month, p=0.0002, OS=18.6 vs. 15.8 months, p=0.0489) (26), monotherapy with eribulin (PFS=3.7 vs. 2.2 months, p=0.137; overall survival=13.1 vs. 10.6 month, p=0.041)(27, 28) or nab-paclitaxel compared to paclitaxel in the second line or greater (PFS=23.0 vs. 16.9 weeks, p=0.006; OS= 56.4 vs. 46.7 weeks, p=0.024)(29) and underline the high degree of efficacy of the combination regimen. In addition, our data suggest that the combination of mitomycin C and capecitabine presents no cross-resistance with anthracyclines or taxanes.
Toxicities according to the National Cancer Institute of Common Toxicity criteria, version 2.0 (13) (n=34).
Overview of efficacy endpoints (n= 34) of mitomycin C plus capecitabine.
Time to progression of the MiX study collective (n=34).
Overall survival data of the MiX study collective (n=34).
Overview of studies analyzing capecitabine monotherapy or the combination of mitomycin C (MMC) and 5-fluorouracil (5-FU)/capecitabine.
The safety profile of the examined chemotherapeutic agents is comparable with the reported data of previous studies (11, 30, 31). Regarding the results of Maisano et al., we also did not observe any events of mitomycin-induced hemolytic uremic syndrome. However the rate of pulmonary symptoms was significantly higher in our study population than in comparative studies. It was the most common grade 3 toxicity and the only grade 4 (8.8%), despite prophylaxis with steroids. It is not clear whether the observed-pulmonary symptoms occurred due to pulmonary/pleural metastases or side-effects of mitomycin C because all grade 3 pulmonary toxicities and 66.0% of grade 4 toxicities occurred in patients with pulmonary or pleural metastases and may have been caused by the disease. Mitomycin-related side-effects such as renal failure or pulmonary symptoms are rare, but can present serious courses. For this reason, the upfront use of mitomycin C is not recommended (21). Nevertheless the majority of adverse events were mild to moderate in intensity. The only grade 3 or 4 adverse events occurring in more than 5% of these patients were dyspnea (20.6%), diarrhea (5.9%), hand-foot syndrome (5.8%) and thrombocytopenia (5.9%). The typical side-effects associated with therapy with taxanes, severe polyneuropathy and neutropenia, were not observed.
This study has several strengths and limitations. In order to improve individualized therapy strategies, biomarker projects, especially in phase I and II trials, are desirable. However, this objective was not included here. Another weakness of the study is the lack of evaluated data on quality of life, which is an important goal for patients with a palliatively treated disease. One strength of our prospective study is the high patient compliance, which is reflected in the high number of cycles performed per patient.
In conclusion, this single-arm prospective multicenter phase II study (MiX) presents clinically meaningful results regarding treatment response, OS and safety profile for the taxane-free combination of mitomycin C and capecitabine in anthracycline-pretreated patients with metastatic breast cancer.
- Received October 28, 2015.
- Revision received November 26, 2015.
- Accepted December 2, 2015.
- Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
