|Year : 2015 | Volume
| Issue : 2 | Page : 287-290
Metronomic oral chemotherapy with old agents in patients with heavily treated metastatic breast cancer
Hasan Mutlu1, Fatma Yalçin Musri1, Mehmet Artaç2, Aysegül Kargi1, Mustafa Özdogan1, Hakan Bozcuk1
1 Department of Medical Oncology, Akdeniz University, School of Medicine, Antalya, Turkey
2 Department of Medical Oncology, Selcuk University, School of Medicine, Konya, Turkey
|Date of Web Publication||7-Jul-2015|
Department of Medical Oncology, Akdeniz University School of Medicine, 07070, Konyaalti/Antalya
Source of Support: None, Conflict of Interest: None
Background: We aimed to assess the efficacy of a metronomic regimen with cyclophosphamide and etoposide in heavily treated patients with metastatic breast cancer (MBC).
Materials and Methods: A total of 77 patients with MBC used continuous oral cyclophosphamide 50 mg/day and oral etoposide given as 2 × 50 mg/day for 2 days per week, were analyzed retrospectively from Akdeniz University and Selcuk University. The patients with MBC are predominantly refractory to antracyclines, taxanes, and antimetabolites.
Results: The patients were treated and followed between May 2005 and June 2014. The median progression-free and overall survival (PFS and OS) were 7.03 (5.06-8.99) and 32.5 (22.5-42.4) months, respectively. No prognostic factor was found for OS.
Conclusions: Metronomic treatment regimen with cyclophosphamide and etoposide is a novel and effective strategy in heavily pretreated MBC patients. This regimen can be used in early or late steps as independently from prognostic factors. Moreover, it has very low toxicity and is cheap. Impressive survival data and low cost may make this regimen a highly preferable option.
Keywords: Breast cancer, heavily treated, metronomic, survival
|How to cite this article:|
Mutlu H, Musri FY, Artaç M, Kargi A, Özdogan M, Bozcuk H. Metronomic oral chemotherapy with old agents in patients with heavily treated metastatic breast cancer. J Can Res Ther 2015;11:287-90
|How to cite this URL:|
Mutlu H, Musri FY, Artaç M, Kargi A, Özdogan M, Bozcuk H. Metronomic oral chemotherapy with old agents in patients with heavily treated metastatic breast cancer. J Can Res Ther [serial online] 2015 [cited 2019 Dec 15];11:287-90. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/287/154008
| > Introduction|| |
Breast cancer (BC) is the most common type among all cancers in women and about 30% of BC patients are metastatic cases. , There are several different treatment modalities in patients with BC. One of them is the metronomic treatment. This treatment method was previously studied in leukemia, lymphoma, lung, ovarian, andprostate tumors. ,,, Recently, phase II trials of BC have been taking place in the literature more frequently. However, these studies seem to have limited effectiveness.
Our study, using the principles of metronomic and cytotoxic therapy, aimed to investigate the impact and toxicity of metronomic treatment in patients with metastatic breast cancer (MBC).
| > Materials and methods|| |
Totally of 77 patients with inoperable or MBC were evaluated retrospectively from Akdeniz University and Selcuk University between May 2005 and June 2014. The age, sex, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, grade, luminal types, comorbidity, Eastern Cooperative Oncology Group performance status (ECOG PS), visceral metastasis, number of metastatic organ, and line of metronomic treatment were recorded to SPSS 16.0 (Statistical Package for Social Sciences-version 16.0) statistical program. All of the patients had previously received chemotherapy regimen with antracycline and taxan-based in adjuvant or metastatic setting. Due to progression or toxicity, chemotherapy regimen that was previously offered to the patients, treatment was stopped before semimetronomic chemotherapy regimen. The patients with HER2 or CerbB2 (+++) or HER2 (++) andfluorescence in situ hybridization (FISH) (+) had previously received treatment regimen with trastuzumab. Except for one patient with HER2 (+++), the others with HER2 (+++) or FISH (+) had received lapatinib in combination with capecitabine before or after metronomic treatment. The patients received metronomic treatment alone. They received oral cyclophosphamide 50 mg daily, andoral etoposide50 mg twice daily for 2 days per week (in the beginning, six patients received etoposide as 50 mg twice daily for 5 days, repeated every 21 days, but the etoposide dose was regulated as 50 mg twice daily for 2 days per week due to grade 3-4 emesis). The treatment protocol inspired by a similar scheme was used to treat prostate cancer and in this phase II study, the patients with hormone refractory prostate cancer were orally treated with cyclophosphamide (100 mg/day) and etoposide (50 mg/day) for 14 days every 28 days until there was evidence of disease progression. 
The progression-free survival (PFS) and overall survival (OS) were evaluated. Frequency analysis, mean, Kaplan-Meier, and Cox regression statistical methods were used for evaluating data analysis. P < 0.05 was considered to be statistically significant.
| > Results|| |
The properties of 77 patients are shown in [Table 1] and [Table 2]. The median follow-up time was 18.7 months. Mean age was51.1 ± 12.8 years. ER and PR positivity were 53.2 and 54.5%, respectively. The ratio of patients with Cerb B2 positive was 45.5%. The ratio ofluminal A, luminal B, HER2-like, and triple negative/unclassified patients were 22.9, 22.1, 24.7, and 23.4%, respectively. Most of the patients had grade 2 BC (33.8%). Of the patients, 45.5% had ECOG PS 2. There was a comorbid disease in 28.6% of the patients. Diabetes mellitus and hypertension were mostly seen comorbid diseases (14.3%). Most of the patients (31.2%) received metronomic treatment as the third line. There was visceral metastasis (except for bone metastasis) in 84.4% patients. The median number of metastatic organ was 2.
The median PFS was 7.03 (5.06-8.99) months. After univariate Cox regression analysis, only luminal type had a significantly impact on PFS (P = 0.044). But we did not find any significant difference among luminal types in log-rank analysis (P = 0.057). The median OS was 32.5 (22.5-42.4) months. After univariate Cox regression analysis; ER (P = 0.081), PR (P = 0.091), ECOG PS (P = 0.129), and line of metronomic therapy (P < 0.001) were included for multivariate analysis. But none of them was an independently prognostic factor. The OS and PFS curves are shown in [Figure 1] and [Figure 2].
The toxicities related to metronomic chemotherapy were low. While grade 3-4 anemia was not obtained, grade 3 and 4 leukopenia were 10.4 and 3.9%, respectively. Grade 3 and 4 thrombocytopenia were 2.6 and 0%, respectively. Grade 2, 3, and 4 emesis were 10.4, 2.6, and 0%, respectively and emesis was mostly related to etoposide.
| > Discussion|| |
We evaluated the effectiveness of metronomic treatment protocol for in mostly heavily treatedrefractory breast carcinoma patients. We found that the median PFS and OS were 7.03 (5.06-8.99) and 32.5 (22.5-42.4) months, respectively.
Our study results can be considered as very good even after the first-line chemotherapy in patients with MBC. There are several phase III studies on the second-line or further treatments in MBC. ,,,,,,,, In various phase III studies, the median OSwas found between 13.8 and 23 months.
Metronomic treatment is the frequent application of low doses of chemotherapeutic agents. The dosage is lesser thanthe maximum tolerated doseand generally cumulative doses do not reachto standard doses.  Since the target ofthis treatment is the vascular structure, the goal of metronomic treatment is the antiangiogenic effect ratherthan the cytotoxic effect.  Depending on the dosage, hematogenous or nonhematogenous toxicities are less observed in the metronomic treatment. ,
There are several studies in metronomic treatment area in patients with BC. ,,,,, Looking at metronomic treatments, in the study by Orlando et al., using metronomic cyclophosphamide + methotrexate regimen, the rate of PFS was 15.7% for the 1 st year.  Another study was conducted by Burstein et al., with 55 patients, two arms were created, metronomic cyclophosphamide + methotrexatewas givento first arm, in addition to this treatment bevacizumab was added to the second arm. PFS was 2 months for the first arm and5.5 months for the second arm.  The combination therapy of cyclophosphamide + methotrexate with herceptin, provided a median PFS of 6 months.  In a study including combination of cyclophosphamide + methotrexate + bevacizumab, the median PFSwas determined as 7.5 months.  In this study, trastuzumab was added toevery CerbB2 (+) tumor. The number ofpatients with Cerb B2 (+) tumor who achieved 6-month PFS was doubled.  With metronomic combination of cyclophosphamide + capecitabine + bevacizumab, 42-week PFS was obtained. 
OS is affected by several factors. Mainly the age, hormonal status, grade, and comorbidity affect the OS. Also early treatment line and high PS prolong OS. In a study, it was mentioned that the only factor which influences the duration of tumor disease control (TDC) for each line of treatment was duration of TDC obserded in the previous line.  In addition, response to previous chemotherapy, no liver metastasis, recurrence free survival of 2 years, polychemotherapy in second-line, and performance score were found as prognostic factors in third-line. ,, It was previously reported that each chemotherapy line could contribute to a longer OSin patients with MBC who received multiple lines of treatment.  Our study results were very good in patients with MBC according to literature review. One of the aims of treatment is stabilization of metastatic diseases. Metronomic treatment may succeed to stabilize metastatic disease between cytotoxic regimen in patients with poorer PS and it may achieve to receive the further line treatment regimens in patients with MBC. Because PS of patients is decreasing with sequential andeach combined cytotoxic chemotherapy regimens.
In our study, an important effectiveness was seen by metronomic treatment regimen despite in patients with heavily treated and poor PS. Additionally, metronomic treatment regimen had low toxicity.
The present study was not a randomized and prospective trial and this is the major limitation of this study. Also, the different treatment lines and heterogeneity were one of the limitations.
Metronomic treatment regimen with cyclophosphamide + etoposide can be used in early or late steps as independently from prognostic factors in patients with MBC. This regimen may bea preferable and suitable treatment option in all MBC patients even if they refuse any cytotoxic chemotherapy regimen. Owing to the relatively higher activity and lower costs, this treatment regimen should be investigated in further studies for the treatment of BC.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]