A Systemic Analysis on Pemetrexed in Treating Patients with Breast Cancer

The incidence and mortality rate of breast cancer increased significantly in China over the last several decades (Yu et al., 2007). It was estimated that 121,269 new cases of breast cancer were diagnosed in China in 2000 and 168,013 in 2005 (Yang et al., 2005). Despite advances in prevention, risk factor reduction, early diagnosis and treatment, breast cancer remains a main public health concern, with more than a million new cases diagnosed annually, resulting in >400,000 deaths worldwide (Ferlay et al., 2002; Huang et al., 2004). Now, combined chemotherapy is mostly prescribed in neoadjuvant, adjuvant and in metastatic settings of breast cancer. Although CMF regimen represented the gold standard in the 1970s (Bonadonna et al., 1976), anthracycline-based regimens are the mainstay of adjuvant chemotherapy for early breast cancer since the 1990s (EBCTCG, 2005). When singleagent chemotherapy was used in hormone-resistant metastatic setting, agents considered to be active include cyclophosphamide, phenylalanine mustard, vincristine, vinblastine, methotrexate and 5-fluorouracil. Response rates are ranged from 0-38% (Akram et al., 2012). Pemetrexed has been tested in five phase II trials in locally


Introduction
The incidence and mortality rate of breast cancer increased significantly in China over the last several decades (Yu et al., 2007). It was estimated that 121,269 new cases of breast cancer were diagnosed in China in 2000and 168,013 in 2005(Yang et al., 2005. Despite advances in prevention, risk factor reduction, early diagnosis and treatment, breast cancer remains a main public health concern, with more than a million new cases diagnosed annually, resulting in >400,000 deaths worldwide (Ferlay et al., 2002;Huang et al., 2004). Now, combined chemotherapy is mostly prescribed in neoadjuvant, adjuvant and in metastatic settings of breast cancer. Although CMF regimen represented

A Systemic Analysis on Pemetrexed in Treating Patients with Breast Cancer
Fang Wan, Xin Chen, Li-Fan Dong, Yue-Hong Cheng, Jing-Pei Long* advanced or metastatic breast cancer, and has shown an activity of around 30% in advanced breast cancer patients with minimal or no prior chemotherapy. In patients who received prior anthracyclines, response rates of 21% were reported. Responses have also been observed in patients who had been pretreated with anthracyclines, taxanes, and capecitabine. Some studies have suggested that a correlation exists between thymidylate synthase tumor expression with pemetrexed antitumor activity; this attractive hypothesis should be confirmed in further studies (Martin, 2006).
According to this background, we hypothesize that pemetrexed originated regimen could be established as an optimal schedule for patients with advanced breast cancer.

Search strategy
We searched PUBMED, by using the following search term: (breast cancer) and (pemetrexed). All clinical studies evaluating the impact of pemetrexed on the response or survival and side effects for breast cancer published in English prior to May 1st of 2014 were identified. If samples of two studies overlap, only the latest one was included. Additional articles were obtained from references within the articles identified by the electronic search. We did not consider meeting abstracts or unpublished reports.

Inclusion and exclusion criteria
We reviewed abstracts of all citations and retrieved studies. The following criteria were used to include published studies: (1) clinical studies, conbined with gemcitabine, epirubicine or a platinum; (2) The study was performed in accordance with the Helsinki Declaration (1964, amended in 1975 and 1983) of the World Medical Association. Eligibility criteria included histologically or cytologically verified metastatic and/or locally advanced breast cancer, the presence of at least one bidimensionally measurable lesion, a performance status (WHO) 2, age 18 years. Studies were excluded if one of the following existed: (1) duplicate data; (2) no sufficient data were reported.

Data collection and analysis
Selection of trials and data extraction: The titles and abstracts of publications identified according to the above search strategy were assessed independently for inclusion by two authors, the full text was selected for further assessment if the abstract suggests relevance. Disagreement was resolved by discussion. Data was extracted by independent authors. The following recorded data were extracted: author, publication data, and country of the first or corresponding author, the number of patients.

Results
There were 114 papers relevant to the search words by the end of April, 2014. Via steps of screening the title and reading the abstract, 10 studies were identified (Amadori D 2013; Dittrich C 2012; Robert NJ 2011;Martin M.2009
Pemetrexed has been tested by previous phase II trials in locally advanced or metastatic breast cancer patients and shown an activity of around 30% in advanced breast cancer patients with minimal or no prior chemotherapy. In patients who received prior anthracyclines, response rates of 21% were reported. Responses were also observed in patients who had been pretreated with anthracyclines, taxanes, and capecitabine. Some studies suggested that a correlation could exist between thymidylate synthase tumor expression with pemetrexed antitumor activityis (Martin, 2006); and this hypothesis is supported by this current study.
T h e m a i n t o x i c i t i e s o f p e m e t r e x e d a r e myelosuppression, skin rash, and mucositis. Addition of folic acid and vitamin B12 significantly reduced the toxicity of pemetrexed, especially hematologic toxicity and gastrointestinal toxicity. Pemetrexed is the expected agent for use in high risk patients, especially elderly or poor performance status patients (Sudoh et al., 2008). Hematological toxicity was considerable, and thrombocytopenia was the most prominent toxicity. Nadirs of blood counts were observed between days 14 and 16 after lobaplatin administration. The majority of patients experienced grade 4 thrombocytopenia (Jan Welink et al., 1999). The count of leukocyte and platelet returned to normal after the treatment of colony-stimulating factor, interleukin 11 and recombinant human thrombopoietin.
From previous study, digestive tract reaction ranged from 1 to 2 could be alleviated by symptomatic treatment. By hepatoprotective drugs, transaminase could return to normal. For patients had oral mucositis, with the supplements of vitamins and oral care, the oral mucosal healing with no fungal infection. 1 patient had rash with pruritus, rash subsided gradually after symptomatic treatment of the antipruritic and anti allergic.
In conclusion, this systemic analysis suggests that pemetrexed based first line regimens are associated with reasonable response rate and accepted toxicities, however with low response rate for treating patients with metastatic breast cancer when it is used in the second line.. Future studies with a randomized controlled group are needed to further evaluate the efficacy and tolerability of pemetrexed in this setting.