Cantharidin Combined with Chemotherapy for Chinese Patients with Metastatic Colorectal Cancer

Colorectal cancer is the third most commonly cancer in the world, with over 1.2 million new cancer cases and 608, 700 deaths estimated to occurred in 2008 (Jemal et al., 2011). Approximately half of all patients will develop metastatic cancer (Parkin et al., 2005). On many occasions, disease is too advanced and only palliative therapy could be considered. Doublets such as irinotecan plus infusional 5-FU/LV (FOLFIRI) or oxaliplatin plus infusional 5-FU/ LV (FOLFOX) prolonged median survival to more than 20 months (De Gramont et al., 2000; Douillard et al., 2000; Goldberg et al., 2004; Kohne et al., 2005). Nevertheless, many patients still failed to treatment due to tumor recurrence and metastasis, and 5-year survival rate still less than 10%. Cantharidin is a sesquiterpene derivatives extracted from the Mylabris body (Verma et al., 2012). Cantharidin sodium is a semi-synthetic derivative of cantharidin. By reducing the cancer cells to the uptake of amino acids, inhibit protein synthesis, stimulating macrophages, lymphocytes, polymorphonuclear cells produce interleukin, and finally to improve immunity and enhance anticancer efficacy (Bajsa et al., 2011; Hsieh et al., 2011). Cantharidin sodium injection has been developed and manufactured by Guizhou magic Pharmaceutical Co., Ltd in China. Studies have shown that the main active ingredient is cantharidin, which has characteristics of anti-cancer without causing myelosuppression, and it


Introduction
Colorectal cancer is the third most commonly cancer in the world, with over 1.2 million new cancer cases and 608, 700 deaths estimated to occurred in 2008 (Jemal et al., 2011). Approximately half of all patients will develop metastatic cancer (Parkin et al., 2005). On many occasions, disease is too advanced and only palliative therapy could be considered. Doublets such as irinotecan plus infusional 5-FU/LV (FOLFIRI) or oxaliplatin plus infusional 5-FU/ LV (FOLFOX) prolonged median survival to more than 20 months (De Gramont et al., 2000;Goldberg et al., 2004;Kohne et al., 2005). Nevertheless, many patients still failed to treatment due to tumor recurrence and metastasis, and 5-year survival rate still less than 10%.
Cantharidin is a sesquiterpene derivatives extracted from the Mylabris body (Verma et al., 2012). Cantharidin sodium is a semi-synthetic derivative of cantharidin. By reducing the cancer cells to the uptake of amino acids, inhibit protein synthesis, stimulating macrophages, lymphocytes, polymorphonuclear cells produce interleukin, and finally to improve immunity and enhance anticancer efficacy (Bajsa et al., 2011;Hsieh et al., 2011).
Cantharidin sodium injection has been developed and manufactured by Guizhou magic Pharmaceutical Co., Ltd in China. Studies have shown that the main active ingredient is cantharidin, which has characteristics of anti-cancer without causing myelosuppression, and it

Patients with Metastatic Colorectal Cancer
Li Han 1 , Yi-Jie Sun 1 , Yong-Fu Pan 1 , Hao Ding 2 , Xi Chen 3 , Xu Zhang 1 * can promote hematopoietic stem cells to accomplish differentiation into myelomonocytic in order to increase the leukocyte (Liu et al., 2009). So, our hypothesis is that the combination of Chemotherapy and cantharidinate sodium could be superior to chemotherapy alone regarding the efficacy and toxicity when treating patients with colorectal cancer.

Search strategy
We searched http: //www.cnki.net/ (a website for Chinese research), by using the following search term: (cantharidin) and (colorectal cancer). All clinical studies evaluating the impact of cantharidin on the response or survival and side effects for colorectal cancer published in Chinese prior to October 1 st 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: (a) clinical studies, with cantharidin; (b) 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 verified with colorectal 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: (a) duplicate data; (b) 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 122 papers relevant to the search words on 1 st of October, 2014. Via steps of screening the title and reading the abstract, 4 studies were identified (Chen and Wu 2004;Fan, 2009;Fan and Wang, 2013;He and Fan, 2014) when cantharidin was used in chemotherapy. All these studies had been carried out in China. The following outcomes were presented in all studies and extracted for combined analysis: response rate, including the rate of complete or partial response (CR or PR) and toxicities.
Characteristics of cantharidin as a component of chemotherapy, studies included in this study are presented as short-term outcomes: the response rate of He and Fan was 50%, of Fan and Wang was 56.5%, 39.5% for Chen and Wu, 42.9% for Fan. Totally, 155 patients were enrolled and 72 patients achieved CR or PR, the pooled response rate thus was 46.5% (72/155).
Observation on toxicities: Nausea and vomiting, were exceedingly common. Grade 3/4 toxicities included neutropenia, thrombocytopenia, and anemia (graded according to the World Health Organization grading system). No treatment related death occurred in cantharidin based treatment.

Discussion
Colorectal cancer, the second leading cause of cancer death in the USA, has increased in frequency in China in recent years. Based on a registry in Shanghai, a city with a population of 23 million, colorectal cancer has become the third most prevalent malignancy (Shanghai, 2007). Approximately 50-60% of patients diagnosed with colorectal cancer will develop metastases (Van Cutsem et al., 2006;Yoo et al., 2006), for whom systematic chemotherapy is the standard treatment. Irinotecan combined with continuous infusion of 5-fluorouracil (5-FU) and folinic acid (the FOLFIRI regimen) is an established option for first-and/or second-line treatment of metastatic colorectal cancer. Capecitabine, an oral fluoropyrimidine that mimics continuous 5-FU infusion by generating 5-FU preferentially in the tumor tissues (Miwa et al., 1998), has been shown to have comparable efficacy to 5-FU/folinic acid as first-line treatment of metastatic colorectal cancer, with an additional benefit of convenient administration without hospitalization (Va n Cutsem et al., 2000). The combination of irinotecan and capecitabine (XELIRI) has been assessed, but the associated gastrointestinal toxicity, especially the incidence of severe diarrhea, affected the feasibility of this regimen (Fuchs et al., 2007;Kohne et al., 2008). The incidence of grade 3/4 diarrhea was higher (17-36% vs 12-15%) with a 3-week XELIRI regimen than with the FOLFIRI regimen (Bajetta et al., 2004;Borner et al., 2005;Cartwright et al., 2005;Patt et al., 2007), and nonsuperior time to progression (TTP; 6-9 months vs 6.7-8.5 months) and overall survival (OS; 13-20 months vs 14.8-17.4 months) were observed (Andre et al., 1999;Saltz et al., 2000). Toxicity-induced dose reduction and treatment delay weakened the efficacy of the XELIRI regimen. To reduce the side effect of diarrhea, a 2-week XELIRI regimen was tried recently. The 2-week regimen (irinotecan on day 1, capecitabine on days 2-8 or days 1-5 and 8-12) exhibited promising activity (TTP,(8)(9)(10)OS,(15)(16)(17)(18)(19) with improved tolerability (grade 3/4 diarrhea, 8.1-15.0%) (Garcia-Alfonso et al., 2009), but an increased rate of severe diarrhea was noted in elderly patients, which resulted in dose reduction (Garcia-Alfonso et al., 2009). So, in this field no standard regimen is available. How to increase efficacy and decrease toxicities of chemotherapy remains a focus in this area. It is a distinguishing feature of traditional Chinese medicine to contribute in this area (Xu et al., 2012).
Cantharidin is a sesquiterpene derivatives extracted from the Mylabris body (Verma et al., 2012). Cantharidin sodium is a semi-synthetic derivative of cantharidin. By reducing the cancer cells to the uptake of amino acids, inhibit protein synthesis, stimulating macrophages, lymphocytes, polymorphonuclear cells produce interleukin, and finally to improve immunity and enhance anticancer efficacy (Bajsa et al., 2011;Hsieh et al., 2011).
Our current clinical study evaluated the efficacy and safety of cantharidin combined with chemotherapy on response and safety for Chinese patients with colorectal cancer Our results demonstrate that in all patients, pooled RR was 46.5% (72/155) in cantharidin combined regimens. Major adverse effects were neutropenia, leukopenia, fatigue, and anemia in cantharidin combined treatment; No treatment related death occurred in cantharidin combined regimens. In conclusion, this systemic analysis suggests that cantharidin combined regimens are associated with high response rate and accepted toxicities in treating Chinese patients with metastatic colorectal cancer, however, this result should be confirmed by randomized clinical trials.