Clinical Study on Safety and Efficacy of Qinin ® ( Cantharidin Sodium ) Injection Combined with Chemotherapy in Treating Patients with Gastric Cancer

Based on the GLOBOCAN 2008 estimates, stomach cancer is the third most common cause of death from cancer in males and the forth in females,with 989,600 new cancer cases and 738,000 deaths in this year (Jemal et al., 2011). The highest incidence rates are in Eastern Asia including China. Therefore, now, Stomach cancer has become the common and frequently-occurring disease which seriously hazard to human health (Ferlay et al., 2010). Chemotherapy is one of important treatment of gastric cancer and is the only treatment option available in advanced gastric cancer. Chemotherapy may relieve gastric cancer-related symptoms, improve quality of life and prolong survival in some patients with gastric cancer. how to increase efficacy and decrease toxicities of chemotherapy remains a focus in this area. Qinin® (Cantharidin sodium) injection, which is Semisynthetic derivative of cantharidin, has been developed and manufactured by Guizhou magic Pharmaceutical Co., Ltd in China, Cantharidinate sodium Injection is one of Chinese herbal preparation with anti-cancer activity, which mainly used for the treatment of solid tumor including gastric cancer (Cui et al., 2008; Guo et al., 2009; Liang


Introduction
Based on the GLOBOCAN 2008 estimates, stomach cancer is the third most common cause of death from cancer in males and the forth in females,with 989,600 new cancer cases and 738,000 deaths in this year (Jemal et al., 2011).The highest incidence rates are in Eastern Asia including China.Therefore, now, Stomach cancer has become the common and frequently-occurring disease which seriously hazard to human health (Ferlay et al., 2010).Chemotherapy is one of important treatment of gastric cancer and is the only treatment option available in advanced gastric cancer.Chemotherapy may relieve gastric cancer-related symptoms, improve quality of life and prolong survival in some patients with gastric cancer.how to increase efficacy and decrease toxicities of chemotherapy remains a focus in this area.
Qinin ® (Cantharidin sodium) injection, which is Semisynthetic derivative of cantharidin, has been developed and manufactured by Guizhou magic Pharmaceutical Co., Ltd in China, Cantharidinate sodium Injection is one of Chinese herbal preparation with anti-cancer activity, which mainly used for the treatment of solid tumor including gastric cancer (Cui et al., 2008;Guo et al., 2009

Patient eligibility
All the Patients were diagnosed pathologically as stomach cancer, with karnofsky performance status≥60, age between 18 to 75 years, the survival time≥3 months, adequate bone marrow (white blood cell count > 3.0×10 9 and platelet count >80×10 9 ), liver function (bilirubin and transaminases < 2 times the upper limit normal), no evidence of heart and kidney disease, signed an informed consent before chemotherapy.
Patients excluded from the study if they failed to complete more than two cycles of chemotherapy, candidate with any serious medical or psychiatric condition, other malignancies, or pregnant and lactating women.

Treatment
In experimental group, Qinin ® (Cantharidin sodium) injection was combined with chemotherapy, which

Efficacy Observation
Treatment efficacy was evaluated according to RECIST criteria (Sohaib, A. 2012) after more than two cycles of chemotherapy.In details Complete Remission (CR), partial response (PR), stable disease (SD), and progressive disease (PD) was seperately defined.General performance was evaluated in accordance with the Karnofsky Scale (Yates et al.1980).Quality of life was designated increasing if the KPS score increased by 10 after treatment, decreasing if the score decreased by 10 and otherwise stable.

Toxicity Assessment
All Patients were assessed and graded for toxicities according to WHO criteria (De Angelis, V. 2004).

Results
Efficacy 70 patients fulfilled eligibility had completed at least 2 cycles of treatment.No CR was observed in both two groups.The response rate of experimental group (CR+PR)/(CR+PR+SD+PD) was 34%,while that in control group was 25%.The differences were not statistically significant (p>0.05).The disease control rates of two groups (CR+PR+SD)/(CR+PR+SD+PD) were 80% (experimental group), 57% (control group) respectively, with statistical significance (p<0.05)(Table 1).

Quality of life before and after treatment
KPS score of experimental group increased in 18 cases (51%), 12 cases stable and 5 cases decreased, while that of control group increased in 10 cases (28%), 17 cases stable and 8 cases decreased.The difference between two groups was statistically significant (p<0.05)(Table2).

Toxicity
All patients underwent toxicities assessment.Treatment related side effects were reversible, and no termination of chemotherapy or death caused occurred.In table 3, the main adverse effects were myelosuppression and gastrointestinal reactions.In experimental group, leukopenia rate was 48%, 8% of them with grade III-IV; 17% patients showed grade I-II thrombocytopenia and 2% with grade III thrombocytopenia; grade I-II nausea and vomiting was 48%, and none of grade III-IV.In control group, leukopenia rate was 74%, 25% of them with grade III-IV; 31% patients with grade I-II thrombocytopenia and 8% with grade III thrombocytopenia; grade I-II nausea and vomiting was 68%, and 5% with grade III-IV.Liver dysfunction of the experimental group was significantly lower than the control group.Both of two groups were not observed with impaired renal function

Discussion
Chemotherapy for gastric cancer still is not normalized and standardized (Okines et al., 2010).Chemotherapy is reported with associated ability to improve the clinical symptoms, reduce the rate of recurrence and metastasis, and prolongs survival.But, chemotherapy is reported often brings about serious side effects.Therefore, how to reduce side effects of chemotherapy, in the mean time increase efficacy and improve quality of life have aroused more and more attention.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).
Qinin ® (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 can promote hematopoietic stem cells to accomplish differentiation into myelomonocytic in order to increase the leukocyte (Liu et al., 2009).Our study shows that the differences of short-term efficacy in two groups were not statistically significant, but the clinical benefit rate, and KS score improvement of experimental group were significantly higher than that of control group.Thus, Sodium Cantharidinate Injection combined with Chemotherapy could reduce side effects causing by chemotherapy, and improve quality of life.However, our results deserves to be further investigated by randomized controlled clinical trails.