Clinical Comparison between Paclitaxel Liposome ( Lipusu ® ) and Paclitaxel for Treatment of Patients with Metastatic Gastric Cancer

According to a latest estimation, 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 2010 (Jemal et al., 2011). The highest incidence rates are in Eastern Asia including China. Therefore, stomach cancer is a common disease which seriously hazard to human health (Ferlay et al., 2010). In the treatment of unresectable or metastatic gastric cancer, chemotherapy leads to a significant survival difference compared to best supportive care, and could relieve gastric cancer-related symptoms, and improve quality of life (Kucukzeybek et al., 2012). However, no standard regimen of chemotherapy has been established for patients with advanced gastric cancer. Cytotoxic agents that are considered effective in this setting include docetaxel, paclitaxel, oxaliplatin, irinotecan, 5-Fu, etc. (Kucukzeybek et al., 2012). How to increase efficacy and decrease toxicities of chemotherapy remains a focus in this area. Paclitaxel is an alkaloid, which stabilizes microtubules and inhibits endothelial cell proliferation, motility, and tube formation (Belotti et al., 1996). It is widely used


Introduction
According to a latest estimation, 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 2010 (Jemal et al., 2011).The highest incidence rates are in Eastern Asia including China.Therefore, stomach cancer is a common disease which seriously hazard to human health (Ferlay et al., 2010).In the treatment of unresectable or metastatic gastric cancer, chemotherapy leads to a significant survival difference compared to best supportive care, and could relieve gastric cancer-related symptoms, and improve quality of life (Kucukzeybek et al., 2012).However, no standard regimen of chemotherapy has been established for patients with advanced gastric cancer.Cytotoxic agents that are considered effective in this setting include docetaxel, paclitaxel, oxaliplatin, irinotecan, 5-Fu, etc. (Kucukzeybek et al., 2012).How to increase efficacy and decrease toxicities of chemotherapy remains a focus in this area.
Paclitaxel is an alkaloid, which stabilizes microtubules and inhibits endothelial cell proliferation, motility, and tube formation (Belotti et al., 1996).It is widely used

Clinical Comparison between Paclitaxel Liposome (Lipusu ® ) and Paclitaxel for Treatment of Patients with Metastatic Gastric Cancer
Xu Xu1,2 , Lin Wang 1,2 , Huan-Qin Xu 2 , Xin-En Huang 1,2 *,Ya-Dong Qian 2 *, Jin Xiang 3 in treating a variety of carcinomas including refractory ovarian cancer, gastric cancer and non-small-cell lung cancer (NSCLC) (Drummond et al., 1999), but one problem associated with the administration of paclitaxel is its low solubility in most pharmaceutically-acceptable solvents.The paclitaxel formulation used clinically contains polyethoxylated castor oil (Cremophor EL) and dehydrated ethanol in a 1:1 (vol:vol) ratio.Cremophor EL is reported to cause toxic effects, e.g., life-threatening anaphylaxis (Szebeni et al., 1998;Van Zuylen et al., 2001).The administration of antihistamines and glucocorticoids is necessary to manage these adverse effects (Bookman et al., 1997), but these co-administered drugs have raised the possibility of additional pharmacokinetic and pharmacodynamic interactions with paclitaxel.This problem is sought to be alleviated either by synthesizing more soluble derivatives or by the administration of paclitaxel bound to more soluble formulation vehicles (Kobayashi et al., 2006).A variety of drug-delivery approaches were investigated to eliminate vehicle toxicity from paclitaxel formulations (Sharma et al., 1996;Scialli et al., 1997).Sharma and Straubinger developed a liposomebased paclitaxel formulation (Sharma et al., 1994).It provides a formulation alternative for the administration  of paclitaxel and can confer beneficial effects on the pharmacology and toxicology of the drug.First data from a clinical phase I study using paclitaxel liposome are encouraging with respect to reducing toxic side effects (Treat et al., 2001).Lipusu ® (Sike Pharmaceutical Co. Ltd., Nanjing, Jiangsu, P.R. China) is approved by the State Food and Drug Administration of China.It is the first paclitaxel liposome injection which is clinical used in China in 2006.It retained the growth-inhibitory activity of the free drug and reduced the toxicities (Chen et al., 2003;Yang et al., 2006;Kong et al., 2007).Yang et al. (2006) reported the cytotoxic effects and antitumor activities of Lipusu and concluded that Lipusu possesses the same antitumor activities in vitro and in vivo but its toxicity is lower than that of paclitaxel injection under the same dosage.Kong et al. (2007) suggested that the response rate (RR) is 39.1% in the treatment of NSCLC patients with Lipusu and cisplatin.Chen et al. (2003) compared Lipusu with conventional paclitaxel on treatments of breast cancer and NSCLC and demonstrated that both of them have similar efficacy but the former reduces the incidence of serious hypersensitive reactions significantly more than the latter.However, it is not clear whether the efficacy of paclitaxel liposome is superior to conventional paclitaxel.We hypothesize that paclitaxel liposome could be superior to conventional paclitaxel in treating patients with advanced gastric cancer.

Patient
All the patients were required to be pathologically diagnosed with gastric cancer, with Karnofsky performance status ≥ 60, aged between 18 and 75 years, predicted survival time ≥ 3 months.With adequate bone marrow (white blood cell count > 4.0×10 9 and platelet count > 100×10 9 ), and liver function (bilirubin and transaminases < 2 times the upper limit normal), no heart and kidney disease, and signed an informed consent before chemotherapy.Patients excluded from this study if they failed to complete two cycles of chemotherapy, with any serious medical or psychiatric condition, or other malignancies.Pregnant or lactating women are excluded from the study.

Treatment method
Eligible patients were divided into paclitaxel liposome group (Group A) or paclitaxel group (Group B).

Response Evaluation
Response evaluation with RECIST tumor chemotherapy criterion requirements was divided into complete remission (CR), partial response (PR), stability (SD), and disease progression (PD).It is defined that response rate (RR) = (CR + PR)/total, and clinical control (DCR) = (CR + PR + SD) /total (Van Zuylen et al., 2001).According to the WHO acute and subacute toxicity of anticancer drugs to identify performance and classification standard, adverse reaction is divided into 0 -Ⅳ degrees.

Results
Sixty-two patients meet the study criteria and entered two study groups.General characteristics of patients are shown in Table 1.

Efficacy Observation
There are 32 patients in group A and 30 in group B. However each group has 2 patients who cannot complete at least 2 cycles of chemotherapy and dropped out.Other cases are eligible for evaluating RR, which was conducted Table 1 2.

Toxicity Assessment
In 2 groups, main adverse reactions are hematologic and gastrointestinal, and nervous system toxicities (P > 0.05).The difference of incidence in alopecia, diarrhea and constipation between two groups is not statistically significant (P > 0.05), but the incidence of nausea and vomiting, rash, shortness of breath, muscle pain and peripheral neuritis in group A is lower than those in group B, with statistically significant difference (P < 0.05) (Table 3).

Discussion
Paclitaxel is a broad-spectrum plant kind of anticancer drugs.Through combination with cellular microtubules beta, it is reported to promote the microtubule polymerization, suppress the depolymerization and block mitosis, and further to inhibit tumor growth (Szebeni et al., 1998).In recent years, clinical studies suggested that paclitaxel has significant curative effect for a variety of solid tumors.But ordinary paclitaxel is almost insoluble in water, paclitaxel formulation used clinically contains Cremophor EL.Cremophor EL is associated with toxic effects, e.g., life-threatening anaphylaxis (Szebeni et al., 1998;Van Zuylen et al., 2001).Premedication with antihistamines and glucocorticoids is necessary (Bookman et al., 1997).Study in recent years suggested that, liposomes as a drug carrier could improve the histocompatibility and cellular affinity, improve the stability of paclitaxel, and reduce toxicity (Kobayashi et al., 2006).
This study suggested that the RR of paclitaxel liposome combined with tegafur and oxaliplatin be slightly superior to conventional paclitaxel in treating patients with advanced gastric cancer.The incidence of allergy, nausea and vomiting, rash, muscle pain in paclitaxel liposome group was lower than that in conventional paclitaxel group.In this study, RR of paclitaxel liposome and conventional paclitaxel was 47% and 46%.No statistically significant difference was detected between two groups, and this result is consistent with previous studies (Sharma et al., 1994;Sharma et al., 1996;Scialli et al., 1997).Before paclitaxel, patients should take premedication.But patients do not need strong premedication before paclitaxel liposome.Thus the latter is proper for patients who can not tolerate heavy dose of hormone.
In conclusion, paclitaxel liposome is as effective as conventional paclitaxel when combined with tegafur and oxaliplation in treating patients with advanced gastric cancer, and adverse reactions of paclitaxel liposome are less common.

Table 2 . The Response Rate of Patients with Advanced Gastric Cancer in Two Groups
CR, complete remission; PR, partial response; SD, stability; PD, disease progression; RR, response rate; DCR, clinical control