Phase II Study on Safety and Efficacy of Yadanzi ® ( Javanica oil emulsion injection ) Combined with Chemotherapy for Patients with Gastric Cancer

Gastric cancer is one of the most common malignant tumors in china. It continues to be a fatal disease with majority of cases presenting with advanced disease (Blum et al., 2013). Chemotherapy is a main treatment option for patients with advanced gastric cancer. However, chemotherapy is reported to be associated with a series of adverse reaction, eg, bone marrow suppression, gastrointestinal toxicity, immunosuppression, etc (Yamamoto and Iwase, 2012). Traditional Chinese Medicine (TCM) is widely used in treating patients with gastric cancer in China (Liu et al., 2011). On this background, it is possible to develop a chemotherapy regimen containing TCM to enhance response rate, reduce toxicity and improve quality of life for patients in this setting (Man et al., 2012). Yadanzi® (Javanica oil emulsionsemulsion) is a product with Brucea Jen petroleum ether extracts as raw materials, and purified soybean lecithin as emulsifier. The main active ingredient is not well clarified (Liu et al., 2012). Javanica oil emulsion is reported to be active in treating patients with lung cancer, brain metastases from lung and gastrointestinal cancer (Wang et al., 2012). Possible mechanism includes inhibition of topoisomerase


Introduction
Gastric cancer is one of the most common malignant tumors in china.It continues to be a fatal disease with majority of cases presenting with advanced disease (Blum et al., 2013).Chemotherapy is a main treatment option for patients with advanced gastric cancer.However, chemotherapy is reported to be associated with a series of adverse reaction, eg, bone marrow suppression, gastrointestinal toxicity, immunosuppression, etc (Yamamoto and Iwase, 2012).Traditional Chinese Medicine (TCM) is widely used in treating patients with gastric cancer in China (Liu et al., 2011).On this background, it is possible to develop a chemotherapy regimen containing TCM to enhance response rate, reduce toxicity and improve quality of life for patients in this setting (Man et al., 2012).
Yadanzi ® (Javanica oil emulsionsemulsion) is a product with Brucea Jen petroleum ether extracts as raw materials, and purified soybean lecithin as emulsifier.The main active ingredient is not well clarified (Liu et al., 2012).Javanica oil emulsion is reported to be active in treating patients with lung cancer, brain metastases from lung and gastrointestinal cancer (Wang et al., 2012).Possible mechanism includes inhibition of topoisomerase

Phase II Study on Safety and Efficacy of Yadanzi ® (Javanica oil emulsion injection) Combined with Chemotherapy for Patients with Gastric Cancer
Jin Liu1 , Xin-En Huang 1 *, Guang-Yu Tian2 , Jie Cao 1 , Yan-Yan Lu 1 , Xue-Yan Wu 1 , Jin Xiang 3 II, blockage of cell cycle in S phase and a direct damage on the structure of plasma membrane.Our hypothesis is that the addition of Yadanzi ® to chemotherapy could increase the response rate of chemotherapy and quality of life of patients with advanced gastric cancer.

Patients
Patients were required to be pathologically/ cytologically diagnosed with gastric cancer in Jiangsu Cancer Hospital & Research Institute from January 2011 to December 2012; to sign an informed consent before treatment; to expose to long term chemotherapy or supportive care; to have a score of karnofsky performance status (KPS) ≥ 70; to be 25 to 75 years of age.Other eligibility criteria included: adequate hematological (white blood cell count > 3.0× 10 9 and platelet count > 150×10 9 ), liver (bilirubin and transaminases < 1.5 times the upper normal limit) and renal function (creatinine leval < 1.5 times the upper normal limit); patients were excluded from this study if they failed to complete two cycles of chemotherapy, or with any serious medical or psychiatric condition, or other malignancies.Pregnant or lactating women are also excluded from this study.

Methods
Chemotheraphy agents including oxaliplatin, irinotecan, paclitaxel, docetaxel, fluorouracil, tegafur, etc.And combination is as following: DOC regimen, which consisted of docetaxel, oxaliplatin and capecitabine; Xelodal-contained chemotherapy regimens, which consisted of xelodal and oxaliplatin; tegafur-based regimen, which consisted of tegafur, taxol and leucovorin; and other regimens.Detailed information of these chemotherapy was reported elsewhere (Li et al., 2011;Xu et al., 2011).Chemotherapy for all patients was applied with javanica oil emulsion injection (Yadanzi ® , made by ZheJiang Jiuxu Pharmaceutical Co., Ltd.).Yadanzi ® 30 ml, dissolved in 250 ml normal saline, was intravenous infused during chemotherapy, once daily and continued for 2 cycles.Routine blood test, blood biochemistry and tumor markers were reviewed prior, during and after chemotherapy.CT scan was reviewed after two cycles of treatment to evaluate efficacy.

Efficacy evaluation
Before the chemotherapy, all patients received physical examination, routine blood test and blood biochemical examination.Treatment efficacy was evaluated according to RECIST criteria (Response Evaluation Criteria In Solid Tumor) (Sohaib, 2012) after more than two cycles of chemotherapy.Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) was separately defined.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.We have enough experience in conducting medical researches, and have published some results elsewhere (Huang et al., 2004;Zhou et al., 2009;Jiang et al., 2010;Yan et al., 2010;Gao et al., 2011;Huang et al., 2011;Li et al., 2011;Li et al., 2011;Li et al., 2011;Xu et al., 2011;Xu et al., 2011;Xu et al., 2011;Yan et al., 2011;Zhang et al., 2011;Gong et al., 2012;Li et al., 2012;Yu et al., 2012).

Toxicity Assessment and Safety:
All Patients were assessed and graded for toxicities according to WHO criteria (De Angelis, 2004).During the Yadanzi ® (Javanica oil emulsion) Injection and chemotherapy, all adverse reactions were documented.

Results
From January 2011 to December 2012, we recruited 75 patients with gastric cancer satisfied all study criteria.General characteristic of patients is listed in Table 1.Among them, 47 were male and 28 female, average age was 61 years.All patients had completed medical records, including results of CT scan, endoscopy or pathology biopsy.Of all 75 patients, 39 diagnosed with tubular adenocarcinoma, 22 with poor differentiated adenocarcinoma, 4 mucinous adenocarcinoma, 9 signet ring cell carcinoma and 1 squamous cell carcinoma.After 2 cycles of Yadanzi ® and chemotherapy, bone marrow suppression was recorded for 44 patients: I° in 24, II° in 8, III° in 6 and IV° in 6 patients.Forty patients reported of poor appetite and nausea, 5 watery diarrhea, 4 coprostasis, and 8 vomiting were recorded.One patient reported red skin rash with fever, and 17 cases with hepatic function enzymes higher than normal.One patient was diagnosed with allergy.Main side effects were listed in Table 3.

Discussion
The principle of advanced cancer treatment is to prolong survival time of patients and improve the quality of life.Combination chemotherapy can significantly prolong the survival of patients with advanced gastric cancer, and improve the quality of life.However, in the treatment of advanced gastric cancer, chemotherapy will produce toxicity such as gastrointestinal reactions and bone marrow depression, seriously affect the quality of life of patients, many patients had to discontinued therapy due to inability to tolerate chemotherapy reactions.Javanica oil emulsion is product which use Brucea Jen petroleum ether extracts as raw materials, and purified soybean lecithin as emulsifier (Liu et al., 2012).The main active ingredient are oleic acid and linoleic acid, and the antitumor activity of both have already been confirmed.Javanica oil emulsion is mainly used in lung cancer, brain metastases from lung and gastrointestinal cancer treatment in clinical, and have achieved satisfactory results.Its possible mechanism of action includes specifically inhibit the vitality of topoisomerase II, arrest cell cycle in S phase and the directly damage the structure of plasma membrane.It can also kill tumor cells through regulating the body immune.Javanica oil emulsion can protect the bone marrow hematopoietic stem cells, and promote its proliferation.It can also enhance immunity, improve physical fitness and reduce chemotherapy side effects.The patient's quality of life has been improved.It subjectively enhance their confidence of overcoming the disease, and objectively create the conditions for better treatment.Our results show as follows: after 2 cycle, short-term effect is not obvious, probably due to the combination therapy cycle is short (2 cycles), older patients response slower to treatment (median age ≥ 60 years) and traditional Chinese medicine effects slowly.The significantly effective rate of improvement in quality of life was 12%.In conclusion, in this study, the effective rate of (Yadanzi ® ) combined with chemotherapy in treating patients with advanced gastric cancer was 85.3%.The KPS score improvement was 12%.Thus, Javanica oil emulsion injection combined with chemotherapy could reduce side effects caused by chemotherapy, and improve quality of life of patients.However, our results deserve to be further investigated by randomized controlled clinical trails.