Phase II Study on EANI Combined with Hydrochloride Palonosetron for Prevention of Chemotherapy-induced Nausea and Vomiting Following Highly Emetogenic Chemotherapy

At present, Chemotherapy is still an effective methods for treating patients with advanced and metastatic cancer. However, chemotherapy induced nausea and vomiting (CINV) is one of the most common gastrointestinal side effects of chemotherapy, especially for patients who were treated with highly emetogenic chemotherapy (Akyuz et al., 2013; Baykara et al., 2013; Fu et al., 2013; Huang et al., 2013; Keat et al., 2013; Keat et al., 2013; Kubota et al., 2013; Abe et al., 2014; Akkuzu et al., 2014; Li et al., 2014; Tas et al., 2014). It is estimated that more than 90% of patients will suffer nausea and vomiting, repeatedly, and persistent nausea, vomiting, or unbearable pain, will makes patients not tolerable to chemotherapy and fear, further even reject chemotherapy. Hydrochloride palonosetron is a new type of 5-HT3 receptor antagonist with high selectivity, good affinity, and curative effect due to long half-life (about 40 H), as well as good safety profile. But when hydrochloride palonosetron is used to prevent acute nausea/vomiting caused by chemotherapy, there are still some patients presenting with severe


Introduction
At present, Chemotherapy is still an effective methods for treating patients with advanced and metastatic cancer.However, chemotherapy -induced nausea and vomiting (CINV) is one of the most common gastrointestinal side effects of chemotherapy, especially for patients who were treated with highly emetogenic chemotherapy (Akyuz et al., 2013;Baykara et al., 2013;Fu et al., 2013;Huang et al., 2013;Keat et al., 2013;Keat et al., 2013;Kubota et al., 2013;Abe et al., 2014;Akkuzu et al., 2014;Li et al., 2014;Tas et al., 2014).It is estimated that more than 90% of patients will suffer nausea and vomiting, repeatedly, and persistent nausea, vomiting, or unbearable pain, will makes patients not tolerable to chemotherapy and fear, further even reject chemotherapy.Hydrochloride palonosetron is a new type of 5-HT3 receptor antagonist with high selectivity, good affinity, and curative effect due to long half-life (about 40 H), as well as good safety profile.But when hydrochloride palonosetron is used to prevent acute nausea/vomiting caused by chemotherapy, there are still some patients presenting with severe

Phase II Study on EANI Combined with Hydrochloride
Palonosetron for Prevention of Chemotherapy-induced Nausea and Vomiting Following Highly Emetogenic Chemotherapy Yang Xiao 1& , Jun Liu 1& , Yang-Chen Liu1,2 , Xin-En Huang 2 *, Jian-Xong Guo 1,2 , Wei Wei 1 gastrointestinal reaction, and even led to suspension of chemotherapy.Electronic anti-nausea instrument (EANI) is a new therapy apparatus that effects through a particular low frequency electric stimulus percutaneously, reduces 5-HT3 release in gastrointestine and brain, so as to prevent the occurrence of nausea and vomiting.From June 2013 to March 2014, we conducted clinical trial using EANI combined with hydrochloride palonosetron to prevent acute gastrointestinal reaction induced by chemotherapeutic regimens, and presented the main results here.

Patients
From June 2013 to March 2014, cancer patients hospitalized and scheduled to be treated by highly emetogenic chemotherapy containing adriamycin, cisplatin and epirubicine, aged 23 to 74 years old, and randomly assigned to control group (hydrochloride palonosetron) and treatment group (EANI combined with hydrochloride palonosetron).Hydrochloride palonosetron injection (0.25 mg/unit) was provided by Jiangsu Zhengda Tianqin Pharmaceutical co., LTD.EANI was provided by Kunming Luo Shi Technology co., LTD.
Other eligibility criteria: (1) all patients had CT, MRI, cytological or pathological diagnosis (2) with normal liver and renal function before chemotherapy (3) no nausea, vomiting, and 24 h before chemotherapy and did not use anti-nausea medications before chemotherapy.(4) emotionally stable.
Exclusion criteria: with a clear brain metastases or intracranial hypertension; with epilepsy; with vomiting caused by digestive tract obstruction or due to a variety of causes; pregnant women and nursing mothers; allergic to metal contact; skin damage around wrist; with a pacemaker, with an implanted glucose meter or with an artificial cochlear.

Treatment Methods
Control group: hydrochloride palonosetron at a dose of 0.25 mg (5 ml) was injected for no less than 5 minutes before chemotherapy.
Treatment group: hydrochloride palonosetro at a dose of 0.25 mg (5 ml) was injected for no less than 5 minutes before chemotherapy, and on the contralateral wrist of infusion, to wear an EANI.
Nausea classification: no change (level 0); loss of appetite, but no obvious change in food intake, eating habits and food species (level 1); Ⅱ, obviously reduction in food intake (level 2); almost can't eat, need nutritional support intravenously (level 3).Response rate = (level 0 + level 1)/total number of cases.

Statistical Analysis
SPSS19.0 software was used for data analysis.Chisquare test was used to detect change in nausea and vomiting in two groups.P< 0.05 is considered to be statistically significant.

Results
The results showed that during chemotherapy, complete control rates of vomiting were 40%, and 35% in treatment and control respectively, no statistical difference was detected between two groups (p > 0.05), however response rates were 95.0% and 78.3%, respectively, with statistically significant difference (p< 0.05) (Table 1).Complete control rates of nausea were 36.7% and 30% respectively in treatment and control group without statistical difference (p >0.05), but response rates were 90.0% and 76.7%, respectively, statistically significant difference (p< 0.05) (Table 2).
Some patients in this study presented anti-nausea treatment related adverse reactions (headache, dizziness, vertigo, diarrhea, constipation, etc.), but were mild ( less than degree 2).No significant difference was detected between two groups.No severe adverse reactions were diagnosed, and no patients suspended treatment due to adverse reactions suggesting EANI, and hydrochloride palonosetron both has statisfactory safety profile.

Discussion
According to 2014 national comprehensive cancer network guideline on anti-nausea treatment, highly emetogenic chemotherapeutic regimen including carmustine (> 250 mg/m 2 ), cisplatin, doxorubicin (≥60 mg/m 2 ), dacarbazine, cyclophosphamide (> 1500 mg/m 2 ), epirubicine (> 90 mg/m 2 ), and ifosfamide (≥2 g /m 2 /d or higher), etc.The mechanism of vomiting is not yet fully elucidated, supposing that serotonin (5 -HT3) plays an important role in CINV (Richard et al., 2002), Nausea caused by chemotherapy, could be divided into acute, delayed and anticipatory based on the time of onset (Jordan et al., 2005).Acute nausea and vomiting: refers to nausea or vomiting, occurring within 24 hours of administration of chemotherapeutic drugs, and usually 5 to 6 hours, and could sustain for 18 hours (Jordan et al., 2005).The delayed nausea and vomiting: refers to nausea or vomiting, occurring after 24 hours of administration of chemotherapeutic drugs, and usually 40% -50% of delayed nausea and vomiting occurring within 24 to 48 hours after administration of chemotherapeutic drugs, sometimes sustainable for 5 ~ 7 days (Dranitsaris et al., 2001).
Since the mid of 1980s, a variety of selective 5 -HT receptor antagonists were developed, eg., ONDANSETRON, Tropisetron, Ramosetron, etc. because of the short half-life, affinity is not high, vomiting is difficult to fully control (Uygun et al., 2013;Wang et al., 2013;Wang et al., 2013;Wang et al., 2013;Wu et al., 2013;Xu et al., 2013;Yan et al., 2013;Yusuf et al., 2013;Wei et al., 2014).Hydrochloride palonosetron is an efficient, second generation of 5-HT3 receptor antagonist, with 5-HT3 receptor binding affinity of about 100 times stronger than ONDANSETRON (Ingersoll et al., 2010).Hydrochloride palonosetron is reported to have a long half-life plasma clearance, about 40 h (Ingersoll et al EANI is a newly developed therapeutic apparatus functioning by percutaneously electric stimulus.EANI is a pulse generator with the appearance similar to a wristwatch, and is usually weared around the wrist.EANI has two metal plate and should be pressed to the radial side of wrist flexor.it is functioning by producing a low frequency electric pulse and then transfering the pulse through wrist median nerve to the brain cortex, to adjust a variety of biological and physical activities, including mechanism that controls nausea and vomiting.This electric pulse could also adjust signals to and from stomach transferred by vagus nerve, prevent or delay signal transmission inducing vomit from brain to stomach.EANI could significantly reduce the release of 5-HT3 from gastrointestinal tissue and brain tissue, and downregulate 5-HT3 receptors.Therefore, EANI could inhibite vomiting center through both peripheral and central ways.
This study suggests that in the acute phase of chemotherapy, the control rate of nausea and vomiting in treatment group was higher than that in control group, and was statistically significant.In terms of complete control rate, although no statistical difference in both groups, it is higher in treatment group than that in control group.Suggesting that EANI and hydrochloride palonosetron combined could achieve better effects in controlling chemotherapy related acute gastrointestinal reactions, eg., nausea, vomiting, than hydrochloride palonosetron alone.The mechanism may be associated with above mentioned description.Hydrochloride palonosetron is a new generation 5-HT3 receptor antagonist, functioning by 5-HT3 receptors; and EANI functioning through a low frequency pulse to stimulate cerebral cortex, and to reduce the release of 5-HT3 from gastrointestinal and brain tissue, thereby, could synergistically inhibite vomiting center through both peripheral and central ways, and enhance the anti-nausea effect.And in the aspect of adverse reaction, this study shows that when hydrochloride palonosetron and EANI were used together, toxic reactions were similar to hydrochloride palonosetron used alone, the most common degree I to II toxic reactions were constipation, headache, fatigue and abdominal distention.No degree Ⅲ toxic effects occurred.All adverse reactions could be alleviated after symptomatic treatment, and part of patients could recover without any special treatment.
In conclusion, EANI combined with hydrochloride palonosetron is associated with curative effect of gastrointestinal reaction induced by chemotherapeutic drugs and the control effectiveness is better than hydrochloride palonosetron alone.Thus, could be used as the prevention and treatment for chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy.However, further study should be encouraged to investigate if EANI combined with hydrochloride palonosetron is effective in prevention and treatment of delayed and anticipatory vomiting.

Table 1 . A comparison on the Response Rate of Anti-vomiting Effect Between Two Groups
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