Cell Biochem Biophys DOI 10.1007/s12013-014-0489-0

ORIGINAL PAPER

Effectiveness of Olanzapine Combined with Ondansetron in Prevention of Chemotherapy-Induced Nausea and Vomiting of Non-small Cell Lung Cancer Xin Wang • Lei Wang • Huayong Wang Hao Zhang



Ó Springer Science+Business Media New York 2015

Abstract The objective of this study is to compare the effectiveness of olanzapine combined with ondansetron or ondansetron alone in preventing chemotherapy-induced nausea and vomiting (CINV) of non-small cell lung cancer (NSCLC). A total of 84 NSCLC patients were equally randomized into intervention group and control group. Both groups were intravenously administered with ondansetron 8 mg 30 min before chemotherapy. In the intervention group, olanzapin 10 mg was orally administered for 8 days, beginning from the first morning of chemotherapy. The antiemetic effectiveness was evaluated in the first chemotherapy cycle. The incidence of acute vomiting was 33.33 % (14/42) and 54.76 % (23/42) in the intervention group and control group (p \ 0.05) whereas that of delayed vomiting was 16.57 % (7/42) and 47.62 % (20/42) (p \ 0.05). Compared with ondansetron alone, the combination of olanzapine with ondansetron has better effectiveness in preventing CINV in NSCLC patients, particularly for the delayed type. Keywords Non-small-cell lung cancer  Olanzapine  Ondansetron  Chemotherapy  Nausea/vomiting

Introduction Lung cancer is the most common cancer worldwide and its prevalence is increasing rapidly in recent years. Non-small cell lung cancer (NSCLC) accounts for about 80 % of all lung cancer cases [1]. Among the multidisciplinary management of NSCLC, chemotherapy remains one of the most important approaches. However, most NSCLC patients will suffer from chemotherapy-induced nausea and vomiting (CINV); without proper antiemetic treatment, the incidence of CINV can reach 70–80 % [2]. Severe CINV can lower the quality of life and even lead to nutritional deficiencies and water and electrolyte imbalance. It can also reduce the patient adherence to chemotherapy, which may hamper the timely and adequate treatment and affect the therapeutic effectiveness. In our current study, we compared the effectiveness of ondansetron alone or in combination with olanzapine in treating CINV in NSCLC patients.

Subjects and Methods Subjects

Wang Lei and Wang Xin have contributed equally to the study and should be considered as co-first authors. X. Wang  L. Wang (&)  H. Wang  H. Zhang Department of Thoracic Surgery, Xuzhou Central Hospital, Xuzhou, China e-mail: [email protected]

A total of 84 pathologically and/or cytologically confirmed NSCLC patients who were treated in our hospital from February 2010 to June 2012 were enrolled in this study. These patients required pre-operative chemotherapy, had become inoperable, or had experienced post-operative relapse/metastasis, with a clinical phase of IIB-IV. The inclusion criteria were as follows: (a) a Kamofsky score (KPS) of C60 points; (b) without severe heart disease or diabetes; (c) with normal liver and kidney functions and routine blood test results; (d) without brain metastases,

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gastrointestinal obstruction, or other primary diseases that may cause CINV; and (e) chemotherapy-naive. These 84 patients were equally randomized into intervention group and control group. In the control group, there were 30 men and 12 women, with 26 cases of squamous cell carcinoma and 16 cases of adenocarcinoma; these patients aged 40–76 years (median 60 years), and the mean KPS score was 85. In the intervention group, there were 31 men and 11 women, with 28 cases of squamous cell carcinoma and 14 cases of adenocarcinoma; these patients aged 39–74 years (median 59 years), and the mean KPS score was 86. The two groups showed no significant differences in terms of gender, age, pathologic type, and KPS score (all p [ 0.05).

The cisplatin–gemcitabine regimen was applied for all these 84 patients. Gemcitabine (Stockhausen Pharmaceutical Co., Ltd., Jiangsu) 1,000 mg/m2 was intravenously infused on days 1 and 8; cisplatin (Stockhausen Pharmaceutical Co., Ltd) 75 mg/m2 was intravenously infused on days 2 and 3. The control group was intravenously administered with ondansetron 8 mg 30 min before chemotherapy. In the intervention group, however, the patients were intravenously administered with ondansetron 8 mg 30 min before chemotherapy, then olanzapin 10 mg was orally administered for 8 days, beginning from the first morning of chemotherapy. The CINV was evaluated after one chemotherapy cycle. Evaluation Criteria Based on the standard WHO anti-cancer drug toxicity grading criteria (1998), the CINV was divided as grade 0 (none), 1 (nausea), 2 (transient vomiting), 3 (vomiting, which needs to be treated), and 4 (uncontrollable vomiting). The nausea/vomiting occurred within 24 h after the final chemotherapy was defined as the acute nausea/vomiting, whereas those occurred after the 24 h as the delayed nausea/vomiting.

a

p \ 0.05, compared with the control group

b

p \ 0.01, compared with the control group

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Data were analyzed using the SPSS 13.0 software, and inter-group comparison was performed using the v2 test.

Results The incidence of acute vomiting was 33.33 % (14/42) and 54.76 % (23/42) in the intervention group and control group, respectively (v2 = 3.91, p \ 0.05), and the incidence of delayed CINV was 16.67 % (7/42) and 47.62 % (20/42) (v2 = 9.22, p \ 0.01) (Table 1).

Discussion

Treatment

Table 1 Incidences of CINV in the intervention group and control group

Statistical Analysis

Grade

During the multidisciplinary management of NCLC, chemotherapy is applied for a variety of purposes including the treatment of advanced or recurrent diseases, post-operative adjuvant chemotherapy, pre-operative chemotherapy, and in combination with radiotherapy [3] CINV is a common adverse reaction of chemotherapy, refers to the process of chemotherapy caused by the chemotherapy nausea and vomiting. Based on the onset time of vomiting, CINV can be classified as acute, delayed, or anticipatory. In our current study, we mainly observed the occurrence of acute and delayed CINV during the chemotherapy. The mechanisms of CINV are complicated. It has been recognized that most cytotoxic drugs can stimulate the gastrointestinal mucosa, causing the mucosal damage. As a result, the mucosa, particularly the chromaffin cells of the gastrointestinal mucosa (from stomach to ileum), releases 5-TH, which, after having been bound with the 5-TH3 receptor, can produce nerve impulses, which is transmitted to the vomiting center via the vagal nerve afferents and thus triggers vomiting [4].Chemotherapy drugs and their metabolites stimulate the chemoreceptor zone, which transmits the signals to the vomiting center and therefore also causes vomiting. These stimulations expert their activities through a series of receptors including dopamine receptors, histamine receptors, muscarinic receptor, and

Acute CINV (n)

Delayed CINV (n)

Intervention group

Control group

Intervention group

Control group

0

28

19

35

22

1

10

14

5

12

2 3

3 1

6 2

1 1

5 2

4

0

1

0

1–4 (%)

a

33.33

54.76

1 b

16.67

47.62

Cell Biochem Biophys

5-TH3 receptor [5] In addition, sensory and mental factors (by stimulating the cortical pathways) and P substance (by binding the NK-1 receptor) also play important roles in the development of CINV [6, 7].Some early drugs for preventing CINV in clinical settings included dopamine receptor blockers (e.g., metoclopramide, chlorpromazine, and domperidone), histamine receptor blockers (e.g., promethazine), and muscarinic receptor blockers (e.g., scopolamine). These drugs have shown certain effectiveness in preventing CINV but still remain unsatisfactory. In particular, it is well recognized that 5-TH exerts its effect on the 5-TH3 receptor and thus triggers vomiting. Thus, the 5-TH3 receptor inhibitors (particularly ondansetron) have become the mainstream drugs for the clinical prevention of CINV. In recent years, the wide application of 5-TH3 receptor inhibitors has successfully controlled about 70 % of acute CINV; unfortunately, about 30 % of acute and delayed CINV have not been effectively controlled. According to Navari et al., olanzapine could effectively control CINV, especially the delayed CINV [8, 9]. As a new atypical antipsychotic, olanzapine has been widely used for various psychiatric disorders. Clinical research has shown that olanzapine can inhibit the 5-TH2A, 5-TH3, dopamine D1-5, muscarinic Ml-5,adrenergical, and histamine H1 receptors [10–12]. In our current study, the incidences of both acute CINV and delayed CINV were significantly decreased in the intervention group when compared with the control group (p \ 0.05), indicating that olanzapine has good preventive effect for CINV; also, our data showed that olanzapine was particularly effective in preventing the delayed CINV. It has been proposed that most acute CINV is triggered by the 5-TH released by the chromaffin cells of the gastrointestinal mucosa, and such vomiting is responsive to the 5-TH3 receptor inhibitors [13] Olanzapine can inhibit the receptors of 5-TH3, dopamine, histamine, and muscarine, which may explain why olanzapine can prevent the onset of acute CINV. The delayed CINV, however, might not be caused by the 5-TH released by the chromaffin cells. Its exact mechanism remains unclear. Factors such as substance P mediation, blood–brain barrier damage, imbalanced gastrointestinal motility, and adrenal hormone secretion may play certain roles [14]. Our study also demonstrated that olanzapine can also prevent the delayed CINV, and such preventive effect was even superior to that for the acute CINV. However, the underlying mechanism is also poorly understood. A possible explanation is that olanzapine can exert its effect on the central nervous system and block a variety of receptors. In addition, only one patient in the intervention group experienced mild drowsiness, whereas

the remaining patients did not suffer from any adverse reaction. This may be explained by the low dosage, short treatment course, and small sample size. In summary, olanzapine in combination with ondansetron has better effectiveness than ondansetron alone in preventing CINV in NSCLC patients, particularly for the delayed type.

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Effectiveness of Olanzapine Combined with Ondansetron in Prevention of Chemotherapy-Induced Nausea and Vomiting of Non-small Cell Lung Cancer.

The objective of this study is to compare the effectiveness of olanzapine combined with ondansetron or ondansetron alone in preventing chemotherapy-in...
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