A prospective observational study to compare the antiemetic efficacy and safety profile of two combinations namely ondansetron-dexamethasone versus palonosetron-dexamethasone in prophylaxis of cisplatin induced emesis.
Chemotherapy-Induced Nausea and Vomiting (CINV) are two of the major factors which contribute to fear, anxiety and apprehension in patients with cancer. (1,2) In addition to various medical complications like dehydration, electrolyte imbalance and Mallory-Weiss tears of the oesophagus. (1,3) It also has considerable economic implications which include costs of antiemetic drugs, additional patient care, extended hospitalization and reduced productivity at work or workdays lost. (1,3,4) Preventing CINV from the start of chemotherapy is important, because successful control in acute phase (0-24 hours after chemotherapy) is associated with reduced incidence of CINV in delayed phase (2-5 days after chemotherapy) and control of emesis in 1st cycle is associated with reduced incidence in subsequent cycles. (4,5)
Moreover patients who experience CINV in previous cycle may develop anticipatory nausea and vomiting in later cycles. (1,6,7) Introduction of serotonin (5-HT3) receptor antagonists in 1990's revolutionized the control of emesis and have now become the cornerstone of therapy for prevention of CINV. (8,9,10) First-generation 5-HT3 receptor antagonists, Ondansetron, Granisetron, Dolasetron and Tropisetron in combination with corticosteroids significantly improved the control of acute chemotherapy-induced nausea and vomiting. (8,11) But delayed nausea and vomiting remains a clinical problem. (11,12)
The second-generation 5-[HT.sub.3] receptor antagonist, Palonosetron with high receptor binding affinity and long elimination half-life of 40 hours is found to be effective in delayed CINV also. (13,14,15) Palonosetron also inhibits substance P responses in a serotonin-independent
manner. (13,16,17) Cisplatin provides a model for antiemetic testing, as it is highly emetogenic and found to cause emesis in 99% of patients without antiemetics. (18,19)
Hence, a comparative study on the antiemetic efficacy and safety profile of two antiemetic regimens, Ondansetron-Dexamethasone combination versus Palonosetron-Dexamethasone combination in Cisplatin-induced emesis was conducted in our tertiary care hospital.
The maxim for managing chemotherapy-induced emesis is that, prevention is far more effective than treatment of established nausea and vomiting. (20) It also improves the patient compliance to chemotherapy and patients can tolerate dose intensified chemotherapy regimens. (21) With these objectives in mind, we embark upon this study.
This was a prospective observational study conducted in the Department of Radiotherapy, Govt. Medical College, Calicut, Kerala, during the 1-year period from September 2009 to September 2010. The Institutional Human Ethics Committee approved the study. Based on the data from previous studies, minimum sample size required for our study was calculated to be 53 patients in each group. (22) Expecting noncompliance to the cytotoxic chemotherapy, 60 patients were included in each group and thus a total of 120 patients were included in the study. Written informed consent was obtained from all patients before the study procedure.
* Patients of both sexes, between the age groups 20 to 70 years.
* Patients scheduled to receive first course of Cisplatin chemotherapy (70-100 mg/[m.sup.2] BSA) in combination with 5FU or Paclitaxel or Etoposide.
* Presence of nausea and vomiting and the use of other antiemetic agents during the 24 hours prior to administration of chemotherapy.
* Severely debilitated and patients with known brain, hepatic and renal metastasis.
* Presence of other causes of vomiting such as gastrointestinal obstruction.
* Patients in whom the administration of Dexamethasone was contraindicated.
Age and sex matched patients receiving either Ondansetron with Dexamethasone or Palonosetron with Dexamethasone as antiemetic prophylaxis were selected and grouped. Group 1 patients received first dose of Ondansetron (8 mg) with Dexamethasone (8 mg) injections, 30 minutes prior to Cisplatin administration and was repeated two more times at an interval of 6 hours on the same day. These patients were given oral Ondansetron (8 mg) and Dexamethasone (8 mg) tablets twice daily on 2nd to 5th days. Group 2 patients received only a single injection of Palonosetron (0.25 mg) with Dexamethasone (8 mg), which was given on the first day, 30 minutes prior to Cisplatin administration and it suffice 5 days post-chemotherapy period. These patients were given MAT (Multinational association of supportive care in cancer antiemetic tool).23 questionnaire and were advised to mark,
1. Presence or absence of vomiting.
2. Number of emetic episodes.
3. Presence or absence of nausea.
4. Grade of nausea.
During the 1st, 2nd, 3rd, 4th and 5th days of post-chemotherapy period, grade of nausea was marked in a visual analogue scale of 0 to 10. (0 to 3 taken as no significant nausea, 3 to 6 as moderate nausea and 7 to 10 as severe nausea) in the MAT format.
Adverse effects in both the groups, due to antiemetic drugs were also noted during these periods. The same parameters were again assessed in the same patients when they come for 2nd cycle of chemotherapy after 21 days.
Nausea and vomiting in two groups were assessed between two groups in terms of complete response rate [CR rate: no emesis and no significant nausea (nausea <3 in nausea scale)]. Other parameters that were assessed are number of emetic episodes, frequency of nausea and treatment related adverse effects between two groups in acute (0-24 hours) and delayed (>24-120 hours) phases of 1st and 2nd cycles of Cisplatin chemotherapy.
Statistical analysis was done using Statistical Package for Social Service (SPSS) software version 16. Chi-square test and Unpaired 't' test were done for the analysis of data. Results were tabulated and significance was expressed according to the P value, which was kept at a significant level of <0.05. Drop out cases were excluded.
120 patients, 60 patients each in Ondansetron with Dexamethasone (Group I) and Palonosetron with Dexamethasone (Group II) were included in the study. Comparison of demographic characters of patients showed no significant difference between two groups (Figures 1, 2 and 3).
In group I 25% of patients were males and the mean age was 59.08, whereas in group II 30% of patients were males and the mean age was 53.6. P value=0.540 (>0.05). Gender distribution between two groups compared using independent 't' test. (P value=0.733 and t value=2.813). There was no significant difference between two groups.
Comparison of type of malignancies between two groups showed no significant difference between two groups (P value=0.943). Carcinoma lung was the most common type of malignancy seen followed by carcinoma stomach and carcinoma oral cavity (Figure 3). Two groups were then compared in terms of achieving complete response rate [CR rate: no emesis and no significant nausea (nausea <3 in nausea scale)] in acute and delayed phases of 1st and 2nd cycles of chemotherapy.
CR rate was significantly higher in Palonosetron group than in Ondansetron group in delayed phases of both 1st (73.3% vs. 50%, P=0.009) and 2nd (78.3% vs. 55%, P=0.007) cycles of chemotherapy. In acute phases even though better responses were seen in Palonosetron group in both the cycles (70% vs. 58.3%, P=0.183 and 71.7% vs. 61.7%, P=0.245), the difference was not statistically significant (Figure 4). Among the patients with nausea and vomiting, the severity of emesis in terms of number of emetic episodes and frequency of nausea were also compared between two groups in acute and delayed phases of 1st and 2nd cycles (Figures 5, 6 and Tables 1, 2).
[FIGURE 5 OMITTED]
Emetic episodes were assessed between two groups by calculating percentage of patients with no emesis, 1 episode, 2 episodes and >2 episodes of emesis.
Compared to Ondansetron group, percentage of patients with no emesis were much higher in Palonosetron group in all phases and was significantly higher in delayed phases of Palonosetron group in both 1st (81.7% vs. 55%, P=0.002) and 2nd (85% vs. 60%, P=0.002) cycles of chemotherapy. Among the patients with emesis, percentage of patients with severe emesis (with >2 emetic episodes) were much lower in Palonosetron group in all phases and significant difference were seen in delayed phases of both the cycles (8.3% vs. 30%, P=0.003 and 6.7% vs. 23.3%, P=0.011).
[FIGURE 6 OMITTED]
Frequency of Nausea was also assessed between two groups. Percentage of patients with no significant nausea (<3 in nausea scale) were much higher in Palonosetron group in all phases and significant differences were seen in delayed phases of both 1st (73.3% vs. 50%, P=0.009) and 2nd (76.7% vs. 55%, P=0.012) cycles of chemotherapy. Among the patients with nausea, percentage of patients with severe nausea (>7 in nausea scale) were much lower in Palonosetron group and was significantly lower in delayed phase of 2nd cycle (10% vs. 26.7%, P=0.028) (Figure 6 and Table 2).
[FIGURE 7 OMITTED]
[FIGURE 8 OMITTED]
Treatment related adverse effects in both the groups were mild and there was no significant difference between two groups (Figures 7 and 8). More commonly reported side effects were headache and constipation.
In this prospective observational study, we have selected the lowest effective dose of Ondansetron (8 mg) and Palonosetron (0.25 mg), both in combination with Dexamethasone (8 mg) to determine the most effective and safe, prophylactic antiemetic regimen for Cisplatin-induced emesis in patients attending our tertiary care hospital. Effect of drugs were compared in acute (0-24 hours) and delayed (>24-120 hours) phases of 1st and 2nd cycles of Cisplatin chemotherapy.
Comparison of demographic characteristics of both the groups showed no significant difference between two groups. Palonosetron-Dexamethasone combination provided superior prophylaxis for CINV than Ondansetron-Dexamethasone combination in all phases of chemotherapy. Complete Response rate [CR rate: no emesis and no significant nausea (nausea <3 on nausea scale)] of Palonosetron group was significantly higher in delayed phases of both 1st (73.3% vs. 50%, P=0.009) and 2nd (78.35 vs. 55%, P=0.007) cycles and in acute phases, even though better responses were seen in Palonosetron group in both the cycles (70% vs. 58.3%, P=0.183 and 71.7% vs. 61.7%, P=0.245), the difference was not statistically significant.
Our study results were consistent with previous study done by Aapro et al, which reported that Palonosetron-Dexamethasone combination provided significantly higher CR rate in delayed emesis (42% vs. 28.3%).24 In a similar study done by Gralla and Colleagues, Palonosetron achieved higher CR rate in acute (81% vs. 68.6%, P<0.01), delayed (74.1% vs. 55.1%, P=0.001) and overall phases (69.3% vs. 50.3%, P<0.001) of CINV after moderately emetogenic chemotherapy. (25)
Analysis of patients with nausea and vomiting showed that number of emetic episodes and frequency of nausea were much lower in Palonosetron group compared to Ondansetron group. Number of patients with >2 emetic episodes were found to be significantly lower in delayed phases of Palonosetron group in both the cycles (8.3% vs. 30%, P=0.003 and 6.7% vs. 23.3%, P=0.011). Though we observed lesser control of nausea than vomiting in all cycles for both the groups, compared to Ondansetron-Dexamethasone combination, Palonosetron-Dexamethasone combination provided better results. Number of patients with severe nausea were much lower in Palonosetron group in all phases and was significantly lower in the delayed phase of 2nd cycle of chemotherapy (10% vs. 26.7%, P=0.018).
When both the groups were compared between 1st and 2nd cycles for persistence of their antiemetic efficacy, it was seen that there was decreased incidence of vomiting in 2nd cycle compared to 1st cycle. This emphasizes the fact that protection obtained in previous cycles of chemotherapy is one of the most important prognostic factors for CINV and steps to prevent this can definitely improve the quality of life of patients. (5,26) The incidence of treatment related adverse effects were mild and there was no significant difference between two groups. The more common adverse effects seen were headache and constipation.
Moreover, Palonosetron had the advantage of taking a single dose, which suffice 5 days post-chemotherapy period, whereas Ondansetron had to be administered two to three times daily. The introduction of sustained release tablets of Ondansetron has overcome this drawback to a certain extent, which can provide sustained plasma level of the drug by a single daily dose. It also has the advantage of minimal side effects as rapid and high peak blood levels are not attained. (27) Main limitation of Palonosetron is its cost, whereas Ondansetron injections and tablets are much cheaper.
This prospective observational study comparing the prophylactic antiemetic efficacy and safety of Palonosetron-Dexamethasone combination with Ondansetron Dexamethasone combination demonstrates that
Palonosetron provided superior prophylaxis of CINV and significantly higher responses were seen in delayed phase of chemotherapy. The number of emetic episodes and frequency of nausea were also significantly lower for Palonosetron and it has a safety profile similar to that of Ondansetron. Palonosetron thus provides an effective option for delayed onset CINV, which was difficult to manage previously due to limited efficacy of older 5HT3 receptor antagonists like Ondansetron and also had the advantage of taking a single dose, which greatly improves the patient compliance. This study also revealed reduced incidence of CINV in 2nd cycle, compared to 1st cycle of chemotherapy, emphasizing the fact that protection obtained in previous cycles is an important factor to prevent emesis in subsequent cycles.
Financial or Other, Competing Interest: None.
Submission 01-03-2016, Peer Review 31-03-2016, Acceptance 06-04-2016, Published 25-04-2016.
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Sneha Prabha M. P , Anuradha M , Bindu Latha Nair R 
 Assistant Professor, Department of Pharmacology, Government Medical College, Kottayam, Kerala.
 Professor & HOD, Department of Pharmacology, Government Medical College, Idukki, Kerala.
 Professor & HOD, Department of Pharmacology, Government Medical College, Kottayam, Kerala.
Dr. Sneha Prabha M. P, Assistant Professor, Department of Pharmacology, C- Block, Government Medical College, Kottayam-686008, Kerala.
E-mail: drsneha121 @gmail.com
Table 1: Comparison of Emetic Episodes in 1st and 2nd Cycles of Chemotherapy Number of Emetic Episodes Cycle Phase Drugs 0 1 1st Cycle Acute Ondansetron 40 (66.7%) 4 (6.7%) Palonosetron 43 (71.71%) 2 (33%) Delayed Ondansetron 33 (55%) 4 (6.7%) Palonosetron 49 (81.7%) 3 (5%) 2nd Cycle Acute Ondansetron 42 (70%) 4 (6.7%) Palonosetron 47 (78.3%) 3 (5%) Delayed Ondansetron 36 (60%) 3 (5%) Palonosetron 51 (85%) 2 (3.3%) Number of Emetic Episodes Cycle Phase Drugs 2 >2 1st Cycle Acute Ondansetron 4 (6.7%) 12 (20%) Palonosetron 4 (6.7%) 11 (18.31%) Delayed Ondansetron 5 (8.31%) 18 (30%) Palonosetron 3 (5%) 5 (8.3%) 2nd Cycle Acute Ondansetron 4 (6.7%) 10 (16.7%) Palonosetron 4 (6.7%) 6 (10%) Delayed Ondansetron 7 (11.7%) 14 (23.3%) Palonosetron 3 (5%) 4 (6.7%) Table 2: Comparison of Frequency of Nausea in 1st and 2nd Cycles of Chemotherapy Frequency of Nausea No Significant Cycle Phase Drugs Nausea Moderate Severe 1st Acute Ondansetron 37 (61.7%) 6 (10%) 17 (28.3%) Cycle Palonosetron 42 (70%) 8 (13.3%) 10 (16.7%) Delayed Ondansetron 30 (50%) 14 (23.3%) 16 (26.7%) Palonosetron 44 (73.3%) 7 (11.7%) 9 (15%) 2nd Acute Ondansetron 38 (63.3%) 9 (15%) 13 (21.7%) Cycle Palonosetron 44 (73.3%) 6 (10%) 10 (16.7%) Delayed Ondansetron 33 (55%) 11 (18.3%) 16 (26.7%) Palonosetron 46 (76.7%) 8 (13.3%) 6 (10%) Fig. 1: Comparison of Gender Ondansetron Group Male 75% Female 25% Palonosetron Group Male 70% Female 30% Note: Table made from pie chart. Fig. 2: Comparison of Age Ondansetron Palonosetron Group Group Mean 59.08 53.6 Std. Deviation 11.27 10.05 Note: Table made from bar graph. Fig. 3. Comparison of Type of Malignancies Palonosetron Ondansetron Others 5% 6.67% Other GI Cancers 8.33% 15% Ca lung 28.33% 23.33% Ca Stomach 23.33% 20% Ca Ovary 6.67% 8.33% Ca Oral cavity 16.67% 18.33% Ca Cervix 5% 3.33% Ca Breast 6.67% 5% Note: Table made from bar graph. Fig. 4: Complete Response Rate in 1st and 2nd Cycles of Chemotherapy OND PAL 1st cycle acute phase 58.3% 70% 1st cycle delayed phase 50% 73.3% 2nd cycle acute phase 61.7% 71.7% 2nd cycle delayed phase 55% 78.3% Note: Table made from bar graph.
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|Author:||Sneha, Prabha M.P.; Anuradha, M.; Bindu, Latha Nair R.|
|Publication:||Journal of Evolution of Medical and Dental Sciences|
|Date:||Apr 25, 2016|
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