Comparison of ondansetron with metoclopramide in prevention of acute emesis associated with low dose & high dose cisplatin chemotherapy

Indian J Med Res 118, July 2003, pp 33-41 Comparison of ondansetron with metoclopramide in prevention of acute emesis associated with low dose & high dose cisplatin chemotherapy Ashima Bhatia, K.D. Tripathi & Manoj Sharma* Department of Pharmacology, Maulana Azad Medical College & *Department of Radiotherapy, LN Hospital, New Delhi, India Received March 27, 2003 Background & objectives: Nausea and vomiting remain the most distressing side effects of cancer chemotherapy. The present study aimed to study the efficacy and tolerability of ondansetron versus (vs) metoclopramide in different dose related grades of cisplatin induced acute emesis. Methods: A total of 137 patients were enrolled and 80 completed the study. Cisplatin 60mg/m 2 was given intravenously (iv) either as a single dose on day 1 (high dose regimen) or in three doses of 20 mg/m 2 each on days 1-3 (low dose regimen) along with bleomycin +5-flurouracil in 40 patients each. Patients were randomized in each cisplatin regimen to receive either 20 mg metoclopramide (20 patients) or 8 mg ondansetron (20 patients) iv 30 min prior to cisplatin administration followed by 20 mg metoclopramide or 8 mg ondansetron orally 8 h respectively for 24 h after the last cisplatin administration. Ten patients receiving high dose cisplatin in each group were also given dexamethasone 8 mg iv with the primary antiemetic. Patients were assessed for 24 h after the last cisplatin injection. Results: In low dose cisplatin regimen, complete suppression of acute emesis occurred in 65 per cent patients receiving ondansetron versus 30 per cent receiving metoclopramide, while in high dose regimen, complete response rate was 20 per cent with ondansetron versus 0 per cent with metoclopramide. Dexamethasone significantly augmented the antiemetic efficacy of metoclopramide but not that of ondansetron. Protection from nausea in the acute phase was seen in 95 per cent patients receiving ondansetron vs 70 per cent receiving metoclopramide in low dose regimen. With high dose the protection rates were 90 vs 0 per cent respectively. Combination of dexamethasone + metoclopramide achieved 70 per cent protection while dexamethasone + ondansetron was effective in 90 per cent. Dropouts and withdrawals were more among patients receiving high dose cisplatin and antiemetic regimens without dexamethasone. Thirty nine adverse events were reported by 20 out of 80 patients. All adverse events were mild. Interpretation & conclusion: The results demonstrate dose related emetogenicity of cisplatin and superior antiemetic efficacy of ondansetron, especially against high dose cisplatin regimen. Dexamethasone potentiated efficacy of metoclopramide but not that of ondansetron. The combination of metoclopramide plus dexamethasone was found to be as efficacious as ondansetron monotherapy. Key words acute emesis - cisplatin - dexamethasone - metoclopramide - ondansetron The most distressing side effect associated with cytotoxic chemotherapy is nausea and vomiting 1. Cisplatin, 33 a commonly used cytotoxic drug, induces emesis in 78-100 per cent of patients within the first 24 h with the

34 INDIAN J MED RES, JULY 2003 median number of emetic episodes between 5-12 2. Cisplatin induces a biphasic pattern of emesis. The initial phase referred to as acute emesis is more severe and peaks over the first 6-8 h 3. The second phase or delayed emesis which begins 24 h after cisplatin infusion is pathophysiologically distinct from acute emesis 4. The two most common antiemetic agents used with cytotoxic chemotherapy are metoclopramide and ondansetron 5. Ondansetron, a 5HT 3 antagonist lacks the extrapyramidal side effects associated with metoclopramide, a D2 antagonist 6. Comparative studies of metoclopramide and ondansetron have been reported from the West 7-12 but the same are few in our country. Ethnic, socio-cultural and educational level differences may play a major role in the attitudes towards acceptability of cancer chemotherapy as well as in the need for and response to antiemetic medication. Though ondansetron has proven to be superior to metoclopramide in the Western population 10-11, the same may not hold true for the Indian population. In an Indian study by Advani et al 13, a wide dosage range of cisplatin (100-180 mg/m 2 ) and nonuniform chemotherapy regimens have been used making the extrapolation of results to cisplatin induced emesis difficult. Moreover many of these studies have used combination regimens, and the addition of dexamethasone has been reported to provide subjective improvement 14-15. There is a paucity of literature on the comparison of ondansetron and metoclopramide monotherapies in cisplatin induced emesis in Indian patients. There have been some reports on the dose related emetogenicity of cisplatin 16-20 but no studies have been done to compare the efficacy of antiemetics against the different grades of emetogenicity of cisplatin. In view of the paucity of information in Indian patients the present study was undertaken to compare the efficacy and tolerability of ondansetron with metoclopramide in acute emesis induced by 60mg/m 2 cisplatin either given as a single dose (high dose regimen) or in doses of 20mg/ m 2 /day over 3 days (low dose regimen). Material & Methods The study was conducted at the Department of Radiotherapy, Lok Nayak Hospital and Department of Pharmacology, Maulana Azad Medical College, New Delhi, over a period of 10 months (April 1998 to February 1999). A total of 137 patients of either sex, aged 18 yr or above with histologically proven malignancy and Karnofsky Performance Status 21 of at least 60 per cent presenting to the outdoor services of the Radiotherapy Department were enrolled in the study. All patients were scheduled to receive cisplatin on the first treatment day of a combination chemotherapy regimen. Patients with malignancy who had received any prior chemotherapy, had severe concurrent illness other than neoplasia, who were taking benzodiazepines except when given for night sedation, those who had experienced vomiting/retching in the previous 24 h or had emesis due to some other etiologies, those receiving concurrent radiation therapy and pregnant or lactating women were excluded from the study. Patients with malignancy having impaired renal function (serum creatinine>2.0mg/dl), jaundice (serum bilirubin > 2.0mg/dl) or an elevated amino transferase level (SGOT/ SGPT>twice the upper normal limit) were also excluded from the study. Study protocol : The study was approved by the institutional ethical committee. After taking informed consent from each patient, complete medical history was elicited and a thorough physical examination was performed. Blood biochemistry and haematological profile were also investigated for each patient. Chemotherapy: Patients were randomized according to a table of random numbers to receive either low dose cisplatin regimen (Groups I and II)) or high dose cisplatin regimen (Groups III and IV). In the high dose regimen, patients were given 60 mg/m 2 cisplatin intravenously (iv) as a single dose on first day and in low dose regimen, cisplatin was split into three iv doses of 20mg/m 2 each on first, second and third day. In addition, all patients received bleomycin 15 mg iv on first and fifth day and 5-fluorouracil 500 mg iv for 5 days as was required in their regimens. Antiemetic regimen : Patients in Groups I and III received metoclopramide 20 mg iv 30 min prior to each cisplatin administration followed by 20 mg metoclopramide orally 8 hourly for 24 h after the last cisplatin administration. These groups were designated by the symbols M+C-20 and M+C-60 respectively.

BHATIA et al : ONDANSETRON VERSUS METOCLOPRAMIDE IN CISPLATIN INDUCED ACUTE EMESIS Patients in Groups II and IV similarly received 8 mg ondansetron iv 30 min prior to each cisplatin administration followed by oral 8 mg ondansetron 8 hourly for 24 h and were designated as O+C-20 and O+C-60 respectively. In Groups III and IV, dexamethasone (8 mg iv 30 min prior to cisplatin administration) was added to the respective antiemetic regimens in 10 patients each and these groups were given the symbol M+D+C-60 and O+D+C-60 respectively. The groups are described in Table I. Efficacy assessment : Patients were kept under observation for the first 6 h after cisplatin infusion after which they were allowed to go home. All patients kept an emetic diary in which a complete record of nausea and emetic episodes was maintained. The observation period lasted till 24 h after the last cisplatin administration. The efficacy parameters monitored were latency of first emetic episode, number of emetic episodes on each day and intensity of nausea. An emetic episode was defined as a single vomit (expulsion of stomach contents through mouth)) or retch (an attempt to vomit but not productive of stomach contents) or any number of continuous vomits or retches separated by the absence of vomiting or retching for at least one minute. 35 The antiemetic response was defined as complete response - no emesis; major response - 1 to 2 emetic episodes; minor response - 3 to 5 emetic episodes and failure - more than 5 emetic episodes. The severity of nausea was graded on a visual analogue scale (0-100 mm) where 0 corresponded to no nausea and 100 to extreme nausea 22. Nausea was also graded as none, or mild did not interfere with normal daily life, or moderate interfered with normal daily life or, severe confined to bed due to nausea. Since increased salivary secretion frequently accompanies nausea, an attempt was made to quantify salivary secretion during the initial 6 h after cisplatin. Cottonwool balls of approximately 3cm diameter were used to measure salivation before and after chemotherapy. The cotton ball was kept in side the patient s cheek for 5 min at 0,1,2,3,4,5 and 6 h after cisplatin administration. The cotton balls removed from the patients mouth were kept in sealed polythene packets and weighed to measure the amount of saliva collected. Adverse events were monitored during the study by interviewing the patients and also from the diary records of the patients. Table I. Group-wise chemotherapy, antiemetic regimens and number of patients enrolled, dropouts and withdrawals Groups Cisplatin dose Antiemetic No. of patients regimen Enrolled Dropouts Withdrawals Completed I (M+C-20) 20mg/m 2 3 days Metoclopramide 30 10 0 20 II (O+C-20) 20mg/m 2 3 days Ondansetron 21 1 0 20 IIIa(M+C-60) 60mg/m 2 single dose Metoclopramide 36 15 11 10 IIIb(M+D+C-60) 60mg/m 2 single dose Metoclopramide + 17 6 1 10 Dexa IVa(O+C-60) 60 mg/m 2 single dose Ondansetron 20 10 0 10 IVb(O+D+C-60) 60 mg/m 2 single dose Ondansetron + 13 3 0 10 Dexa Dexa - Dexamethasone, M - Patients receiving metoclopramide prophylaxis, C-20 Patients receiving low dose cisplatin, C-60 patients receiving high dose cisplatin, M+D patients receiving metoclopramide and dexamethasone prophylaxis, O Patients receiving ondansetron prophylaxis, O+D patients receiving ondansetron and dexamethasone prophylaxis

36 INDIAN J MED RES, JULY 2003 Patient compliance was checked by patient interview and by counting the number of tablets brought back each day. Statistical analysis : Quantitative data like latency of first emetic episode, number of emetic episodes were analysed using student s t test. Graded data like intensity of nausea and magnitude of antiemetic response were analysed using Mann Whitney U test. Withdrawal and dropout data were analysed using Chisquare test. The limit of significance was set at P<0.05 in all instances. In Groups I and II, the worst day outcomes were taken for statistical analysis which were incidentally the first day of cisplatin administration in all patients. Results Of the 137 patients enrolled, 80 successfully completed the study; 45 dropped out and 12 were withdrawn from the study due to severe nausea and vomiting (Table I). Maximum dropouts and withdrawals were seen in group M+C-60. The number of dropouts and withdrawals taken together was more in patients receiving metoclopramide than those receiving ondansetron irrespective of low/high dose cisplatin regimen. The difference was statistically significant (P<0.05) only in low dose cisplatin groups. The dropouts and withdrawals were also significantly (P<0.001) higher in the high dose cisplatin groups irrespective of whether ondansetron or metoclopramide was used as an antiemetic. There was no significant difference in the patient profiles of different groups (Table II). Vomiting : The mean latency to first emetic episode varied from 1.9 to 5.0 h. The number of emetic episodes were more in patients given metoclopramide in comparison to those receiving ondansetron irrespective of dose of cisplatin (P<0.05). Dexamethasone significantly potentiated the antiemetic effect of metoclopramide but the potentiation was not significant in case of ondansetron. The effectiveness of ondansetron was not different against the two regimens of cisplatin whereas metoclopramide was significantly less effective against high dose cisplatin. The combination of metoclopramide and dexamethasone matched the antiemetic efficacy of ondansetron monotherapy (Table III). Table II. Characteristics of patients in the various treatment groups Group I Group II Group III Group IV M+C-20 O+C-20 M(±D) +C-60 O(±D) +C-60 Age (yr) [mcan ± SD (range)] 45.1±11.8 (21-65) 43.9±11.2 (24-60) 48.3±7.7 (35-60) 45.5±10.3 (32-63) Sex (M: F) 10:10 7:13 9:11 13:7 Malignancy Head & neck 11 9 10 13 Cervix 7 10 9 7 Others 2 1 1 0 Tumour surgery (Yes:no) 1:19 4:16 2:18 4:16 Alcohol intake # (none:<7u/wk : >7U/wk) 18:2:0 15:3:2 15:3:2 16:3:1 H/o tobacco chewing (positive : negative) 3:17 4:16 6:14 4:16 Smoking (Yes: no) 9:11 8:12 9:11 13:7 Karnofsky performance score (mean±sd) 97.5±4.4 96.5±4.9 97.5±4.4 96±5.0 H/o motion sickness (Yes: no) 0:20 0:20 0:20 0:20 Description of group symbols as in Table I M(±D)+C-60 : Metoclopramide prophylaxis with or without dexamethason in cisplatin 60mg/m 2 group. O(±D)+C-60 : Ondansetron prophylaxis with or without dexamethasone in cisplatin 60mg/m 2 group. # Alcohol intake: 1U= 150 ml wine/500 ml beer/50 ml distilled spirit

BHATIA et al : ONDANSETRON VERSUS METOCLOPRAMIDE IN CISPLATIN INDUCED ACUTE EMESIS 37 Table III. Effect of different antiemetic regimens on vomiting, nausea and salivation accompanying cisplatin induced acute emesis Group N Vomiting * Nausea Salivation* Latency No. of Maximal Latency of of emesis episodes of VAS scores (mm) Basal increase max. increase (h) vomiting (Mean±SD) (µg/5min) (µg) (h) M+C-20 20 3.2±0.4 3.9±1.0 26.7±25.9 179±2 43.1±4.36 4.1±0.3 O+C-20 20 3.1±0.3 1.1±0.5 13.0±18.9 181±1 28.7±3.39 4.4±0.3 M+C-60 10 1.9±0.4 9.9±1.0 70.0±11 176±2 41.0±6.2 3.2±0.35 O+C-60 10 5.0±0.7 3.2±1.2 22.5±19.2 186±2 36.4±3.3 3.7±0.6 M+D+C-60 10 3.2±0.8 5.9±1.0 37.5±27.3 181±1 18.3±2.7 4.9±0.5 O+D+C-60 10 3.6±1.2 2.8±0.7 20.5±16.6 188±2 28.3±4.5 4.8±0.5 N= number of patients, VAS - visual analogue scale. *Values are mean ± SE; Group symbols as described in Table I. Comparison among groups P values Groups compared Latency of No. of episodes of Intensity of nausea Maximal increase Vomiting vomiting in salivation M+C-20 vs O+C-20 >0.05 <0.05* >0.05 <0.02* M+C-60 vs O+C-60 <0.01* <0.001* <0.002* >0.05 M+D+C-60 vs O+D+C-60 >0.05 <0.02* >0.05 >0.05 M±D+C-60 vs O±D+C-60 >0.05 <0.001* <0.002* >0.05 M+C-60 vs M+D+C-60 >0.05 <0.01* <0.02* <0.01* O+C-60 vs O+D+C-60 >0.05 >0.05 >0.05 >0.05 M+D+C-60 vs O+C-60 >0.05 >0.05 >0.05 <0.001* M+C-20 vs M+C-60 <0.05* <0.001* <0.002* >0.05 O+C-20 vs O+C-60 <0.05* >0.05 >0.05 >0.05 *significant values M±D+C-60 - Metoclopramide prophylaxis with or without dexamethasone in high dose cisplatin groups (n=20), O±D+C-60 - Ondansetron prophylaxis with or without dexamethasone in high dose cisplatin groups (n=20) Ondansetron achieved complete suppression of emesis in 65 per cent (13) and 30 per cent (3) patients in low and high dose cisplatin regimen respectively whereas metoclopramide achieved the same in 20 per cent (4) patients in the low dose cisplatin regimen and none in the high dose regimen (Fig. 1). Nausea : Ondansetron and metoclopramide were equally effective in the reduction of intensity of nausea in patients receiving the low dose cisplatin regimen. However, ondansetron was significantly (P<0.002) superior to metoclopramide against high dose cisplatin regimen. Dexamethasone significantly potentiated the reduction in nausea when given with metoclopramide; the combination was as effective as ondansetron alone against nausea (Table III). Salivation : The mean (±SD) values of base-line salivation were almost similar in all the groups, ranging from 179±9µg/5min to 188±8µg/5min (Table III). The

38 INDIAN J MED RES, JULY 2003 Table IV. Adverse effect profile of different anti emetic regimens in cisplatin based chemotherapy recipients Number of patients reporting each side effect Side effect M+C-20 O+C-20 M+C-60 O+C-60 M+D+C-60 O+D+C-60 (n=20) (n=20) (n=10) (n=10) (n=10) (n=10) Dystonia/Akathisia - - - - - - Constipation - 1 1 5-1 Headache 3 2 1 3 1 1 Heart burn - - 2 3-1 Weakness 2-2 1 1 1 Epigastric pain 2 1 1 1 - - Nervousness 1 - - 1 - - Group symbols as described in Table I time to maximal increase of salivation varied from 3.2±1.1 to 4.9±1.8 h which roughly coincided with the latency of the first emetic episode. The maximal increase was significantly more in patients receiving metoclopramide as compared to ondansetron in the low dose cisplatin regimen. Addition of dexamethasone to metoclopramide significantly reduced the maximal increase in salivation as compared to metoclopramide monotherapy (P<0.01) and ondansetron monotherapy (P<0.001). There were no significant differences in maximal increase of salivation among the other antiemetic regimens. Adverse effect profile : A total of 39 adverse events were reported by 20 patients (Table IV). Seven of 40 patients receiving ondansetron had constipation and 5 of 40 patients receiving metoclopramide complained of weakness. All the adverse events were mild and did not need discontinuation of the drug. No dystonic reaction was noted in any of the patients given metoclopramide. Discussion Since emetogenicity of cisplatin is dose dependent, and the efficacy of antiemetics may differ according to the intensity of emetogenic stimulus, it was decided to Fig. 1. Antiemetic responses obtained with metoclopramide or ondansetron with or without dexamethasone. *Group symbols as described in Table I. Fig. 2. Intensity of nausea observed with metoclopramide or ondansetron with or without dexamethasone. *Group symbols as described in Table I.

BHATIA et al : ONDANSETRON VERSUS METOCLOPRAMIDE IN CISPLATIN INDUCED ACUTE EMESIS study the antiemetic efficacy of metoclopramide and ondansetron against a high dose regimen (60 mg/m 2 iv single dose) and low dose regimen (20 mg/m 2 iv in 3 daily doses) of cisplatin. Assessment criteria taken for comparison of various antiemetics used in our study were based on those used in earlier studies 8,23,24. Of the 137 patients enrolled, 80 completed the study. The adherence of patients to the chemotherapy regimen appears to depend on the efficacy of the antiemetic prophylaxis. The significantly fewer dropouts and withdrawals with low dose cisplatin regimen corroborates the dose dependent emetogenicity of cisplatin reported earlier 16-20. Fewer dropouts and withdrawals with ondansetron compared to metoclopramide in both cisplatin regimens reflects a higher antiemetic efficacy of ondansetron though the difference was statistically not significant in high dose cisplatin regimen. Addition of dexamethasone to both ondansetron and metoclopramide reduced the dropouts, which may be due to superior efficacy of the combination prophylaxis. The high dose cisplatin regimen was found to be more emetogenic than low dose regimen; again confirming the dose dependent emetogenicity of cisplatin. Ondansetron was found to be superior to metoclopramide in control of emesis (complete protection: 65 vs 20% against low dose regimen and 30% vs 0 against high dose). Comparable results have been obtained by Marty et al 3 (75 vs 42%) and de Mulder et al 7 (72 vs 42%) through a higher dose (3mg/kg loading dose+0.5mg/kg/h iv for 8 h) of metoclopramide was used. The addition of dexamethasone significantly improved the antiemetic response to metoclopramide. Similar potentiation has been reported by earlier studies 25-27. Some studies 28-30 have found dexamethasone to augment the efficacy of ondansetron against cisplatin induced emesis. However, in the present study, dexamethasone failed to augment the antiemetic response to ondansetron. This may be due to a high level of response of ondansetron alone. The antiemetic regimen of dexamethasone plus metoclopramide was as efficacious as ondansetron monotherapy in control of acute emesis in the present study. In contrast, an earlier study 12 has reported superior efficacy of ondansetron monotherapy over metoclopramide and dexamethasone combination. This disparity may be due to differences in the dosage 39 regimens used in the earlier and present study and may reflect differences in the response pattern of the two patient populations. In the present study, the first episode of vomiting occurred more promptly in patients given high dose cisplatin and metoclopramide reflecting high emetogenicity of the regimen and poor efficacy of the antiemetic. Ondansetron delayed the latency of vomiting induced by high dose cisplatin to a greater extent compared to metoclopramide. No earlier study has reported on the effect of drugs on the latency of cisplatin induced emesis, though most studies have found peak acute emesis to occur between 4-8 h after cisplatin. In the control of nausea in the acute phase, the directional superiority of the two antiemetic drugs was the same as that for vomiting though some of the comparisons did not reach statistical significance. Acute phase nausea also was worse in patients on the high dose cisplatin regimen and ondansetron was found to be superior to metoclopramide in the reduction of intensity of nausea but in contrast to acute vomiting, this effect was evident only with high dose cisplatin. With low dose cisplatin regimen, protection (mild or no nausea) against nausea was obtained in 95 per cent patients receiving ondansetron versus 70 per cent receiving metoclopramide; with high dose regimen, the rates were 90 per cent versus 0. Earlier studies report rates of 73 vs 67 per cent 7 and 58 vs 42 per cent 3 in patients receiving 50-100 mg/m 2 cisplatin. The very low success rate with metoclopramide in our study appears to be due to the lower dose of metoclopramide used compared to that in Western studies. Though nausea is almost always accompanied by salivation, this parameter has not been used previously to quantify nausea. We tried to measure if the increase in salivation could serve as an index of nausea during acute emesis. Though in some cases increase in salivation corresponded to the intensity of nausea, in other cases this association was not found. However, the time of peak salivation roughly coincided with the latency of the first episode of nausea and vomiting. Salivation was thus, found to be an imprecise index of nausea. All the antiemetics used in the present study were equally well tolerated. It was very difficult to differentiate

40 INDIAN J MED RES, JULY 2003 the side effects due to chemotherapy from those due to the antiemetics used since both were given concurrently. Constipation was reported in seven of 40 patients receiving ondansetron. Constipation with ondansetron has been reported earlier also 31. It is noteworthy that extrapyramidal side effects did not occur in any of the patients receiving metoclopramide. The dose of metoclopramide used in the present study appears not to produce acute dystonic reactions in adult patients. In conclusion, ondansetron was found to be superior to metoclopramide in the suppression of cisplatin induced acute emesis and the difference was more marked in case of high dose cisplatin regimen, which was more emetogenic. The highlight of the present study is the finding of similar efficacy of metoclopramide and dexamethasone combination to ondansetron monotherapy. 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