Efficacy & tolerability of ondansetron compared to metoclopramide in dose dependent cisplatin-induced delayed emesis

Indian J Med Res 120, September 2004, pp 183-193 Efficacy & tolerability of ondansetron compared to metoclopramide in dose dependent cisplatin-induced delayed emesis Ashima Bhatia, K.D. Tripathi & Manoj Sharma* Department of Pharmacology, Maulana Azad Medical College & *Department of Radiotherapy, LN Hospital, New Delhi, India Received September 19, 2003 Background & objectives: Delayed emesis with cisplatin is a significant problem, which is often poorly controlled with conventional antiemetics. There is a relative paucity of data on the control of delayed emesis and rather inconsistent results have been reported. The present study aimed to compare the efficacy and tolerability of ondansetron versus metoclopramide in dose related grades of cisplatin-induced delayed emesis. Methods: A total of 80 chemotherapy naïve patients with malignancy were randomized to receive cisplatin 60 mg/m 2 intravenously (iv) either as a single dose on day 1 (high dose regimen) or split into three doses of 20 mg/m 2 each on 3 days (low dose regimen) along with bleomycin +5- flurouracil in 40 patients each. Patients were further 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 the respective antiemetic orally 8 hourly for five days after the last cispaltin administration. Ten patients receiving high dose cisplatin in each group were also given dexamethasone 8 mg iv with the primary antiemetic. The assessment period started 24 h after last cisplatin infusion and ended at midnight on day 5. Results: In low dose cisplatin regimen, complete suppression of delayed emesis occurred in 55 per cent patients receiving ondansetron and in 30 per cent patients receiving metoclopramide. Neither ondansetron nor metoclopramide could completely suppress delayed emesis in high dose cisplatin regimen. Protection from nausea in the delayed phase was seen in 85 per cent patients receiving ondansetron and in 70 per cent patients receiving metoclopramide in low dose regimen, while nausea protection rates were 70 vs 0 per cent respectively in the high dose regimen. Addition of dexamethasone to metoclopramide significantly augmented its antiemetic efficacy (P<0.02) and the combination of metoclopramide + dexamethasone was found to be as efficacious as ondansetron monotherapy. Twenty out of 80 patients reported 39 adverse events of mild intensity. No significant effects on QOL (quality of life) parameters were observed in any group over the 5-day period. Interpretation & conclusion: The results demonstrate that delayed emesis due to cisplatin is also dose related, and superior antiemetic efficacy of ondansetron compared to metoclopramide is maintained, though its superiority is less marked than against acute emesis. Metoclopramide and dexamethasone combination matched the antiemetic efficacy of ondansetron monotherapy. Key words Cisplatin - delayed emesis - dexamethasone - metoclopramide - ondansetron 183

184 INDIAN J MED RES, SEPTEMBER 2004 Nausea and vomiting are the most distressing side effects of cytotoxic chemotherapy 1. In contrast to the prolonged monophasic pattern of emesis induced by agents like cyclophosphamide, 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 2. The second phase delayed emesis, begins after 24 h and lasts for 4-5 days. Though less severe than acute emesis, it is debilitating and more resistant to conventional antiemetics 3. The overall incidence of delayed emesis and nausea has been reported to vary from 43 to 89 per cent 4-6 and its intensity peaks between 24 to 72 h following cisplatin administration 3. The pathophysiology of delayed emesis in contrast to that of acute emesis is largely undefined, though response to the antiemetic medication in the acute phase is the most important predictor for delayed emesis 7,8. The usual practice for prevention of delayed emesis is extended administration of the antiemetic for 4 to 5 days. There is paucity of data on control of delayed emesis and rather inconsistent results have been reported 9-11. Efficacy of 5-hydroxytryptamine (5- HT 3 ) antagonists though established against acute emesis, is controversial against delayed emesis 9-11. Moreover, there are very few studies assessing the effect of antiemetics on quality of life (QOL) of cancer patients. Further, no studies have been done to compare efficacy of antiemetics against dose related grades 12-14 of delayed emesis. We have earlier reported superior antiemetic efficacy of ondansetron in comparison to metoclopramide in cisplatin induced acute emesis 15. The present study compares efficacy and tolerability of ondansetron with metoclopramide in delayed emesis induced by 60 mg/m 2 cisplatin given either as a single dose (high dose regimen) or split into multiple doses of 20 mg/m 2 over three days (low dose regimen) and their effect on QOL parameter. Dexamethasone has been reported to improve the control of nausea and vomiting by the primary antiemetic and the effect of a single dose administered before cispaltin injection may persist beyond the acute phase and help in control of delayed emesis as well 16-18. Therefore, the effect of addition of dexamethasone to the primary antiemetic was also assessed. 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). It was a randomized, observer blind, prospective, parallel group study. The study protocol was approved by the institutional ethics committee. Written informed consent was obtained from all patients before inclusion in the study. Patients: Eighty consecutive chemotherapy naïve patients of either sex aged 18 yr or above with histologically proven malignancy and Kernofsky Performance Grade 19 of more than 60 per cent and presenting to the outdoor services of the Radiotherapy department were included in the study. Patients were excluded if any of the following applied: severe concurrent illness, vomiting due to some other cause, antiemetic therapy administered concurrently or in the 24 h preceding chemotherapy, administration of benzodiazepines except when given for night sedation, vomiting in the 24 h before chemotherapy, pregnant or lactating women, concurrent radiation therapy, impaired renal function (serum creatinine >2.0 mg/dl), jaundice (serum bilirubin >2.0 mg/dl) or an elevated aminotransferase level (SGOT/SGPT > twice the upper normal limit). Chemotherapy: All patients received a regimen consisting of cisplatin, bleomycin and 5-flurouracil, hence making the chemotherapy regimen uniform in all the patients. 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 high dose regimen,patients were given 60mg/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 20 mg/m 2 each on three consecutive days. Cisplatin was administered as continuous iv infusion in a vac of dextrose-normal saline over 1 h. In addition, all patients received bleomycin 15 mg iv on first and fifth day and 5- fluorouracil 500 mg iv for five days as was required in their regimens.

BHATIA et al: ONDANSETRON VERSUS METOCLOPRAMIDE IN CISPLATIN-INDUCED DELAYED EMESIS Antiemetic regimens: Patients in groups I and III received metoclopramide 20 mg iv 30 min prior to each cisplatin administration followed by 20 mg metoclopramide orally eight hourly for five days after the last cisplatin administration. 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 five days. In groups III and IV, dexamethasone (8 mg iv 30 min prior to cisplatin administration) was added to the respective antiemetic regimens in ten patients each (Table I). Patients were withdrawn from the study if they had > 10 episodes of vomiting and given rescue medication according to the attending physician s discretion. Assessment: Only those patients who did not require antiemetic rescue medication during the acute phase (i.e., up to 24 h after the last cisplatin administration) were eligible to continue participation in the study for assessment of delayed emesis. The assessment period started 24 h after last cisplatin infusion and ended at midnight on day 5. Day 1 was defined as the day/days of cisplatin infusion. All patients were provided a daily diary card and asked to keep a record of the time of each emetic episode, their assessment of nausea and global satisfaction and the occurrence of any adverse effects. Additionally, a blinded observer, who was not involved in dispensing 185 of medication, independently recorded the same information daily. The same observer made all the assessments. The primary efficacy parameters were the number of emetic episodes on each study day and the severity of nausea. An emetic episode was defined as a single episode of vomiting (expulsion of stomach contents through mouth), a single episode of retching (an attempt to vomit but not productive of stomach contents) or any number continuous vomits and/or retches. Emetic episodes were by definition, separated by the absence of both vomiting and retching for at least one minute 20. The number of emetic episodes per day were used to define the daily treatment response as follows: complete response: no emetic episode: major response: 1-2 emetic episodes; minor response: 3-5 emetic episodes and failure: more than 5 emetic episodes 20. The severity of nausea was assessed by patients, independently from emesis, using a 4-point categoric scale (none: no nausea, mild: did not interfere with normal daily life; moderate: interfered with normal daily life and severe; bedridden due to nausea) 20,21. Nausea was also assessed on a 0-100 mm visual analogue scale (VAS 0-no nausea to 100-extreme nausea) 21. Nausea assessments were made at the end of each study day. Table I. Group-wise chemotherapy, antiemetic regimens in patients Groups Cisplatin dose Antiemetic regimen Number of patients (Symbols used) I (M+C-20) 20mg/m 2 X 3 days Metoclopramide 20 II (O+C-20) 20mg/m 2 X 3 days Ondansetron 20 IIIa(M+C-60) 60 mg/m 2 single dose Metoclopramide 10 IIIb(M+D+C-60) 60 mg/m 2 single dose Metoclopramide + Dexa 10 IVa(O+C-60) 60 mg/m 2 single dose Ondansetron 10 IVb(O+D+C-60) 60 mg/m 2 single dose Ondansetron + Dexa 10 Dexa, dexamethasone C-20, Patients receiving low dose cisplatin; C-60, Patients receiving high dose cisplatin M, Patients receiving metoclopramide prophylaxis; O, Patients receiving ondansetron prophylaxis M+D, Patients receiving metoclopramide and dexamethasone prophylaxis O+D, Patients receiving ondansetron and dexamethasone prophylaxis

186 INDIAN J MED RES, SEPTEMBER 2004 Effect of therapy on food intake was graded as 1- better than usual; 2- as usual; 3- could take some solid or 4- could take only liquid 22. Global satisfaction with control of nausea and vomiting was assessed by patients, independently from emesis, at the end of the study using a 100 mm VAS (0- not at all satisfied to 100 - totally satisfied) 20,21. QOL was assessed at baseline and at the end of treatment period using Rotterdam symptoms checklist 23. Separate analyses were performed for the psychological, physical and functional activity subscales. The results of each patient were expressed on a scale of 0-3 where 0 corresponded with not at all, 1 with a little, 2 with somewhat and 3 with very much on psychological and physical indices. In the functional activity index subscale, 0 corresponded with without help, 1 with without help with difficulty, 2 with only with help and 3 with unable. Blood samples were taken before the first dose of chemotherapy and at the end of the study to monitor complete cell count and biochemistry. Adverse events were elicited by general questioning of the patients on their daily visits as well as from patients daily records. Patient compliance was checked by daily questioning and by counting the number of tablets brought back each day. Statistical analysis: Analysis for the control of delayed emesis was based on the worst day outcomes through days 2-5. Quantitative data like number of episodes of vomiting were analyzed using Student s t-test. Graded data like intensity of nausea, magnitude of antiemetic response, QOL parameters and food intake scores were analyzed using Mann- Whitney U test. The limit of significance was set at P<0.05 in all cases. Results There was no significant difference in the patient profile of different groups (Table II). Table II. Characteristics of patients in 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 (N=20) (N=20) (N=20) (N=20) Age (yr)* 45.1±11.8 43.9±11.2 48.3±7.7 45.5±10.3 (21-65) (24-60) (35-60) (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 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 dexamethasone in cisplatin 60 mg/m 2 group O(±D)+C-60 : Ondansetron prophylaxis with or without dexamethasone in cisplatin 60 mg/m 2 group *Values are mean ± SD (range) # Alcohol intake: 1U= 150 ml wine/500ml beer/50ml distilled spirit Values are mean ± SD

BHATIA et al: ONDANSETRON VERSUS METOCLOPRAMIDE IN CISPLATIN-INDUCED DELAYED EMESIS 187 Table III. Effect of different antiemetic regimens on delayed emesis, nausea, food intake and patient global satisfaction Group N Vomiting Nausea Food intake scores Patient global (mean) satisfaction No. of No. of episodes VAS scores* Day 0 Day2-5* VAS scores emetic days of vomiting* (mm) (Mean ± SD) (mean) (mean ± SE) (Mean ± SD) M+C-20 20 1.7 2.8±0.8 28.2±25.3 2.0 2.0 75.7±15.2 O+C-20 20 0.95 1.3±0.5 16.0±20.1 2.2 2.3 86±14.6 M+C-60 10 4.0 8.1±1.0 67.0±10 2.0 2.7 45±12.4 O+C-60 10 3.2 4.8±1.4 34.0±20 2.1 2.5 65+16.3 M+D+C-60 10 3.0 5.0±1.2 34.5±24.7 2.1 2.1 68±16.1 O+D+C-60 10 2.1 3.0±0.8 22.5±18.5 2.1 2.1 78.5±17 Group symbols as in Table I. VAS, Visual analogue scale; N, number of patients *Based on worst day outcome; Number of days the patient experienced emesis Comparison among groups P values Groups compared No. of emetic days No. of episodes of Intensity of nausea Patient global vomiting satisfaction M+C-20 vs O+C-20 >0.05 >0.05 >0.05 <0.05* M+C-60 vs O+C-60 <0.05* >0.05 <0.02* <0.02* M+D+C-60 vs O+D+C-60 >0.05 >0.05 >0.05 >0.05 M+D+C-60 vs O+D+C-60 >0.05 <0.05* <0.02* <0.02* M+C-60 vs M+D+C-60 >0.05 >0.05 <0.02* <0.02* 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 >0.05 M+C-20 vs M+C-60 <0.002* <0.001* <0.002* <0.002* O+C-20 vs O+C-60 <0.002* <0.05* <0.02* <0.002* *Significant values M(±D)+C-60 : Metoclopramide prophylaxis with or without dexamethasone in cisplatin 60mg/m 2 group O(±D)+C-60 : Ondansetron prophylaxis with or without dexamethasone in cisplatin 60mg/m 2 group Delayed emesis: The pattern of delayed emesis was more or less similar with all antiemetic regimens i.e., the maximum intensity of delayed emesis was reached on second or third day. Very few patients experienced emesis till the fifth day and these were patients on high dose cisplatin regimen receiving metoclopramide prophylaxis. The number of emetic episodes on the worst day were dependent on the cisplatin regimen. More episodes were observed in patients on high dose regimen as compared to low dose regimen (Table III). In patients receiving the low dose regimen, complete suppression was achieved in 11 (55%) patients on ondansetron prophylaxis and 6 (30%) on metoclopramide prophylaxis (Fig.1). Though the antiemetic response of ondansetron was significantly superior to metoclopramide in high dose cisplatin regimen (P<0.05), none of the two antiemetics could completely suppress emesis in these patients. Dexamethasone significantly potentiated the antiemetic response of metoclopramide (P<0.02) and the response of the combination matched that of ondansetron (Table III). Nausea accompanying delayed emesis: Intensity of nausea in the delayed phase was greater in patients on high dose cisplatin regimen (Table III; Fig.2). Ondansetron and metoclopramide decreased the intensity in patients on low dose regimen but only ondansetron proved effective in case of patients on high dose cisplatin regimen. Dexamethasone significantly augmented efficacy of metoclopramide (P<0.02) and the combination matched the efficacy

188 INDIAN J MED RES, SEPTEMBER 2004 Antiemetic regimen* Fig.1. Antiemetic responses obtained with metoclopramide or ondansetron with or without dexamethasone. Foot note: *Group symbols as described in Table I. Antiemetic regimen* Fig.2. Intensity of nausea observed with metoclopramide or ondansetron with or without dexamethasone. Foot note: *Group symbols as described in Table I.

BHATIA et al: ONDANSETRON VERSUS METOCLOPRAMIDE IN CISPLATIN-INDUCED DELAYED EMESIS of ondansetron monotherapy in protection against nausea. Food intake: Over the five days of the study, there was no appreciable change in food intake of patients on low dose cisplatin regimen (Table III). However, in the patients on high dose regimen there was little deterioration of the scores but not of statistical significance. The deterioration was marginally greater in the metoclopramide group. Addition of dexamethasone prevented this deterioration. Quality of life (QOL): QOL scores were calculated separately for psychological, physical and functional subscales (Table IV). There was a tendency towards improvement in the psychological subscale in almost all the groups though no significant differences among the groups were seen. The indices that showed improvement were mainly anxiety, loneliness, worry and desperation about future. No consistent trend was seen in the physical subscale. The indices mainly affected were loss of appetite, feeling of dizziness, inability to sleep and loss of energy. Patients receiving high dose cisplatin showed deterioration irrespective of the primary antiemetic, but the addition of dexamethasone prevented the deterioration. The functional subscale remained unchanged in all the study groups. 189 Adverse effect profile: A total of 39 adverse events were reported by 20 patients (Table V). The incidence was thus 25 per cent. Seven out of 40 patients receiving ondansetron had constipation and five out 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. There was no significant change in any biochemical or haematological values of the patients from baseline. Patient global satisfaction: Patient satisfaction with the antiemetic therapy was elicited on last day of the study (Table III). In low dose cisplatin regimen, there was no statistically significant difference in global satisfaction in patients receiving metoclopramide or ondansetron. In high dose cisplatin regimen, patients receiving ondansetron prophylaxis were more satisfied with their antiemetic compared to those receiving metoclopramide (P<0.02). Addition of dexamethasone to both metoclopramide (P<0.05) and ondansetron (P=NS) improved patient satisfaction. Patient satisfaction with dexamethasone + metoclopramide combination matched that of ondansetron. Table IV. Effect of cisplatin based chemotherapy and antiemetics on quality of life scores in cancer patients Group* N Mean value of quality of life scores Psychological subscale Physical subscale Functional subscale Day 0 Day 5 Day 0 Day 5 Day 0 Day 5 M+C-20 20 1.1 1.0 1.2 1.0 1.5 1.5 O+C-20 20 2.1 1.8 1.2 1.2 2.4 2.4 M+C-60 10 2.3 1.6 1.7 2.2 1.9 1.9 O+C-60 10 2.9 2.9 1.9 2.2 1.0 1.0 M+D+C-60 10 2.7 1.8 1.9 1.5 2.8 2.8 O+D+C-60 10 0.7 0.4 1.7 1.6 2.1 2.1 *Group symbols as in Table I; N, Number of patients No statistically significant differences

190 INDIAN J MED RES, SEPTEMBER 2004 Table V. 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 Discussion There is paucity of studies comparing efficacy of a 5HT 3 antagonist containing regimen with the widely used metoclopramide monotherapy regimen as well as with mertoclopramide + dexamethasone combination in cisplatin induced delayed emesis in Indian patients. There is one Indian study by Advani et al 24 who have used a wide dosage range of cisplatin (100-180 mg/m 2 ) and a variety of chemotherapy regimens which makes the emetogenecity variable and hence difficult to interpret. In the present study efficacy and tolerability of ondansetron were compared with metoclopramide as well as the effect of addition of dexamethasone to the primary antiemetic in cisplatin-induced delayed emesis. Since emetogenicity of cisplatin is dose dependent 12,14, and efficacy of antiemetics may differ according to the intensity of emetogenic stimulus, it was decided to study the antiemetic efficacy of metoclopramide and ondansetron against a high dose regimen (60 mg/m 2 iv single dose) and a low dose regimen (20 mg/m 2 iv in 3 daily doses) of cisplatin. Assessment criteria taken for comparison of various antiemetics used in the present study were based on those already established in earlier studies 9,20-22. The maximum intensity of delayed emesis was observed on second or third day. These results support earlier observations made by Kris et al 3 who reported the highest incidence and severity of delayed emesis 48-72 h after cisplatin administration. High dose cisplatin regimen was more emetogenic than low dose cisplatin regimen. The dose dependency of delayed emesis has been reported earlier 12,14. Though ondansetron was superior to metoclopramide in control of delayed emesis, the difference did not reach statistical significance. Neither metoclopramide nor ondansetron could provide complete protection against delayed emesis in the high dose cisplatin regimen. Earlier workers 5,11,25,26 have reported conflicting results with ondansetron in delayed emesis. Kris et al 25 found that only 15 per cent of patients given cisplatin ( 100 mg/m 2 ) and ondansetron were free from delayed emesis. This was not different from a placebo response rate of 11 per cent found by the same authors in their earlier study 5. De Mulder et al 11 noted no difference in efficacy between ondansetron and metoclopramide in control of delayed emesis in patients receiving a median cisplatin dose of 75 mg/ m 2. Also in a trial conducted by the Italian group of antiemetic research 8, both ondanseton and metoclopramide offered similar protection from delayed emesis. Whereas, in case of cisplatin induced acute emesis, studies have reported protection rates with ondansetron monotherapy as high as 75 per cent with a dose of cisplatin in the range of 50-100 mg/ m 2,11. In our study 15 on cisplatin induced acute emesis, the protection rates with ondansetron and metoclopramide were 65 vs 30 per cent (P<0.02) in low dose cisplatin regimen and 20 per cent vs 0 per cent (P<0.02) in high dose cisplatin regimen, respectively.

BHATIA et al: ONDANSETRON VERSUS METOCLOPRAMIDE IN CISPLATIN-INDUCED DELAYED EMESIS Addition of dexamethasone improved the antiemetic response to metoclopramide. The improvement in response to ondansetron was also appreciable though not statistically significant. Potentiation of response to metoclopramide by dexamethasone has been reported earlier 11. In the present study, the combination of metoclopramide plus dexamethasone was found to be as efficacious as ondansetron alone in control of delayed emesis. This result is in contrast to that of Lim et al 27 who found ondansetron alone to be superior to the combination especially on days 2 and 4, despite using a higher dose of metoclopramide than in the present study. Potentiation of antiemetic regimens by addition of a single dose of dexamethasone reflects an antiemetic effect of dexamethasone beyond day 1, resulting in a lower incidence of delayed emesis. This effect of dexamethasone could also be a result of enhanced control of acute emesis. Better control of acute emesis has been found to be associated with milder delayed emesis 8. The suppression of nausea accompanying delayed emesis was parallel to the control of delayed emesis. Ondansetron was superior to metoclopramide in providing protection against nausea (protection i.e., mild/no nausea: (17 out of 20 patients) 85 per cent vs (14 out of 20 patients) 70 per cent against low dose regimen and (7 out of 10 patients) 70 per cent vs zero against high dose regimen. The results were similar to our earlier results 15 in cisplatin induced acute emesis. Dexamethasone potentiated the action of metoclopramide and ondansetron against delayed nausea. Combination of dexamethasone and metoclopramide achieved 70 per cent protection while dexamethasone plus ondansetron was effective in 80 per cent patients. The beneficial effect of dexamethasone in delayed nausea has been reported earlier by Roila and co-workers 6. We observed a direct but marginal association between emetic control and the food intake scores in different antiemetic regimens. While there was no deterioration of the scores in patients on low dose cisplatin regimen, patients on high dose regimen, especially the ones given metoclopramide prophylaxis, had more severe emesis and their food intake scores were lower. Comparable results have been reported 191 by Lee et al 22 who graded food intake scores by the same method as followed in the present study. Very few studies have been done to assess the role of antiemetics on QOL of cancer patients. We have used Rotterdam Symptom Checklist 23 to assess the effect of antiemetic regimens on QOL. However, since our study covered a period of only five to eight days, changes in QOL of patients were not very apparent over the study period. An earlier study 28 assessed the QOL in patients of breast cancer receiving cyclophosphamide over 6 courses of chemotherapy using the same questionnaire used in the present study and found that patients receiving ondansetron had better QOL compared to those receiving metoclopramide. Patient preference for ondansetron as opposed to metoclopramide was clear in both low and high dose cisplatin regimens. The present findings are different from some earlier reports 8,11 in which both ondansetron and metoclopramide were found to be equally satisfactory. This disparity could be due to the high doses of metoclopramide employed in the other studies. Patient satisfaction improved on the addition of dexamethasone to metoclopramide against high dose cisplatin regimen which confirms some earlier studies 29-31. Strum et al 32 have pointed out that subjective improvement occurs on addition of corticosteroids even when objective measures of emesis do not improve. All the antiemetics used in the present study were equally well tolerated. It was very difficult to differentiate the side effects due to chemotherapy from those due to antiemetics used since both were given concurrently. Constipation was reported in seven of the 40 patients receiving ondansetron. Constipation with ondansetron has been reported earlier 33. 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, though ondansetron proved superior to metoclopramide for control of delayed emesis, a substantial number of patients suffered from nausea and vomiting especially with high dose regimen. The

192 INDIAN J MED RES, SEPTEMBER 2004 efficacy of ondansetron in delayed emesis was not as good as that in acute emesis. The present findings support the contention that additional mechanisms, not involving 5HT 3 receptors may play a role in cisplatin induced delayed emesis 7,25. Another important finding is the similar efficacy of metoclopramide and dexamethasone combination to ondansetron monotherapy. In view of the lower cost of metoclopramide plus dexamethasone, this antiemetic regimen may be more affordable among Indian patients. However, further studies with larger sample size are needed to confirm these findings. References 1. Coates A, Abraham S, Kaye SB, Sowerbutts T, Frewin C, Fox RM, et al. On the receiving end-patient perception of the side effects of cancer chemotherapy. Eur J Cancer Clin Oncol 1983; 19 : 203-8. 2. Cubeddu LX, Hoffmann IS, Fuenmayor NT, Finn AL. Efficacy of ondansetron (GR 38032F) and the role of serotonin in cisplatin-induced nausea and vomiting. N Engl J Med 1990; 322 : 810-6. 3. Kris MG, Gralla RJ, Clark RA, Tyson LB, O Connell JP, Wertheim MS, et al. Incidence, course and severity of delayed nausea and vomiting following the administration of high dose cisplatin. J Clin Oncol 1985; 3 : 1379-84. 4. Gandara DR. Progress in the control of acute and delayed emesis induced by cisplatin. Eur J Cancer 1991; 27 (Suppl 1) : S9-11. 5. Kris MG, Gralla RJ, Tyson LB, Clark RA, Cirrincione C, Groshen S. Controlling delayed vomiting : double blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin. J Clin Oncol 1989; 7 : 108-14. 6. Roila F, Boschetti E, Tonato M, Basurto C, Bracarda S, Picciafuoco M, et al. Predictive factors of delayed emesis in cisplatin-treated patients and antiemetic activity and tolerability of metoclopramide or dexamethasone. A randomized single-blind study. Am J Clin Oncol 1991; 14 : 238-42. 7. Clark RA, Gralla RJ. Delayed emesis: A dilemma in antiemetic control. Support Care Cancer 1993; 1 : 182-5. 8. Ondansetron versus metoclopramide, both combined with dexamethasone, in the prevention of cisplatin-induced delayed emesis. The Italian group for Antiemetic Research. J Clin Oncol 1997; 15 : 124-30. 9. Navari RM, Madajewicz S, Anderson N, Tchekmedyian NS, Whaley W, Garewal H, et al. Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo. J Clin Oncol 1995; 13 : 2408-16. 10. Johnston D, Latreille J, Laberge F. Preventing nausea and vomiting during days 2-7 following high dose cisplatin chemotherapy. A study by the National Cancer Institute of Canada Clinical Trials Group. Proc Am Soc Clin Oncol 1995; 14 : 529-33. 11. de Mulder PH, Seynaeve C, Vermorken JB, van Liessum PA, Mols-Jevdevic S, Allman EL, et al. Ondansetron compared with high dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind crossover study. Ann Intern Med 1990; 113 : 834-40. 12. Passalacqua R, Cocconi G, Bella M, Monici L, Michiara M, Bandini N, et al. Double-blind, randomized trial for the control of delayed emesis in patients receiving cisplatin : comparison of placebo vs. adrenocorticotropic hormone (ACTH). Ann Oncol 1992; 3 : 481-5. 13. Shinkai T, Saijo N, Eguchi K, Sasaki Y, Tamura T, Fijiwara Y, et al. Control of cisplatin-induced delayed emesis with metoclopramide and dexamethasone: a randomized controlled trial. Jpn J Clin Oncol 1989; 19 : 40-4. 14. Gandara DR, Harvey WH, Monaghan GG, Perez EA, Stokes C, Bryson JC, et al. The delayed emesis syndrome from cisplatin: phase III evaluation of ondansetron versus placebo. Semin Oncol 1992; 19 (4, Suppl 10) : 67-71. 15. Bhatia A, Tripathi KD, Sharma M. Comparison of ondansetron with metoclopramide in prevention of acute emesis associated with low dose and high dose cisplatin chemotherapy. Indian J Med Res 2003; 118 : 33-41. 16. Roila F, Tonato M, Cognetti E, Cortesi F, Favalli G, Marangolo M, et al. Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 1991; 9 : 675-8. 17. Rosell R, Abad-Esteve A, Ribas-Mundo M, Moreno I. Evaluation of a combination of antiemetic regimen including IV high-dose metoclopramide, dexamethasone, and diphenhydramine in cisplatin-based chemotherapy regimens. Cancer Treat Rep 1985; 69 : 909-10. 18. Smyth JF, Coleman RE, Nicolson M, Gallmeier WM, Leonard RC, Cornbleet MA, et al. Does dexamethasone enhance control of acute cisplatin induced emesis by ondansetron? Br Med J 1991; 303 : 1423-6. 19. Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: Maclleod CM, editor. Evaluation of chemotherapeutic agents. New York: Columbia University Press; 1949 p.191-205. 20. Olver LN. Methodology in antiemetic trials. Oncology 1992; 49 : 269-72.

BHATIA et al: ONDANSETRON VERSUS METOCLOPRAMIDE IN CISPLATIN-INDUCED DELAYED EMESIS 193 21. Del Favero AD, Roila F, Basurto C, Minott V, Ballatori E, Patoia L, et al. Assessment of nausea. Eur J Clin Pharmacol 1990; 38 : 115-20. 22. Lee CW, Suh CW, Lee JS, Lee KH, Cho GY, Kim SW, et al. Ondansetron compared with ondansetron plus metoclopramide in the prevention of cisplatin induced emesis. J Korean Med Sci 1994; 9 : 369-75. 23. Kaasa S. Measurement of quality of life in clinical trials. Oncology 1992; 49 : 289-94. 24. Advani SH, Gopal R, Dhar AK, Lal HM, Cooverji ND. Comparative evaluation of the clinical efficacy and safety of ondansetron and metoclopramide in the prophylaxis of emesis induced by cancer chemotherapy regimens including cisplatin. J Assoc Physicians India 1996; 44 : 127-30. 25. Kris MG, Tyson LB, Clark RA, Gralla RJ. Oral ondansetron for the control of delayed emesis after cisplatin. Report of a phase II study and a review of completed trials to manage delayed emesis. Cancer 1992; 70 (4 Suppl 1) : 1012-6. 26. Hesketh P. Management of cisplatin-induced delayed emesis. Oncology 1996; 53(Suppl I) : 73-7. 27. Lim AK, Haron MR, Yap TM. Ondansetron against metoclopramide/dexamethasone - a comparative study. Med J Malaysia 1994; 49 : 231-8. 28. Soukop M, McQuade B, Hunter E, Stewart A, Kaye S, Cassidy J, et al. Ondansetron compared with metoclopramide in the control of emesis and quality of life during repeated chemotherapy for breast cancer. Oncology 1992; 49 : 295-304. 29.Kris MG, Gralla RJ, Tyson LB, Clark RA, Kelsen DP, Reilly LK, et al. Improved control of cisplatin-induced emesis with high-dose metoclopramide and with combinations of metoclopramide, dexamethasone, and diphenhydramine. Results of consecutive trials in 255 patients. Cancer 1985; 55 : 527-34. 30.Allan SG, Cornbleet MA, Warrington PS, Golland IM, Leonard RC, Smyth JN. Dexamethasone and high dose metoclopramide: efficacy in controlling cisplatin induced nausea and vomiting. BMJ 1984; 289 : 878-9. 31.Bruera ED, Roca E, Cedaro L, Chacon R, Estevez R. Improved control of chemotherapy-induced emesis by the addition of dexamethasone to metoclopramide in patients resistant to metoclopramide. Cancer Treat Rep 1983; 67 : 381-3. 32.Strum SB, McDermed JE, Liponi DF. High-dose intravenous metoclopramide versus combination highdose metoclopramide and intravenous dexamethasone in preventing cisplatin-induced nausea and emesis: a single-blind crossover comparison of antiemetic efficacy. J Clin Oncol 1985; 3 : 245-51. 33.Blackwell CP, Harding SM. The clinical pharmacology of ondansetron. Eur J Cancer Clin Oncol 1989; 25 (Suppl 1): S 21-4. Reprint requests: Dr Ashima Bhatia, D-1/B, 39-C, SFS DDA Flats, Janakpuri, New Delhi 110058, India e-mail: docbha@yahoo.com