Prevention of Cisplatin-Induced Emesis: A Double-Blind Multicenter Randomized Crossover Study Comparing Ondansetron and Ondansetron Plus Dexamethasone By Fausto Roila, Maurizio Tonato, Francesco Cognetti, Enrico Cortesi, Giuseppe Favalli, Maurizio Marangolo, Dino Amadori, Maria Angela Bella, Vattilio Gramazio, Donatella Donati, Enzo Ballatori, and Albano Del Favero Ondansetron (OND) is a new 5-HT3 receptor antagonist that gives complete protection from emesis/ nausea in approximately 50% of cisplatin (CDDP)treated patients. To evaluate if dexamethasone (DEX) added to OND increases antiemetic efficacy, we carried out a double-blind randomized crossover study to compare the antiemetic activity of OND with OND plus DEX. One hundred two chemotherapy-naive patients (44 women and 58 men) scheduled to receive CDDP chemotherapy at doses _ 50 mg/m 2 entered the study. Eighty-nine patients completed both cycles with the following results: complete protection from emesis/ nausea was obtained in 57/59 patients (64.0%/66.3%)
with OND and in 81/79 (91.0%/88.8%) with OND plus DEX (P = .0005/P = .0021). At the end of the study, 53%of the patients expressed a treatment preference, and of these, 74%chose OND plus DEX compared with 26% who preferred OND alone, a statistically significant difference (P < .003). Side effects were very mild and not significantly different between the two treatments. We conclude that OND plus DEX is more efficacious than OND in protecting patients from CDDPinduced emesis and nausea. J Clin Oncol 9:675-678. o 1991 by American Society of Clinical Oncology.
NAUSEA
exclusion were the presence of nausea and vomiting and the use of antiemetics in the 24 hours before CDDP chemotherapy, other etiologies for vomiting, severe concurrent illness other than neoplasia (ie, active peptic ulcer, severe diabetes, chronic liver disease), concurrent therapy with corticosteroids unless administered for the purposes of physiologic supplementation, or benzodiazepines except when given for night sedation. Patients with total serum bilirubin greater than twice the upper limit of normal and/or with serum transaminase greater than three times the upper limit of normal were also excluded, except when attributed to liver metastases. The standard prerequisites for admission to chemotherapy protocols (WBC > 4,000 mm', platelets > 120,000 mm3 , serum creatinine < 1.5 mg/mL, serum profile for electrolytes and enzymes) were observed. After providing fully informed consent, patients were randomly assigned, according to a centralized randomization list, to receive either 20 mg DEX in 50 mL of saline or, to assure blinding, 50 mL of placebo-saline as an intravenous infusion over 15 minutes, at 45 minutes before CDDP. Immediately thereafter, all patients received OND in a dose of 0.15 mg/kg made up to 50 mL of saline, as an intravenous infusion over 15 minutes. A further two intravenous doses of 0.15 mg/kg were given at 2-hour intervals.
and vomiting are troublesome side effects of cytotoxic drugs, especially cisplatin (CDDP).' Ondansetron (OND), a selective 5-HT3 antagonist, has been shown in pilot studies to give complete protection from vomiting in 30% to 55% of patients submitted to CDDP-containing chemotherapy and to be well tolerated." More recently, two double-blind crossover studies com-
paring OND with high-dose metoclopramide (MTC), the single most active antiemetic agent for the prevention of nausea and vomiting induced by CDDP, have shown that OND is more efficacious and less toxic than MTC. In particular, as OND is
devoid of dopamine antagonist activity, no extrapyramidal reactions were found. 8, 9
In highly emetic cytotoxic regimens including CDDP, significant improvement in efficacy has been achieved by adding corticosteroids to highdose MTC.1 ,'11 This prompted us to carry out a
double-blind crossover study aimed at evaluating the antiemetic activity and toxicity of DEX plus OND versus OND alone in patients receiving CDDP. PATIENTS AND METHODS From June 1989 to November 1989, all consecutive chemotherapy-naive adult patients admitted to 11 Italian oncologic centers for chemotherapeutic treatment with > 50 mg/m2 of CDDP alone or combined with other chemotherapeutic agents were included in the study. Criteria for
From the Medical Oncology Divisions of Perugia, Rome, Brescia, Ravenna, Forli,Parma,Ancona, and Ferrara,Italy. SubmittedJune 28, 1990; accepted September 24, 1990. Address reprint requests to Fausto Roila, MD, Division of Medical Oncology, Regional Hospital,06100 Perugia,Italy. © 1991 by American Society of Clinical Oncology. 0732-183X/91/0904-0005$3.00/0
Journalof Clinical Oncology, Vol 9, No 4 (April), 1991: pp 675-678
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675
676
ROILA ET AL
Approximately 15 minutes after the first infusion of OND was completed, the infusion of CDDP was started and administered for 20 minutes. The other chemotherapeutic agents were administered immediately after CDDP infusion. Food intake was not permitted until 8 hours after CDDP administration. Inpatients were monitored for nausea and vomiting in the hospital for 24 hours, while outpatients were monitored in the hospital for 8 hours and returned for the final assessment at 24 hours. At the second cycle of CDDP chemotherapy, administered at the same dose and schedule, patients were crossed to receive the alternative antiemetic regimen. Efficacy assessment of antiemetic treatment was based on the number of emetic episodes, the duration of emesis, and the intensity of nausea. An emetic episode was defined as a single vomit or retch or any number of continuous vomits or retches. Emetic episodes had to be separated from each other by the absence of vomiting or retching for at least 1 minute. The duration of emesis was calculated as the time between the beginning of CDDP infusion and the last episode of emesis. Baseline nausea was recorded using the following graded scale according to how it interfered with daily life: 0, none; 1, mild (did not interfere with normal daily life); 2, moderate (interfered with normal daily life); and 3, severe (patients bedridden due to nausea). The absence of emesis was defined as complete protection, one or two episodes as major protection, three to five episodes as minor protection, and more than five episodes as failure of treatment. Side effects were assessed by general questioning of the patients. Following the second cycle of chemotherapy the patient was asked to indicate his or her preference for one or the other of the antiemetic treatments. If a patient totally failed to respond (> five emetic episodes), then he or she could receive rescue medication. StatisticalAnalysis A log-linear model for binary crossover data was performed to analyze separately the complete protection from vomiting, from nausea, and from both nausea and vomiting. As suggested by Kenward and Jones, 12 two parameters were included in these models, the first measuring the dependence of the results at the second cycle against those observed at the first cycle and the second measuring the carry-over effect. The differences between antiemetic treatments regarding the mean number of vomiting episodes, the mean maximum intensity of nausea, and duration of emesis were analyzed by Wilcoxon's rank-sum test. Logistic linear models were used to analyze the complete response from nausea and vomiting at the first cycle (102 patients) considering as relevant prognostic factors sex, age, the dose of CDDP, antiemetic treatment, treatment modality (outpatients or inpatients), and alcohol intake (abstemious or drinker). The 2Ztest with Yates' correction was used to detect the significance of the differences between the treatments of the side effects and of the balance of the above mentioned prognostic factors between the two experimental sequences. The patients' preferences between the treatments and the effect on the preference period were analyzed by Prescott's test. All P values correspond to a two-tailed significance test.
RESULTS Efficacy A total of 102 patients entered the study; their characteristics are reported in Table 1. They are balanced between the two antiemetic sequences of treatments. Thirteen patients did not receive the second antiemetic treatment, leaving 89 who did receive both antiemetic regimens. Reasons for not completing the two cycles were as follows: death or
worsening of condition, seven patients; refusal of chemotherapy, four patients; others, two patients. The OND plus DEX regimen was significantly superior to OND alone for all evaluation parameters considered. Complete protection from vomiting was obtained in 57 of 89 (64.0%) treatments with OND and in 81 of 89 (91.0%) with OND plus DEX (P < .0005), the 95% confidence intervals Table 1. Characteristics of Patients Entering the Study OND Characteristic
Total Sex Men Women Age Average < 60 years > 60 years Treatment modality Outpatient Inpatient Average alcohol intake* Nonuser or < 7 U/wk 1-4 U/d > 4 U/d Type of cancer Genitourinary Lung Head and neck squamous Other Chemotherapy combined CDDP alone CDDP + MTX + ADR + VLB CDDP + CYC CDDP + VPI 6 CDDP + ADR + CYC CDDP + other Dose of CDDP (mg/m 2 ) Average < 90 > 90
No.
OND + DEX %
No.
%
48
47.1
54
52.9
26 22
54.2 45.8
32 22
59.3 40.7
60.8 16 32
33.3 66.7
59.2 26 28
48.1 51.9
36 12
75.0 25.0
39 15
72.2 27.8
28 19 1
58.3 36.6 2.1
30 18 6
55.6 33.3 11.1
22 13 7 6
45.9 27.1 14.6 12.4
23 11 10 9
44.5 20.4 18.5 16.6
13 10 6 8 3 8
27.1 20.8 12.5 16.7 6.2 16.7
12 7 6 9 7 13
22.2 13.0 11.1 16.6 13.0 24.1
78.9 31 17
64.6 35.4
74.1 38 16
70.4 29.6
Abbreviations: ADR, Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy); VLB, vinblastine; CYC, cyclophosphamide. U of alcohol equals one measure of spirit or one glass of wine or 250 mL/0.5 pints of beer.
"1
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ONDANSETRON IN CISPLATIN-INDUCED EMESIS
(CIs) being 54.0% to 74.0% and 85.1% to 96.9%, respectively. Major protection from vomiting (< two emetic episodes) was obtained in 15 (16.8%) further treatments with OND and in five (5.6%) with OND plus DEX, and minor protection (three to five emetic episodes) in another nine and three treatments, respectively. Failure (> six emetic episodes) of treatment was observed in eight cycles (9.0%) only, all with OND. Complete protection from nausea was achieved in 59 patients (66.3%) treated with OND and in 79 (88.8%) of those treated with OND plus DEX (P < .0025), the 95% CIs being 56.5% to 76.1% and 82.2% to 95.4%, respectively. Complete protection from both nausea and vomiting was also significantly greater in patients treated with OND plus DEX (72 of 89, 80.9%; 95% CI, 72.7 to 89.1%) than in those receiving OND alone (50 of 89, 56.2%; 95% CI, 45.9% to 66.5% [P < .0008]). The mean number of vomiting episodes (1.4 v 0.2; P < .0001), mean maximum intensity of nausea (0.5 v 0.1; P < .0001), and mean duration of emesis (355 minutes v 90 minutes; P < .0002) were also significantly decreased in OND plus DEX-treated patients compared with those receiving only OND. The relative efficacies of OND plus DEX and OND alone in controlling emesis and nausea during the first and second treatment period are shown in Table 2. The difference in efficacy of regimens was not influenced by the order in which treatments were given, and no carry-over effect was found. At the end of the study, 53% of patients expressed a treatment preference, and of these, 74% chose OND plus DEX compared with 26% of patients who preferred OND alone, a statistically significant difference (P < .003). The preference expressed by the patients was independent of the sequence of antiemetic treatment received. Table 2. Complete Response for Treatment Periods Period 1
Emesis OND OND + DEX Nausea OND OND + DEX
Period 2
Overall
No.
%
No.
%
No.
%
26/41 44/48
63.4 91.7
31/48 37/41
64.6 90.2
57/89 81/89
64.0 91.0
30/41 44/48
73.2 91.7
29/48 35/41
60.4 85.4
59/89 79/89
66.3 88.8
Table 3. Side Effects Treatment
OND
OND + DEX
No. of treatments Transominases elevation Diarrhea Headache Dry mouth Abdominal pain Slight sedation Nervousness Cutaneous flush Others Total
96 2 5 3 1 1 1 1 0 4 18
95 2 1 1 0 0 0 0 1 1 6
The multifactorial analysis at first cycle of chemotherapy (102 patients) confirmed that only "antiemetic" treatment significantly explained the variability of responses in terms of complete protection from nausea and vomiting. Tolerability Both antiemetic treatments were well tolerated and side effects were not significantly different between the two groups of patients (Table 3). Four patients (two treated with OND and two with OND plus DEX) presented an isolated elevation of transaminases after the chemotherapy and antiemetic treatment. The transaminases returned to the normal range in 10, 12, 20, and 41 days. DISCUSSION
Control of emesis in CDDP-treated patients is still unsatisfactory, and better prophylactic treatments are needed.13 The new 5-HT3 antagonist OND offers advantages over the usual antiemetic prophylactic drug (MTC) in terms of lower toxicity and greater efficacy.8 9' Corticosteroids can in-
crease the antiemetic efficacy of MTC,'" 1 and it is important to investigate whether an improvement can be obtained with a combination including one of the new 5-HT3 antagonists. This is the first randomized controlled trial that demonstrates that the addition of DEX to a 5-HT3 antagonist can significantly increase the antiemetic activity of the drug used alone. The better results obtained with the combination of the two drugs are substantial and clinically significant. The rate of complete protection from emesis compares favorably with that obtained with combined regimens of highdose MTC plus corticosteroids and diphenhydramine or lorazepam.'3 ,14One possible difficulty in interpreting the results of studies that use a
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ROILA ET AL
crossover design is that the results of treatment can differ between the first and second treatment periods of the study. However, in our study, no interaction was found between treatments and treatment periods in either analysis of emesis or nausea. The greater efficacy of the combination cannot be due to any imbalance in the characteristics of the population studied, which could influence the results of antiemetic treatment. In fact, the superiority of the two-drug regimen can be ascertained not only from the overall evaluation of the crossover data but also from the multifactorial analysis of data regarding the first cycle of antiemetic therapy received by the patients. Patients' preferences correlate well with the results of objective evaluation of nausea and vomiting and confirmed the superiority of the combination. The relatively large number of patients who expressed no preference (47%) between the two regimens is not surprising if one
takes into account that more than 50% of the patients achieved complete protection from both nausea and vomiting even when receiving OND alone. Tolerability of both treatments was very good, side effects were mild and similar to those observed in previous studies with OND alone. 29- A
trend that indicates an even better tolerability of combination treatment was observed. If the good safety profile of OND is confirmed in other large studies, this characteristic alone could add weight to the preferential use of 5-HT3 antagonists with respect to MTC administration, which is characterized by a significant incidence of extrapyramidal reactions. In conclusion, our study has shown the combination of OND plus DEX to give the highest rate of complete protection ever found in a large doubleblind comparative study on prophylactic therapy of CDDP-induced emesis, and was very well tolerated.
REFEREIs ICES 1. Anonymous: Vomiting and chemotherapy. Lancet 335: 265-266, 1990 (editorial) 2. Kris MG, Gralla RJ, Clark RA, et al: Dose-ranging evaluation of the serotonin antagonist GR-C507/75 (GR38032F) when used as an antiemetic in patients receiving anticancer chemotherapy. J Clin Oncol 6:659-662, 1988 3. Kris MG, Gralla RJ, Clark RA, et al: Phase II trials of the serotonin antagonist GR38032F for the control of vomiting caused by cisplatin. J Natl Cancer Inst 81:42-46, 1989 4. Grunberg SM, Stevenson LL, Russell CA, et al: Dose ranging phase I study of the serotonin antagonist GR38032F for prevention of cisplatin-induced nausea and vomiting. J Clin Oncol 7:1137-1141, 1989 5. Hesketh PJ, Murphy WK, Lester EP, et al: GR38032F (GR-C507/75): A novel compound effective in the prevention of acute cisplatin-induced emesis. J Clin Oncol 7:700705, 1989 6. Marty M, Droz JP, Pouillart P, et al: GR38032F, a 5HT3 receptor antagonist, in the prophylaxis of acute cisplatin-induced nausea and vomiting. Cancer Chemother Pharmacol 23:389-391, 1989 7. De Haan LD, De Mulder PHM, Beex LVAM, et al: The efficacy of GR38032F, an antagonist of 5-hydroxytryptamine-3 (5-HT3) in the prophylaxis of cisplatin (CDDP)-induced nausea and vomiting. Eur J Cancer Clin Oncol 24:1383-1384, 1988 8. De Mulder P, Seynaeve C, Van Liessum P, et al: A multicentre double-blind comparison of ondansetron (GR38032F) and metoclopramide in the prophylaxis of
acute emesis induced by cisplatin. Proc Eur Can Clin Oncol 1989 (abstr 0-0501) 9. Marty M, Pouillart P, Scholl S, et al: Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR38032F) with high-dose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 322:816-821, 1990 10. Roila F, Tonato M, Basurto C, et al: Antiemetic activity of high doses of metoclopramide combined with methylprednisolone versus metoclopramide alone in cisplatin-treated cancer patients: A randomized double-blind trial of the Italian Oncology Group for Clinical Research. J Clin Oncol 5:141-149, 1987 11. Kris MG, Gralla RJ, Tyson LB, 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 5:527-534, 1985 12. Kenward MG, Jones B: A log-linear model for binary crossover data. Applied Statistics 36:192-204, 1987 13. Roila F, Tonato M, Basurto C, et al: Protection from nausea and vomiting in cisplatin-treated patients: Highdose metoclopramide combined with methylprednisolone versus metoclopramide combined with dexamethasone and diphenhydramine: A study of the Italian Oncology Group for Clinical Research. J Clin Oncol 7:1693-1700, 1989 14. Kris MG, Gralla RJ, Clark RA, et al: Antiemetic control and prevention of side effects of anticancer therapy with lorazepam or diphenhydramine when used in combination with metoclopramide plus dexamethasone. A doubleblind, randomized trial. Cancer 60:2816-2822, 1987
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 6, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
with OND and in 81/79 (91.0%/88.8%) with OND plus DEX (P = .0005/P = .0021). At the end of the study, 53%of the patients expressed a treatment preference, and of these, 74%chose OND plus DEX compared with 26% who preferred OND alone, a statistically significant difference (P < .003). Side effects were very mild and not significantly different between the two treatments. We conclude that OND plus DEX is more efficacious than OND in protecting patients from CDDPinduced emesis and nausea. J Clin Oncol 9:675-678. o 1991 by American Society of Clinical Oncology.
NAUSEA
exclusion were the presence of nausea and vomiting and the use of antiemetics in the 24 hours before CDDP chemotherapy, other etiologies for vomiting, severe concurrent illness other than neoplasia (ie, active peptic ulcer, severe diabetes, chronic liver disease), concurrent therapy with corticosteroids unless administered for the purposes of physiologic supplementation, or benzodiazepines except when given for night sedation. Patients with total serum bilirubin greater than twice the upper limit of normal and/or with serum transaminase greater than three times the upper limit of normal were also excluded, except when attributed to liver metastases. The standard prerequisites for admission to chemotherapy protocols (WBC > 4,000 mm', platelets > 120,000 mm3 , serum creatinine < 1.5 mg/mL, serum profile for electrolytes and enzymes) were observed. After providing fully informed consent, patients were randomly assigned, according to a centralized randomization list, to receive either 20 mg DEX in 50 mL of saline or, to assure blinding, 50 mL of placebo-saline as an intravenous infusion over 15 minutes, at 45 minutes before CDDP. Immediately thereafter, all patients received OND in a dose of 0.15 mg/kg made up to 50 mL of saline, as an intravenous infusion over 15 minutes. A further two intravenous doses of 0.15 mg/kg were given at 2-hour intervals.
and vomiting are troublesome side effects of cytotoxic drugs, especially cisplatin (CDDP).' Ondansetron (OND), a selective 5-HT3 antagonist, has been shown in pilot studies to give complete protection from vomiting in 30% to 55% of patients submitted to CDDP-containing chemotherapy and to be well tolerated." More recently, two double-blind crossover studies com-
paring OND with high-dose metoclopramide (MTC), the single most active antiemetic agent for the prevention of nausea and vomiting induced by CDDP, have shown that OND is more efficacious and less toxic than MTC. In particular, as OND is
devoid of dopamine antagonist activity, no extrapyramidal reactions were found. 8, 9
In highly emetic cytotoxic regimens including CDDP, significant improvement in efficacy has been achieved by adding corticosteroids to highdose MTC.1 ,'11 This prompted us to carry out a
double-blind crossover study aimed at evaluating the antiemetic activity and toxicity of DEX plus OND versus OND alone in patients receiving CDDP. PATIENTS AND METHODS From June 1989 to November 1989, all consecutive chemotherapy-naive adult patients admitted to 11 Italian oncologic centers for chemotherapeutic treatment with > 50 mg/m2 of CDDP alone or combined with other chemotherapeutic agents were included in the study. Criteria for
From the Medical Oncology Divisions of Perugia, Rome, Brescia, Ravenna, Forli,Parma,Ancona, and Ferrara,Italy. SubmittedJune 28, 1990; accepted September 24, 1990. Address reprint requests to Fausto Roila, MD, Division of Medical Oncology, Regional Hospital,06100 Perugia,Italy. © 1991 by American Society of Clinical Oncology. 0732-183X/91/0904-0005$3.00/0
Journalof Clinical Oncology, Vol 9, No 4 (April), 1991: pp 675-678
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 6, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
675
676
ROILA ET AL
Approximately 15 minutes after the first infusion of OND was completed, the infusion of CDDP was started and administered for 20 minutes. The other chemotherapeutic agents were administered immediately after CDDP infusion. Food intake was not permitted until 8 hours after CDDP administration. Inpatients were monitored for nausea and vomiting in the hospital for 24 hours, while outpatients were monitored in the hospital for 8 hours and returned for the final assessment at 24 hours. At the second cycle of CDDP chemotherapy, administered at the same dose and schedule, patients were crossed to receive the alternative antiemetic regimen. Efficacy assessment of antiemetic treatment was based on the number of emetic episodes, the duration of emesis, and the intensity of nausea. An emetic episode was defined as a single vomit or retch or any number of continuous vomits or retches. Emetic episodes had to be separated from each other by the absence of vomiting or retching for at least 1 minute. The duration of emesis was calculated as the time between the beginning of CDDP infusion and the last episode of emesis. Baseline nausea was recorded using the following graded scale according to how it interfered with daily life: 0, none; 1, mild (did not interfere with normal daily life); 2, moderate (interfered with normal daily life); and 3, severe (patients bedridden due to nausea). The absence of emesis was defined as complete protection, one or two episodes as major protection, three to five episodes as minor protection, and more than five episodes as failure of treatment. Side effects were assessed by general questioning of the patients. Following the second cycle of chemotherapy the patient was asked to indicate his or her preference for one or the other of the antiemetic treatments. If a patient totally failed to respond (> five emetic episodes), then he or she could receive rescue medication. StatisticalAnalysis A log-linear model for binary crossover data was performed to analyze separately the complete protection from vomiting, from nausea, and from both nausea and vomiting. As suggested by Kenward and Jones, 12 two parameters were included in these models, the first measuring the dependence of the results at the second cycle against those observed at the first cycle and the second measuring the carry-over effect. The differences between antiemetic treatments regarding the mean number of vomiting episodes, the mean maximum intensity of nausea, and duration of emesis were analyzed by Wilcoxon's rank-sum test. Logistic linear models were used to analyze the complete response from nausea and vomiting at the first cycle (102 patients) considering as relevant prognostic factors sex, age, the dose of CDDP, antiemetic treatment, treatment modality (outpatients or inpatients), and alcohol intake (abstemious or drinker). The 2Ztest with Yates' correction was used to detect the significance of the differences between the treatments of the side effects and of the balance of the above mentioned prognostic factors between the two experimental sequences. The patients' preferences between the treatments and the effect on the preference period were analyzed by Prescott's test. All P values correspond to a two-tailed significance test.
RESULTS Efficacy A total of 102 patients entered the study; their characteristics are reported in Table 1. They are balanced between the two antiemetic sequences of treatments. Thirteen patients did not receive the second antiemetic treatment, leaving 89 who did receive both antiemetic regimens. Reasons for not completing the two cycles were as follows: death or
worsening of condition, seven patients; refusal of chemotherapy, four patients; others, two patients. The OND plus DEX regimen was significantly superior to OND alone for all evaluation parameters considered. Complete protection from vomiting was obtained in 57 of 89 (64.0%) treatments with OND and in 81 of 89 (91.0%) with OND plus DEX (P < .0005), the 95% confidence intervals Table 1. Characteristics of Patients Entering the Study OND Characteristic
Total Sex Men Women Age Average < 60 years > 60 years Treatment modality Outpatient Inpatient Average alcohol intake* Nonuser or < 7 U/wk 1-4 U/d > 4 U/d Type of cancer Genitourinary Lung Head and neck squamous Other Chemotherapy combined CDDP alone CDDP + MTX + ADR + VLB CDDP + CYC CDDP + VPI 6 CDDP + ADR + CYC CDDP + other Dose of CDDP (mg/m 2 ) Average < 90 > 90
No.
OND + DEX %
No.
%
48
47.1
54
52.9
26 22
54.2 45.8
32 22
59.3 40.7
60.8 16 32
33.3 66.7
59.2 26 28
48.1 51.9
36 12
75.0 25.0
39 15
72.2 27.8
28 19 1
58.3 36.6 2.1
30 18 6
55.6 33.3 11.1
22 13 7 6
45.9 27.1 14.6 12.4
23 11 10 9
44.5 20.4 18.5 16.6
13 10 6 8 3 8
27.1 20.8 12.5 16.7 6.2 16.7
12 7 6 9 7 13
22.2 13.0 11.1 16.6 13.0 24.1
78.9 31 17
64.6 35.4
74.1 38 16
70.4 29.6
Abbreviations: ADR, Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy); VLB, vinblastine; CYC, cyclophosphamide. U of alcohol equals one measure of spirit or one glass of wine or 250 mL/0.5 pints of beer.
"1
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ONDANSETRON IN CISPLATIN-INDUCED EMESIS
(CIs) being 54.0% to 74.0% and 85.1% to 96.9%, respectively. Major protection from vomiting (< two emetic episodes) was obtained in 15 (16.8%) further treatments with OND and in five (5.6%) with OND plus DEX, and minor protection (three to five emetic episodes) in another nine and three treatments, respectively. Failure (> six emetic episodes) of treatment was observed in eight cycles (9.0%) only, all with OND. Complete protection from nausea was achieved in 59 patients (66.3%) treated with OND and in 79 (88.8%) of those treated with OND plus DEX (P < .0025), the 95% CIs being 56.5% to 76.1% and 82.2% to 95.4%, respectively. Complete protection from both nausea and vomiting was also significantly greater in patients treated with OND plus DEX (72 of 89, 80.9%; 95% CI, 72.7 to 89.1%) than in those receiving OND alone (50 of 89, 56.2%; 95% CI, 45.9% to 66.5% [P < .0008]). The mean number of vomiting episodes (1.4 v 0.2; P < .0001), mean maximum intensity of nausea (0.5 v 0.1; P < .0001), and mean duration of emesis (355 minutes v 90 minutes; P < .0002) were also significantly decreased in OND plus DEX-treated patients compared with those receiving only OND. The relative efficacies of OND plus DEX and OND alone in controlling emesis and nausea during the first and second treatment period are shown in Table 2. The difference in efficacy of regimens was not influenced by the order in which treatments were given, and no carry-over effect was found. At the end of the study, 53% of patients expressed a treatment preference, and of these, 74% chose OND plus DEX compared with 26% of patients who preferred OND alone, a statistically significant difference (P < .003). The preference expressed by the patients was independent of the sequence of antiemetic treatment received. Table 2. Complete Response for Treatment Periods Period 1
Emesis OND OND + DEX Nausea OND OND + DEX
Period 2
Overall
No.
%
No.
%
No.
%
26/41 44/48
63.4 91.7
31/48 37/41
64.6 90.2
57/89 81/89
64.0 91.0
30/41 44/48
73.2 91.7
29/48 35/41
60.4 85.4
59/89 79/89
66.3 88.8
Table 3. Side Effects Treatment
OND
OND + DEX
No. of treatments Transominases elevation Diarrhea Headache Dry mouth Abdominal pain Slight sedation Nervousness Cutaneous flush Others Total
96 2 5 3 1 1 1 1 0 4 18
95 2 1 1 0 0 0 0 1 1 6
The multifactorial analysis at first cycle of chemotherapy (102 patients) confirmed that only "antiemetic" treatment significantly explained the variability of responses in terms of complete protection from nausea and vomiting. Tolerability Both antiemetic treatments were well tolerated and side effects were not significantly different between the two groups of patients (Table 3). Four patients (two treated with OND and two with OND plus DEX) presented an isolated elevation of transaminases after the chemotherapy and antiemetic treatment. The transaminases returned to the normal range in 10, 12, 20, and 41 days. DISCUSSION
Control of emesis in CDDP-treated patients is still unsatisfactory, and better prophylactic treatments are needed.13 The new 5-HT3 antagonist OND offers advantages over the usual antiemetic prophylactic drug (MTC) in terms of lower toxicity and greater efficacy.8 9' Corticosteroids can in-
crease the antiemetic efficacy of MTC,'" 1 and it is important to investigate whether an improvement can be obtained with a combination including one of the new 5-HT3 antagonists. This is the first randomized controlled trial that demonstrates that the addition of DEX to a 5-HT3 antagonist can significantly increase the antiemetic activity of the drug used alone. The better results obtained with the combination of the two drugs are substantial and clinically significant. The rate of complete protection from emesis compares favorably with that obtained with combined regimens of highdose MTC plus corticosteroids and diphenhydramine or lorazepam.'3 ,14One possible difficulty in interpreting the results of studies that use a
Downloaded from ascopubs.org by University of Newcastle Upon Tyne on April 6, 2019 from 128.240.208.034 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
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crossover design is that the results of treatment can differ between the first and second treatment periods of the study. However, in our study, no interaction was found between treatments and treatment periods in either analysis of emesis or nausea. The greater efficacy of the combination cannot be due to any imbalance in the characteristics of the population studied, which could influence the results of antiemetic treatment. In fact, the superiority of the two-drug regimen can be ascertained not only from the overall evaluation of the crossover data but also from the multifactorial analysis of data regarding the first cycle of antiemetic therapy received by the patients. Patients' preferences correlate well with the results of objective evaluation of nausea and vomiting and confirmed the superiority of the combination. The relatively large number of patients who expressed no preference (47%) between the two regimens is not surprising if one
takes into account that more than 50% of the patients achieved complete protection from both nausea and vomiting even when receiving OND alone. Tolerability of both treatments was very good, side effects were mild and similar to those observed in previous studies with OND alone. 29- A
trend that indicates an even better tolerability of combination treatment was observed. If the good safety profile of OND is confirmed in other large studies, this characteristic alone could add weight to the preferential use of 5-HT3 antagonists with respect to MTC administration, which is characterized by a significant incidence of extrapyramidal reactions. In conclusion, our study has shown the combination of OND plus DEX to give the highest rate of complete protection ever found in a large doubleblind comparative study on prophylactic therapy of CDDP-induced emesis, and was very well tolerated.
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