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Comparative efficacy of oral and intravenous granisetron for the prevention of acute chemotherapy-induced emesis
CLINICAL THERAPEUTICSVVOL. 18, NO. 4, 1996
Comparative Efficacy of Oral and Intravenous Granisetron for the Prevention of Acute Chemotherapy-Induced Emesis Edith A. Perez, MD Division of Hematology/Oncology, Mayo Clinic Jacksonville, Jacksonville, Florida
ABSTRACT Intravenous Shydroxytryptamines (5 HTs) receptor antagonists are now established antiemetics in the treatment of chemotherapy-induced emesis. For optimal convenience and acceptability, oral therapy is desirable. Retrospective comparisons indicate that oral granisetron may have an efficacy comparable with that of intravenous granisetron. Recent new data are available on the use of granisetron in the prophylaxis of acute emesis in randomized, double-masked trials. After moderately emetogenic chemotherapy, the optimal regimen appears to be 1 mg twice daily, although 2 mg once daily is equally effective. Oral granisetron is significantly superior to oral prochlotperazine. After high-dose cisplatin chemotherapy, oral granisetron is as effective as metoclopramide plus dexamethasone; the addition of dexamethasone further enhances its efficacy. Oral granisetron was well tol-
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erated in all these trials. Headache and constipation were the most common adverse events, as has been reported for other MIT, receptor antagonists. No randomized trials of oral-only tropisetron or dolasetron have yet been published.
INTRODUCTION The development of Shydroxytryptamine, (5-HT,) receptor antagonists as antiemetic agents followed the discovery that 5-HT, receptors mediate acute emesis,’ and the recognition that metoclopramide exerts its antiemetic effect via 5HT, receptor antagonism.2~3 It was quickly realized that 5-HT, receptor antagonists administered intravenously presented a distinct advantage over the more traditional agents used to treat chemotberapyinduced nausea and vomiting. The 5-HT, antagonists are at least as effective as conventional treatments and do not produce any of the extrapyramidal adverse events 0149-2918/96/$3.50
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associated with dopamine receptor inhibition.4 Antiemetic prophylaxis with intravenous 5-HT, receptor antagonists during chemotherapy is now well established.5,6 Whereas intravenous antiemetic agents can effectively control chemotherapyinduced emesis, oral therapy may be more convenient and acceptable to patients. An effective, oral 5-HT, receptor antagonist would allow administration in ambulatory and outpatient settings, which is particularly important for patients in whom the onset of emesis may be delayed, such as women receiving treatment with cyclophosphamide for breast cancer. Women are more prone to emesis than are men, as are younger patients7s8; in addition, emesis is more difficult to control in women.9 Outpatient administration would also reduce the requirements for medical resources. The convenience of an oral drug would benefit both patients and staff, translating into a reduction in the overall cost of chemotherapy and associated treatments.
ORAL GRANISETRON The efficacy of oral granisetron has been studied in four recently published, prospective, randomized, double-masked studies1&13 in patients receiving either moderately or highly emetogenic chemotherapy. This paper presents the results of these four studies and a retrospective literature comparison of oral versus intravenous granisetron. Selectingthe Correct Dose Three pilot studies of oral granisetron in patients receiving at least 50 mg/m2 of cisplatin suggested that the optimal dose is between 0.25 mg twice daily (BID) and 2.5 mg BID.14 A dose-finding study con-
ducted in 83 centers in 9 countries (8 in Europe and 1 in South Africa)‘O included 930 patients not previously treated with chemotherapy who were scheduled to receive moderately emetogenic regimens over a 7- or 1Cday period. The patients were randomized in a double-masked manner to one of four doses of oral granisetron: 0.25, 0.5, 1, or 2 mg BID. The study population was predominantly women (87.4%), but the four treatment groups were well matched for sex and other demographic variables. Granisetron was initially administered 1 hour before the start of chemotherapy and then every 12 hours for the duration of the study. Efficacy was evaluated during the first 24 hours (day 0, or the day of starting chemotherapy) and during days 1 to 6. The primary outcome measures were complete response (no vomiting, no more than mild nausea, no use of other antiemetics, and no withdrawal) and total control (no nausea or vomiting, no use of other antiemetics, and no withdrawal). On day 0 there was a significant association between complete response and the dose of oral granisetron (P = O.OOl), with the highest response achieved at a dose of 1 mg BID (Table I). The complete response rate on days 0 to 6 was also significantly higher with 1 mg BID (58.8%) than with either 0.25 mg BID (43.7%) or 0.5 mg BID (53.6%) (P < 0.009). The complete response rate with 2 mg BID was 54.1%. Similar results were obtained for total control. A dose of 2 mg BID offered no advantage over 1 mg BID for complete response or total control. The investigators concluded that oral granisetron was effective in the prophylaxis of acute emesis after moderately emetogenic chemotherapy, and that optimal efficacy was achieved at a dose of 1 mg BID.
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CLINICAL THERAPEUTICS”
Table I. Complete response rates and total control during the first 24 hours with each of four dosing regimens of oral granisetron in patients receiving moderately emetogenie chemotherapy.* Oral Graaisetron Dose (mg twice daily) 0.25 0.5 1.0 2.0
No. of Patients 229 235 233 233
No. (%) of Patients with Complete Response 140 (61.1) 165 (70.2)+ 189 (81.1)+* 168 (72.1)
No. (%) of Patients with Total Control 102 (44.5) 128 (54.5) 140 (60. I)+ 120 (51.5)
Complete response = no vomiting, nothing more severe than mild nausea, no use of other antiemetics, and no withdrawal from the study; total control = no nausea or vomiting, no use of other antiemetics, and no withdrawal from the study. *Data from Bleiberg et al.” +F’< 0.009 versus granisetron 0.25 mg twice daily. *P < 0.009 versus granisetron 0.5 mg twice daily.
At this dose, nausea and vomiting were well controlled in more than 80% of patients. A treatment benefit was shown up to day 6, but whether this finding reflects a real benefit of continued treatment during the 6 days or a carryover effect from better results on day 0 remains debatable.
Oral Granisetron Compared with Prochlolperazine A double-masked, parallel-group study” indicated that oral granisetron, 1 mg BID, is more efficacious in controlling acute emesis than the conventional antiemetic prochlorperazine, 10 mg BID given orally. The study enrolled 230 patients in 3.5 centers in the United States who were scheduled to receive moderately emetogenic chemotherapy. The most commonly used agents, either alone or in combination, were cyclophosphamide (8 1%), 5-fluorouracil (54%), doxorubicin (37%), and methotrexate (32%). The randomized treatment groups were comparable in mean age (58 to 59 years), sex (about 80%
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women), alcohol consumption (mean, 2.4 to 4.0 units/wk [ 1 unit of alcohol is equivalent to 50 mL of wine, 250 mL of beer, or 50 mL of spirits]), and primary diagnosis (about 60% breast cancer and 16% lung cancer). The antiemetic responses, particularly during the first 24 hours (day 0), favored granisetron for all outcome measures assessed. Total control (no emesis or nausea and no use of rescue antiemetics) was achieved on day 0 in 68 (57.6%) of 118 patients receiving granisetron, compared with 37 (33.3%) of 111 patients receiving prochlorperazine (P c 0.001) (Figure 1). With either antiemetic, total control was achieved in more men than women, but the difference between treatments was significant only for women (P = 0.002 in favor of granisetron). Similarly, a significantly greater complete response rate (no emesis, no more than mild nausea, no use of rescue antiemetics) was achieved on day 0 with granisetron (73.7%) than with prochlorperazine (41.0%) (P c 0.001). The treatment differences were signifi-
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0
Prochlorperazine
n Granisetron NS
P = 0.002
Ii
1
i
Combined
ii
Women
Men
Figure 1. Proportion of patients achieving total control of nausea and vomiting in a double-masked comparison of oral granisetron and oral prochlorperazine. Reprinted, with permission, from Hesketh et al.” cant for both men (92.3% vs 61.1%; P = 0.013) and women (68.5% vs 37.6%; P < 0.001). The complete response rate, but not total control, over 7 days was significantly better with granisetron (46.6%) than with prochlorperazine (31.5%) (P = 0.033). For day 0, a significantly greater percentage of patients receiving granisetron compared with prochlorperazine had no emesis (82% vs 48%; P c O.OOl), no nausea (58% vs 35%; P < O.OOl), and did not take rescue antiemetics (21% vs 6%; P = 0.001). It was concluded that oral granisetron, at a dose of 1 mg BID, was significantly superior to oral prochlorperazine in controlling acute nausea and vomiting in patients treated with moderately emetogenic chemotherapy regimens consisting primarily of cyclophosphamide and carboplatin. The treatment benefit was apparent for up to 7 days of follow-up therapy, although again it is not clear whether this is a true benefit or a carryover effect from better control on day 0.
Optimizing Oral Therapy As stated, recent findings have shown that oral granisetron (1 mg BID) is an effective antiemetic. lo The feasibility of modifying this regimen to a once-daily dose of 2 mg of oral granisetron has been investigated in a randomized, doublemasked, parallel-group trial involving 64 centers in the United States.12 Of 700 chemotherapy-naive adult patients randomized to treatment (201 men, 499 women), 3 did not receive chemotherapy and were excluded from the analysis of efficacy. A total of 697 patients, among whom the most common malignancy was breast cancer, received both study drug and chemotherapy and were included in the intent-to-treat analysis of the data. The cytostatic agents and doses varied, but the most commonly used-either singly or in combination-were cyclophosphamide (73.7%), doxorubicin (50.4%) and 5-fluorouracil (38.7%); carboplatin, methotrexate, etoposide, vincristine, and cis-
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CLINICAL THERAPEUTICS”
Table II. Outcome measures during the first 24 hours with two different oral dosing regimens of granisetron in patients receiving moderately emetogenic chemotherapy.* No. (%) of Patients Responding
Total control No vomiting No nausea No rescue antiemetics
Granisetron, 2 mg Once Daily (n = 343)
Granisetron, 1 mg Twice Daily (n = 354)
173 (50.4) 263 (76.7) 180 (52.5) 270 (78.7)
179 (50.6) 290 (81.9) 182 (51.4) 284 (80.2)
Total control = no nausea or vomiting, no use of other antiemetics, and no withdrawal from the study. ‘Data from Ettinger et a1.12
platin were each given to 11% to 17% of patients. Granisetron was given 1 hour before chemotherapy in all patients, and then 12 hours later in the group receiving 1 mg BID; the group receiving 2 mg once daily received placebo at this time. During the 24 hours after administration of chemotherapy, no differences between the two groups could be detected in any of the outcome measures (Table II). Total control (no nausea, no vomiting, and no use of rescue antiemetics) was achieved in at least 50% of all patients; about 52% had no nausea, and more than 76% had no vomiting. The use of rescue antiemetic medication was similar to the incidence of vomiting. Granisetron appeared to be more effective in men than in women, although no statistical comparisons were performed. Analysis of subsets of patients showed no difference in response with different cytostatic regimens.15 It was concluded that a once-daily dose of oral granisetron (2 mg) was as effective as 1 mg BID in preventing nausea and vomiting associated with moderately emetogenic chemotherapy.
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Combination Antiemetic Therapy The addition of a corticosteroid is known to enhance the antiemetic ef&acy of conventional antiemetic regimens,16,17 ondansetron,18 and intravenous granisetron.19*20 A double-masked, randomized study investigated the efficacy of oral granisetron against acute emesis after cisplatin-based chemotherapy, and the additive effect of a single dose of intravenous dexamethasone. The outcomes were compared with results achieved with a combination of intravenous metoclopramide and dexamethasone. l3 A total of 357 chemotherapy-naive patients from 30 centers in Europe and South Africa were assigned to one of three antiemetic treatment regimens: oral granisetron alone, 1 mg BID for 7 days, starting 1 hour before administration of cisplatin; oral granisetron, given as in the first group, plus a single intravenous infusion of dexamethasone, 12 mg, 5 minutes before the start of cisplatin administration; or dexamethasone given in the same way plus intravenous metoclo-
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pramide, as a 3-mg/kg loading dose infused over 30 minutes and completed 5 minutes before cisplatin administration, with a 4-mg/kg continuous infusion for 8 hours commencing at the same time as cisplatin (total metoclopramide dose of 7 mg), and oral metoclopramide, 10 mg three times daily, for an additional 6 days. All the patients received at least 50 mg/m2 of cisplatin (mean dose, 81 mg/m2). The treatment groups were well matched for demographic variables and prognostic factors; overall, 60% were women, and the mean age was 54.7 years. During the first 24 hours (day 0, the day of cisplatin administration), the combination of granisetron plus dexamethasone gave total control (no nausea or vomiting, no use of rescue antiemetics, no withdrawal) in a significantly greater proportion of patients than did metoclopramide plus dexamethasone (54.7% vs 37.2%, respectively; P = 0.007) (Table III). There was no significant difference in total control between patients receiving combination therapy with granisetron and
dexamethasone and patients receiving granisetron alone (54.7% vs 43.7%, respectively). More patients taking the granisetron combination had no nausea and no vomiting, although the differences did not reach significance. Oral granisetron alone gave results similar to metoclopramide plus dexamethasone. Granisetron combination therapy was associated with a significant delay in the appearance of symptoms on day 0 compared with metoclopramide plus dexamethasone (P = 0.0068 for vomiting; P = 0.0012 for nausea) (Figure 2). Interestingly, there was a marked difference between treatment regimens in the group of patients younger than 45 years of age: 15.4% total control on day 0 with metoclopramide plus dexamethasone, compared with 65.2% with granisetron plus dexamethasone (P = 0.01). Overall, women responded less well than men, particularly in the granisetron groups. There were no significant differences between any of the treatment groups for the late phase (days 1 to 3 and days 4 to 6) of emesis.
Table III. Proportion of patients with total control, no nausea, and no vomiting first 24 hours with three different antiemetic regimens.*
during the
Percentage of Patients Responding
Total control No nausea No vomiting
Oral Granisetron plus Single-Dose Intravenous Dexamethasone (n = 117)
High-Dose Metoclopramide plus Dexamethasone (n = 121)
Oral Granisetron (n = 119)
37.2 38.8
43.7 44.5
54.7t 57.3
52.1
56.3
65.8
Total control = no nausea or vomiting, no use of other antiemetics, ‘Data from Heron et aLI tP = 0.007 versus metoclopramide plus dexamethasone.
and no withdrawal
from the study.
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CLINICAL THERAF'EUTICS"
. .. .. ... GRANIDEX
I5 0.0
-
GRAN
*-I---
MET/DEX
P= 0.0068 GRANIDEX vs METIDEX
0
3
6
9
12
15
18
21
24
Time after Cisplatin Therapy (h) Time to first episode of vomiting after cisplatin-based chemotherapy in patients receiving oral granisetron (GRAN), oral granisetron plus dexamethasone (DEX), or metoclopramide (MET) plus dexamethasone. Reprinted, with permission, from Heron et a1.13 The authors concluded that oral granisetron as a single agent was as effective as high-dose metoclopramide plus dexamethasone in preventing cisplatininduced nausea and vomiting, and that oral granisetron in combination with a corticosteroid provided control of symptoms superior to that achieved with conventional antiemetic regimens.
Comparison of Oral and Intravenous Granisetron Despite the fact that there are no published data that directly compare an oral 5-I-H, receptor antagonist with the same agent given intravenously, or an oral 5HT, receptor antagonist with an intravenous preparation of a different agent, the results of the current analysis allow for indirect, retrospective comparisons of the efficacy of oral and intravenous granisetron. Such indirect comparisons of oral and intravenous granisetron are sup-
584
ported by the results of direct comparisons in an experimental study in the ferret, which has emerged as an appropriate animal model for both the elucidation of the emetic pathway and the identification of antiemetic mechanisms. The ferret produces an emetic response to the same compounds that induce emesis in humans. Oral granisetron was as effective and long-lasting as intravenous granisetron in preventing emesis induced in conscious ferrets by intravenous injection of cisplatin. In addition, there was a trend indicating that the oral drug was more potent than the intravenous drug.21 The first indirect comparison is possible between the results of a study of oral granisetron (1 mg BID)13 and results of five studies (mostly European) with the intravenous formulation22-26 in patients receiving high-dose cisplatin chemotherapy (mean dose, approximately 80 mg/m*). The mean overall complete response rate (no vomiting and no more than
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mild nausea) during the first 24 hours in patients receiving intravenous granisetron, 40 ug/kg, was 62% (range, 44% to 93%), compared with 52% total control (no vomiting or nausea) in the oral study. This 10% difference can probably be accounted for by the higher proportion of women in the oral study. Further evidence of the similar efficacy of oral and intravenous granisetron derives from a trial in which intravenous granisetron was compared with a regimen identical to that used in the oral study.2’ Complete control was achieved in 52% of patients receiving either oral granisetron or metoclopramide plus dexamethasone in the same study,13 and in 70% of patients receiving intravenous granisetron compared with 67% given the same metoclopramide plus dexamethasone regimen. 23Although the overall response rates differed in the two studies, the similar relative efficacy of oral and intravenous formulations of granisetron in comparison with an identical conventional antiemetic regimen in both studies suggests that the two formulations will be equally effective in patients receiving high-dose cisplatin.
ORAL ONDANSETRON AND OTHER 5HT, RECEPTOR ANTAGONISTS The only other 5-HT, receptor antagonist that has been investigated in an oral-only regimen is ondansetron. In many of the clinical trials, however, ondansetron was not compared with other antiemetics or was compared only with placebo, which does not represent the standard of care for preventing chemotherapy-induced emesis. 27 In addition, an initial intravenous dose was commonly used, making it difficult to separate the intravenous and oral effects. No clear evidence can be found in
these trials that oral ondansetron is superior to conventional antiemetic regimens.27 A search of the literature, however, reveals 10 trials that assessed the effectiveness of oral ondansetron used alone for control of acute emesis (Table IV). Three of these trials were uncontrolled,28-30 two were placebo controlled,31,32 and two compared ondansetron alone with combinations of ondansetron plus dexametbasonei8 or ondansetron plus the dopamine antagonist metopimazine. 33 The combination therapies showed superior efficacy. The remaining three trials compared oral ondansetron used as a single agent with conventional antiemetic regimens3k36 and showed it to be approximately equal in efficacy to metoclopramide. Indeed, one of these trials showed the combination of dexamethasone and metoclopramide to be superior to oral ondansetron.36 Nine of the 10 trials of oral ondansetron for the prevention of acute emesis involved patients receiving moderately emetogenic chemotherapy. In the one study that enrolled patients due to receive cisplatin chemotherapy,18 complete control of acute emesis (during the first 24 to 48 hours after cisplatin) was achieved in only 7% of patients given oral ondansetron alone, although an additional 22% reported only one or two episodes of emesis. Despite oral ondansetron being given at a dose of 8 mg three times daily, 78% of the patients reported moderate or severe nausea in the 24 to 48 hours after cisplatin. Conclusions are difficult to draw, however, because this study was small, and cisplatin was administered on day 4 of chemotherapy, following other agents. No other studies of oral ondansetron for the prevention of cisplatin-induced acute emesis are available for review.
585
CLINICAL THERAPEUTICS**
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Few clinical studies of tropisetron have been published, and all of them involve administration of the antiemetic either intravenously or via a combination of intravenous and oral routes. Data from randomized trials of the efficacy of oral-only tropisetron given together with the investigational 5-HT, receptor antagonist dolasetron are not yet available.
TOLERABILITY OF ORAL 5HT, RECEPTOR ANTAGONISTS Antiemetic agents are administered in conjunction with cytotoxic drugs, and so assessment of their tolerability is complicated. Nevertheless, oral 5-HT, receptor antagonists, either alone or in combination with dexamethasone, appear to be well tolerated. The most common adverse events reported in the studies of oral granisetron were headache (12.8% to 36.1%) and constipation (19.8% to 31.1%)‘@‘3; similar findings have been reported with ondansetron.18*29,30,32 These findings are similar to the reported incidence of headache following intravenous granisetron.23-26 The incidence of constipation may be slightly higher with oral granisetron, which probably reflects the repeated administration of the oral drug. 37 The incidence of adverse events was not increased at higher doses of oral granisetron, and few patients required additional treatment with other antiemetics.‘O Addition of dexamethasone to oral granisetron or ondansetron reduced the incidence of headache from 20% to 13%13 and from 25% to 13%,18 respectively. Headache (22%) and constipation (11%) were also the most commonly reported adverse events after treatment with tropisetron.38
CONCLUSIONS The data obtained from the trials with oral granisetron support the conclusion that some oral antiemetic agents can match the efficacy of intravenous regimens for the prevention of chemotherapy-induced emesis. This finding is applicable to situations in which patients receive either moderately or highly emetogenic chemotherapy. Specifically, these data indicate that oral granisetron is as effective as intravenous granisetron and can improve on the efficacy of conventional antiemetic regimens. Oral granisetron, given as a single agent, has been shown to provide antiemetic control as effective as that obtained with high-dose metoclopramide plus dexametbasone for patients receiving moderate-to-high doses of cisplatin. In addition, given together with dexamethasone, oral granisetron provides protection superior to that of conventional antiemetic regimens against cisplatin-induced emesis. Oral granisetron demonstrated improved efficacy when compared with prochlorperazine in patients receiving moderately emetogenic chemotherapy. Moreover, as with intravenous graniseu-on, oral granisetron is as effective when administered once daily as a single dose of 2 mg, given 1 hour before the start of chemotherapy, as when given two times a day in a dose of 1 mg. Randomized trials comparing oral ondansetron with conventional antiemetics have essentially shown similar efficacy in prevention of emesis after a moderate challenge. No adequate trial has been performed to compare the efficacy of oral ondansetron with that of intravenous agents in patients receiving cisplatinbased chemotherapy.
587
CLINICAL THERAPEUTICSm
The results of trials using other 5-HT, receptor antagonists and direct comparisons of intravenous ondansetron and oral granisetron for moderately and highly emetogenic chemotherapy are eagerly awaited.
5. Bunce K, Tyers M, Beranek P. Clinical evaluation of 5-HT, receptor antagonists as anti-emetics. Trends Pharmacol Sci. 1991;12:4U8.
ACKNOWLEDGMENT
7. Soukop M, McQuade B, Hunter E, et al. Ondansetron compared with metoclopramide in the control of emesis and quality of life during repeated chemotherapy for breast cancer. Oncology (Switzerland). 1992;49:295-304.
The data given in this paper were presented in part at a satellite symposium at the 19th European Society of Medical Oncology, Lisbon, Portugal, November 1994.
correspondence to: Edith A. Perez, MD, Division of Hematology/ Oncology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. Address
REFERENCES Grunberg SM. Potential for combination therapy with the new antiserotonergic agents. Eur J Cancer. 1993;29A(Suppl l):S39-s41. Gralla RJ, Itri LM, Pisko SE, et al. Antiemetic efficacy of high-dose metoclopramide: Randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. NEJM. 1981;305:905-909. Miner WD, Sanger GJ. Inhibition of cisplatin-induced vomiting by selective 5hydroxytryptamine M-receptor antagonism. Br J Pharmacol. 1986;88:497-499. Merrifield KR, Chafee BJ. Recent advances in the management of nausea and vomiting caused by antineoplastic agents. Clin Pharm. 1989;8:187-199.
6. Smyth JF. New directions for anti-emetic research. Ann Oncol. 1994;5:569-570.
8. 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. 1987;5:141-149. 9. Tonato M, Roila F, Del Favero A. Methodology of antiemetic trials: A review. Ann Oncol. 1991;2:107-114. 10. Bleiberg HH, Spielmann M, Falkson G, Romain D. Antiemetic treatment with oral granisetron in patients receiving moderately emetogenic chemotherapy: A doseranging study. Clin Thel: 1995;17:38-51. 11. Hesketh P, Burris H, Cohn J, et al. A double-blind comparison of the efficacy and safety of oral granisetron with oral prochlorperazine in preventing nausea and emesis in patients receiving moderately emetogenic chemotherapy. Cancer J. In press. 12. Ettinger D, Eisenberg P, Fitts D, et al. A double-blind comparison of the efficacy of two dose regimens of oral granisetron in preventing acute emesis in patients receiving moderately emetogenic chemotherapy. Cancel: 1996;78: 144-15 1.
.A. PEREZ
13. Heron JF, Goedhals L, Jordaan JP, et al. Oral granisetron alone and in combination with dexamethasone: A double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis. Ann Oncol. 1994;5:579-584.
21. Marr HE, Davey PT, Boyle EA, Blower PR. Further studies of the antiemetic activity of granisetron against whole body X-irradiation or cisplatin-induced emesis in the ferret. Pharmacology. 1994;48: 283-292.
14. Hacking A, on behalf of the Granisetron Study Group. Oral granisetron-simple and effective: A preliminary report. Eur J Cancel: 1992;28A(Suppl l):S28-S32.
22. Cupissol DR, Serrou B, Caubel M. The efficacy of granisetron as a prophylactic anti-emetic and intervention agent in highdose cisplatin-induced emesis. Eur J Cancer. 1990;26(Suppl l):S23S27.
15. Johnsonbaugh RE, Mason BA, Friedman CJ, Fitts D. Oral granisetron is an effective anti-emetic in patients receiving moderately emetogenic chemotherapy. Proc Am Sot Clin Oncol. 1994;13:437. Abstract.
23. Chevallier B, on behalf of the Granisetron Study Group. The control of acute cisplatin-induced emesis-a comparative study of granisetron and a combination regimen of metoclopramide and dexamethasone. Br J Cancel: 1993;68:176-180.
16. Aapro MS. Controlling emesis related to cancer therapy. Eur J Cancer. 1991;27: 356-361. 17. Seynaeve C, De Mulder PHM, Verweij J, Gralla RJ. Controlling cancer chemotherapy-induced emesis. Pharm Weekbl Sci. 1991;13:189-197. 18. Smith DB, Newlands ES, Rustin GJS, et al. Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatincontaining chemotherapy. Lancer. 1991; 338:487-490. 19. Latreille J, Stewart D, Laberge F, et al. Dexametbasone improves the efficacy of granisetron in the first 24 hours following high dose cisplatin chemotherapy. Proc Am Sot Clin Oncol. 1993;12:133. Abstract. 20. Carmichael J, Bessel1 E, Harris AL, et al. Comparison of granisetron alone and granisetron plus dexamethasone in the prophylaxis of cytotoxic-induced emesis. Br J Cunce,: 1994;70:1161-1164.
24. Navari RM, Kaplan HG, Gralla RJ, et al. Efficacy and safety of granisetron, a highly selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin. J Clin Oncol. 1994;12:22042210. 25. Riviere A, on behalf of the Granisetron Study Group. Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. Br J Cancer 1994;69:967-971. 26. Soukop M, on behalf of the Granisetron Study Group. A dose-finding study of granisetron, a novel antiemetic, in patients receiving high-dose cisplatin. Support Cure Cancel: 1994;2:177-183. 27. Cooke CE, Mehra IV. Oral ondansetron for preventing nausea and vomiting. Am J Hosp Pharm. 1994;51:762-771. 28. Marschner NW, Adler M, Jaenicke F, et al. Langzeitergebnisse der antiemetischen Effectivimt des 5-HTs-Antagonisten Ondansetron. Onkologie. 1990;13:313-315.
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29. Campora E, Oliva C, Mammoliti S, et al. Oral ondansetron (GR 38032F) for the control of CMFinduced emesis in the outpatient. Breast Cancer Res Treat. 1991;19: 129-132. 30. Rosso R, Campora E, Cetto G, et al. Oral ondansetron (GR 38032F) for the control of acute and delayed cyclophosphamideinduced emesis. Anticancer Res. 199 1; 11: 937-940. 31. Beck TM, Ciociola AA, Jones SE, et al. Efftcacy of oral ondansetron in the prevention of emesis in outpatients receiving cyclophosphamide-based chemotherapy. Ann Intern Med. 1993;118:407-413. 32. Cubeddu LX, Pendergrass K, Ryan T, et al. Efficacy of oral ondansetron, a selective antagonist of 5-HT, receptors, in the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapies. Am J Clin Oncol Cancer Clin TriaZs. 1994;17:137-146. 33. Herrstedt J, Sigsgaard T, Boesgaard M, et al. Ondansetron plus metopimazine compared with ondansetron alone in patients receiving moderately emetogenic chemotherapy. NEJM. 1993;328:1076-1080.
590
34. Fraschini G, Ciociolo A, Esparza L, et al. Evaluation of three oral dosages of ondansetron in the prevention of nausea and emesis associated with cyclophosphamide-doxorubicin chemotherapy. J Clin Oncol. 1991;9:1268-1274. 35. Marschner NW, Adler M, Nagel GA, et al. Double-blind randomised trial of the antiemetic efficacy and safety of ondansetron and metoclopramide in advanced breast cancer patients treated with epirubicin and cyclophosphamide. Eur J Cancer: 1991;27:1137-1140. 36. Levitt M, Warr D, Yelle L, et al. Ondansetron compared with dexamethasone and metoclopramide as antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotrexate and fluorouracil. NEJM. 1993;328:1081-1084. 37. Yarker YIE, McTavish D. Granisetron. An update of its therapeutic use in nausea and vomiting induced by antineoplastic therapy. Drugs. 1994;48:761-793. 38. De Bruijn KH. Tropisetron: A review of clinical experience. Drugs. 1992;43(Suppl 3):11-22.
Comparative Efficacy of Oral and Intravenous Granisetron for the Prevention of Acute Chemotherapy-Induced Emesis Edith A. Perez, MD Division of Hematology/Oncology, Mayo Clinic Jacksonville, Jacksonville, Florida
ABSTRACT Intravenous Shydroxytryptamines (5 HTs) receptor antagonists are now established antiemetics in the treatment of chemotherapy-induced emesis. For optimal convenience and acceptability, oral therapy is desirable. Retrospective comparisons indicate that oral granisetron may have an efficacy comparable with that of intravenous granisetron. Recent new data are available on the use of granisetron in the prophylaxis of acute emesis in randomized, double-masked trials. After moderately emetogenic chemotherapy, the optimal regimen appears to be 1 mg twice daily, although 2 mg once daily is equally effective. Oral granisetron is significantly superior to oral prochlotperazine. After high-dose cisplatin chemotherapy, oral granisetron is as effective as metoclopramide plus dexamethasone; the addition of dexamethasone further enhances its efficacy. Oral granisetron was well tol-
578
erated in all these trials. Headache and constipation were the most common adverse events, as has been reported for other MIT, receptor antagonists. No randomized trials of oral-only tropisetron or dolasetron have yet been published.
INTRODUCTION The development of Shydroxytryptamine, (5-HT,) receptor antagonists as antiemetic agents followed the discovery that 5-HT, receptors mediate acute emesis,’ and the recognition that metoclopramide exerts its antiemetic effect via 5HT, receptor antagonism.2~3 It was quickly realized that 5-HT, receptor antagonists administered intravenously presented a distinct advantage over the more traditional agents used to treat chemotberapyinduced nausea and vomiting. The 5-HT, antagonists are at least as effective as conventional treatments and do not produce any of the extrapyramidal adverse events 0149-2918/96/$3.50
E.A. PEREZ
associated with dopamine receptor inhibition.4 Antiemetic prophylaxis with intravenous 5-HT, receptor antagonists during chemotherapy is now well established.5,6 Whereas intravenous antiemetic agents can effectively control chemotherapyinduced emesis, oral therapy may be more convenient and acceptable to patients. An effective, oral 5-HT, receptor antagonist would allow administration in ambulatory and outpatient settings, which is particularly important for patients in whom the onset of emesis may be delayed, such as women receiving treatment with cyclophosphamide for breast cancer. Women are more prone to emesis than are men, as are younger patients7s8; in addition, emesis is more difficult to control in women.9 Outpatient administration would also reduce the requirements for medical resources. The convenience of an oral drug would benefit both patients and staff, translating into a reduction in the overall cost of chemotherapy and associated treatments.
ORAL GRANISETRON The efficacy of oral granisetron has been studied in four recently published, prospective, randomized, double-masked studies1&13 in patients receiving either moderately or highly emetogenic chemotherapy. This paper presents the results of these four studies and a retrospective literature comparison of oral versus intravenous granisetron. Selectingthe Correct Dose Three pilot studies of oral granisetron in patients receiving at least 50 mg/m2 of cisplatin suggested that the optimal dose is between 0.25 mg twice daily (BID) and 2.5 mg BID.14 A dose-finding study con-
ducted in 83 centers in 9 countries (8 in Europe and 1 in South Africa)‘O included 930 patients not previously treated with chemotherapy who were scheduled to receive moderately emetogenic regimens over a 7- or 1Cday period. The patients were randomized in a double-masked manner to one of four doses of oral granisetron: 0.25, 0.5, 1, or 2 mg BID. The study population was predominantly women (87.4%), but the four treatment groups were well matched for sex and other demographic variables. Granisetron was initially administered 1 hour before the start of chemotherapy and then every 12 hours for the duration of the study. Efficacy was evaluated during the first 24 hours (day 0, or the day of starting chemotherapy) and during days 1 to 6. The primary outcome measures were complete response (no vomiting, no more than mild nausea, no use of other antiemetics, and no withdrawal) and total control (no nausea or vomiting, no use of other antiemetics, and no withdrawal). On day 0 there was a significant association between complete response and the dose of oral granisetron (P = O.OOl), with the highest response achieved at a dose of 1 mg BID (Table I). The complete response rate on days 0 to 6 was also significantly higher with 1 mg BID (58.8%) than with either 0.25 mg BID (43.7%) or 0.5 mg BID (53.6%) (P < 0.009). The complete response rate with 2 mg BID was 54.1%. Similar results were obtained for total control. A dose of 2 mg BID offered no advantage over 1 mg BID for complete response or total control. The investigators concluded that oral granisetron was effective in the prophylaxis of acute emesis after moderately emetogenic chemotherapy, and that optimal efficacy was achieved at a dose of 1 mg BID.
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CLINICAL THERAPEUTICS”
Table I. Complete response rates and total control during the first 24 hours with each of four dosing regimens of oral granisetron in patients receiving moderately emetogenie chemotherapy.* Oral Graaisetron Dose (mg twice daily) 0.25 0.5 1.0 2.0
No. of Patients 229 235 233 233
No. (%) of Patients with Complete Response 140 (61.1) 165 (70.2)+ 189 (81.1)+* 168 (72.1)
No. (%) of Patients with Total Control 102 (44.5) 128 (54.5) 140 (60. I)+ 120 (51.5)
Complete response = no vomiting, nothing more severe than mild nausea, no use of other antiemetics, and no withdrawal from the study; total control = no nausea or vomiting, no use of other antiemetics, and no withdrawal from the study. *Data from Bleiberg et al.” +F’< 0.009 versus granisetron 0.25 mg twice daily. *P < 0.009 versus granisetron 0.5 mg twice daily.
At this dose, nausea and vomiting were well controlled in more than 80% of patients. A treatment benefit was shown up to day 6, but whether this finding reflects a real benefit of continued treatment during the 6 days or a carryover effect from better results on day 0 remains debatable.
Oral Granisetron Compared with Prochlolperazine A double-masked, parallel-group study” indicated that oral granisetron, 1 mg BID, is more efficacious in controlling acute emesis than the conventional antiemetic prochlorperazine, 10 mg BID given orally. The study enrolled 230 patients in 3.5 centers in the United States who were scheduled to receive moderately emetogenic chemotherapy. The most commonly used agents, either alone or in combination, were cyclophosphamide (8 1%), 5-fluorouracil (54%), doxorubicin (37%), and methotrexate (32%). The randomized treatment groups were comparable in mean age (58 to 59 years), sex (about 80%
580
women), alcohol consumption (mean, 2.4 to 4.0 units/wk [ 1 unit of alcohol is equivalent to 50 mL of wine, 250 mL of beer, or 50 mL of spirits]), and primary diagnosis (about 60% breast cancer and 16% lung cancer). The antiemetic responses, particularly during the first 24 hours (day 0), favored granisetron for all outcome measures assessed. Total control (no emesis or nausea and no use of rescue antiemetics) was achieved on day 0 in 68 (57.6%) of 118 patients receiving granisetron, compared with 37 (33.3%) of 111 patients receiving prochlorperazine (P c 0.001) (Figure 1). With either antiemetic, total control was achieved in more men than women, but the difference between treatments was significant only for women (P = 0.002 in favor of granisetron). Similarly, a significantly greater complete response rate (no emesis, no more than mild nausea, no use of rescue antiemetics) was achieved on day 0 with granisetron (73.7%) than with prochlorperazine (41.0%) (P c 0.001). The treatment differences were signifi-
E.A. PEREZ
0
Prochlorperazine
n Granisetron NS
P = 0.002
Ii
1
i
Combined
ii
Women
Men
Figure 1. Proportion of patients achieving total control of nausea and vomiting in a double-masked comparison of oral granisetron and oral prochlorperazine. Reprinted, with permission, from Hesketh et al.” cant for both men (92.3% vs 61.1%; P = 0.013) and women (68.5% vs 37.6%; P < 0.001). The complete response rate, but not total control, over 7 days was significantly better with granisetron (46.6%) than with prochlorperazine (31.5%) (P = 0.033). For day 0, a significantly greater percentage of patients receiving granisetron compared with prochlorperazine had no emesis (82% vs 48%; P c O.OOl), no nausea (58% vs 35%; P < O.OOl), and did not take rescue antiemetics (21% vs 6%; P = 0.001). It was concluded that oral granisetron, at a dose of 1 mg BID, was significantly superior to oral prochlorperazine in controlling acute nausea and vomiting in patients treated with moderately emetogenic chemotherapy regimens consisting primarily of cyclophosphamide and carboplatin. The treatment benefit was apparent for up to 7 days of follow-up therapy, although again it is not clear whether this is a true benefit or a carryover effect from better control on day 0.
Optimizing Oral Therapy As stated, recent findings have shown that oral granisetron (1 mg BID) is an effective antiemetic. lo The feasibility of modifying this regimen to a once-daily dose of 2 mg of oral granisetron has been investigated in a randomized, doublemasked, parallel-group trial involving 64 centers in the United States.12 Of 700 chemotherapy-naive adult patients randomized to treatment (201 men, 499 women), 3 did not receive chemotherapy and were excluded from the analysis of efficacy. A total of 697 patients, among whom the most common malignancy was breast cancer, received both study drug and chemotherapy and were included in the intent-to-treat analysis of the data. The cytostatic agents and doses varied, but the most commonly used-either singly or in combination-were cyclophosphamide (73.7%), doxorubicin (50.4%) and 5-fluorouracil (38.7%); carboplatin, methotrexate, etoposide, vincristine, and cis-
581
CLINICAL THERAPEUTICS”
Table II. Outcome measures during the first 24 hours with two different oral dosing regimens of granisetron in patients receiving moderately emetogenic chemotherapy.* No. (%) of Patients Responding
Total control No vomiting No nausea No rescue antiemetics
Granisetron, 2 mg Once Daily (n = 343)
Granisetron, 1 mg Twice Daily (n = 354)
173 (50.4) 263 (76.7) 180 (52.5) 270 (78.7)
179 (50.6) 290 (81.9) 182 (51.4) 284 (80.2)
Total control = no nausea or vomiting, no use of other antiemetics, and no withdrawal from the study. ‘Data from Ettinger et a1.12
platin were each given to 11% to 17% of patients. Granisetron was given 1 hour before chemotherapy in all patients, and then 12 hours later in the group receiving 1 mg BID; the group receiving 2 mg once daily received placebo at this time. During the 24 hours after administration of chemotherapy, no differences between the two groups could be detected in any of the outcome measures (Table II). Total control (no nausea, no vomiting, and no use of rescue antiemetics) was achieved in at least 50% of all patients; about 52% had no nausea, and more than 76% had no vomiting. The use of rescue antiemetic medication was similar to the incidence of vomiting. Granisetron appeared to be more effective in men than in women, although no statistical comparisons were performed. Analysis of subsets of patients showed no difference in response with different cytostatic regimens.15 It was concluded that a once-daily dose of oral granisetron (2 mg) was as effective as 1 mg BID in preventing nausea and vomiting associated with moderately emetogenic chemotherapy.
582
Combination Antiemetic Therapy The addition of a corticosteroid is known to enhance the antiemetic ef&acy of conventional antiemetic regimens,16,17 ondansetron,18 and intravenous granisetron.19*20 A double-masked, randomized study investigated the efficacy of oral granisetron against acute emesis after cisplatin-based chemotherapy, and the additive effect of a single dose of intravenous dexamethasone. The outcomes were compared with results achieved with a combination of intravenous metoclopramide and dexamethasone. l3 A total of 357 chemotherapy-naive patients from 30 centers in Europe and South Africa were assigned to one of three antiemetic treatment regimens: oral granisetron alone, 1 mg BID for 7 days, starting 1 hour before administration of cisplatin; oral granisetron, given as in the first group, plus a single intravenous infusion of dexamethasone, 12 mg, 5 minutes before the start of cisplatin administration; or dexamethasone given in the same way plus intravenous metoclo-
E.A. PEREZ
pramide, as a 3-mg/kg loading dose infused over 30 minutes and completed 5 minutes before cisplatin administration, with a 4-mg/kg continuous infusion for 8 hours commencing at the same time as cisplatin (total metoclopramide dose of 7 mg), and oral metoclopramide, 10 mg three times daily, for an additional 6 days. All the patients received at least 50 mg/m2 of cisplatin (mean dose, 81 mg/m2). The treatment groups were well matched for demographic variables and prognostic factors; overall, 60% were women, and the mean age was 54.7 years. During the first 24 hours (day 0, the day of cisplatin administration), the combination of granisetron plus dexamethasone gave total control (no nausea or vomiting, no use of rescue antiemetics, no withdrawal) in a significantly greater proportion of patients than did metoclopramide plus dexamethasone (54.7% vs 37.2%, respectively; P = 0.007) (Table III). There was no significant difference in total control between patients receiving combination therapy with granisetron and
dexamethasone and patients receiving granisetron alone (54.7% vs 43.7%, respectively). More patients taking the granisetron combination had no nausea and no vomiting, although the differences did not reach significance. Oral granisetron alone gave results similar to metoclopramide plus dexamethasone. Granisetron combination therapy was associated with a significant delay in the appearance of symptoms on day 0 compared with metoclopramide plus dexamethasone (P = 0.0068 for vomiting; P = 0.0012 for nausea) (Figure 2). Interestingly, there was a marked difference between treatment regimens in the group of patients younger than 45 years of age: 15.4% total control on day 0 with metoclopramide plus dexamethasone, compared with 65.2% with granisetron plus dexamethasone (P = 0.01). Overall, women responded less well than men, particularly in the granisetron groups. There were no significant differences between any of the treatment groups for the late phase (days 1 to 3 and days 4 to 6) of emesis.
Table III. Proportion of patients with total control, no nausea, and no vomiting first 24 hours with three different antiemetic regimens.*
during the
Percentage of Patients Responding
Total control No nausea No vomiting
Oral Granisetron plus Single-Dose Intravenous Dexamethasone (n = 117)
High-Dose Metoclopramide plus Dexamethasone (n = 121)
Oral Granisetron (n = 119)
37.2 38.8
43.7 44.5
54.7t 57.3
52.1
56.3
65.8
Total control = no nausea or vomiting, no use of other antiemetics, ‘Data from Heron et aLI tP = 0.007 versus metoclopramide plus dexamethasone.
and no withdrawal
from the study.
583
CLINICAL THERAF'EUTICS"
. .. .. ... GRANIDEX
I5 0.0
-
GRAN
*-I---
MET/DEX
P= 0.0068 GRANIDEX vs METIDEX
0
3
6
9
12
15
18
21
24
Time after Cisplatin Therapy (h) Time to first episode of vomiting after cisplatin-based chemotherapy in patients receiving oral granisetron (GRAN), oral granisetron plus dexamethasone (DEX), or metoclopramide (MET) plus dexamethasone. Reprinted, with permission, from Heron et a1.13 The authors concluded that oral granisetron as a single agent was as effective as high-dose metoclopramide plus dexamethasone in preventing cisplatininduced nausea and vomiting, and that oral granisetron in combination with a corticosteroid provided control of symptoms superior to that achieved with conventional antiemetic regimens.
Comparison of Oral and Intravenous Granisetron Despite the fact that there are no published data that directly compare an oral 5-I-H, receptor antagonist with the same agent given intravenously, or an oral 5HT, receptor antagonist with an intravenous preparation of a different agent, the results of the current analysis allow for indirect, retrospective comparisons of the efficacy of oral and intravenous granisetron. Such indirect comparisons of oral and intravenous granisetron are sup-
584
ported by the results of direct comparisons in an experimental study in the ferret, which has emerged as an appropriate animal model for both the elucidation of the emetic pathway and the identification of antiemetic mechanisms. The ferret produces an emetic response to the same compounds that induce emesis in humans. Oral granisetron was as effective and long-lasting as intravenous granisetron in preventing emesis induced in conscious ferrets by intravenous injection of cisplatin. In addition, there was a trend indicating that the oral drug was more potent than the intravenous drug.21 The first indirect comparison is possible between the results of a study of oral granisetron (1 mg BID)13 and results of five studies (mostly European) with the intravenous formulation22-26 in patients receiving high-dose cisplatin chemotherapy (mean dose, approximately 80 mg/m*). The mean overall complete response rate (no vomiting and no more than
E.A. PEREZ
mild nausea) during the first 24 hours in patients receiving intravenous granisetron, 40 ug/kg, was 62% (range, 44% to 93%), compared with 52% total control (no vomiting or nausea) in the oral study. This 10% difference can probably be accounted for by the higher proportion of women in the oral study. Further evidence of the similar efficacy of oral and intravenous granisetron derives from a trial in which intravenous granisetron was compared with a regimen identical to that used in the oral study.2’ Complete control was achieved in 52% of patients receiving either oral granisetron or metoclopramide plus dexamethasone in the same study,13 and in 70% of patients receiving intravenous granisetron compared with 67% given the same metoclopramide plus dexamethasone regimen. 23Although the overall response rates differed in the two studies, the similar relative efficacy of oral and intravenous formulations of granisetron in comparison with an identical conventional antiemetic regimen in both studies suggests that the two formulations will be equally effective in patients receiving high-dose cisplatin.
ORAL ONDANSETRON AND OTHER 5HT, RECEPTOR ANTAGONISTS The only other 5-HT, receptor antagonist that has been investigated in an oral-only regimen is ondansetron. In many of the clinical trials, however, ondansetron was not compared with other antiemetics or was compared only with placebo, which does not represent the standard of care for preventing chemotherapy-induced emesis. 27 In addition, an initial intravenous dose was commonly used, making it difficult to separate the intravenous and oral effects. No clear evidence can be found in
these trials that oral ondansetron is superior to conventional antiemetic regimens.27 A search of the literature, however, reveals 10 trials that assessed the effectiveness of oral ondansetron used alone for control of acute emesis (Table IV). Three of these trials were uncontrolled,28-30 two were placebo controlled,31,32 and two compared ondansetron alone with combinations of ondansetron plus dexametbasonei8 or ondansetron plus the dopamine antagonist metopimazine. 33 The combination therapies showed superior efficacy. The remaining three trials compared oral ondansetron used as a single agent with conventional antiemetic regimens3k36 and showed it to be approximately equal in efficacy to metoclopramide. Indeed, one of these trials showed the combination of dexamethasone and metoclopramide to be superior to oral ondansetron.36 Nine of the 10 trials of oral ondansetron for the prevention of acute emesis involved patients receiving moderately emetogenic chemotherapy. In the one study that enrolled patients due to receive cisplatin chemotherapy,18 complete control of acute emesis (during the first 24 to 48 hours after cisplatin) was achieved in only 7% of patients given oral ondansetron alone, although an additional 22% reported only one or two episodes of emesis. Despite oral ondansetron being given at a dose of 8 mg three times daily, 78% of the patients reported moderate or severe nausea in the 24 to 48 hours after cisplatin. Conclusions are difficult to draw, however, because this study was small, and cisplatin was administered on day 4 of chemotherapy, following other agents. No other studies of oral ondansetron for the prevention of cisplatin-induced acute emesis are available for review.
585
CLINICAL THERAPEUTICS**
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E.A. PEREZ
Few clinical studies of tropisetron have been published, and all of them involve administration of the antiemetic either intravenously or via a combination of intravenous and oral routes. Data from randomized trials of the efficacy of oral-only tropisetron given together with the investigational 5-HT, receptor antagonist dolasetron are not yet available.
TOLERABILITY OF ORAL 5HT, RECEPTOR ANTAGONISTS Antiemetic agents are administered in conjunction with cytotoxic drugs, and so assessment of their tolerability is complicated. Nevertheless, oral 5-HT, receptor antagonists, either alone or in combination with dexamethasone, appear to be well tolerated. The most common adverse events reported in the studies of oral granisetron were headache (12.8% to 36.1%) and constipation (19.8% to 31.1%)‘@‘3; similar findings have been reported with ondansetron.18*29,30,32 These findings are similar to the reported incidence of headache following intravenous granisetron.23-26 The incidence of constipation may be slightly higher with oral granisetron, which probably reflects the repeated administration of the oral drug. 37 The incidence of adverse events was not increased at higher doses of oral granisetron, and few patients required additional treatment with other antiemetics.‘O Addition of dexamethasone to oral granisetron or ondansetron reduced the incidence of headache from 20% to 13%13 and from 25% to 13%,18 respectively. Headache (22%) and constipation (11%) were also the most commonly reported adverse events after treatment with tropisetron.38
CONCLUSIONS The data obtained from the trials with oral granisetron support the conclusion that some oral antiemetic agents can match the efficacy of intravenous regimens for the prevention of chemotherapy-induced emesis. This finding is applicable to situations in which patients receive either moderately or highly emetogenic chemotherapy. Specifically, these data indicate that oral granisetron is as effective as intravenous granisetron and can improve on the efficacy of conventional antiemetic regimens. Oral granisetron, given as a single agent, has been shown to provide antiemetic control as effective as that obtained with high-dose metoclopramide plus dexametbasone for patients receiving moderate-to-high doses of cisplatin. In addition, given together with dexamethasone, oral granisetron provides protection superior to that of conventional antiemetic regimens against cisplatin-induced emesis. Oral granisetron demonstrated improved efficacy when compared with prochlorperazine in patients receiving moderately emetogenic chemotherapy. Moreover, as with intravenous graniseu-on, oral granisetron is as effective when administered once daily as a single dose of 2 mg, given 1 hour before the start of chemotherapy, as when given two times a day in a dose of 1 mg. Randomized trials comparing oral ondansetron with conventional antiemetics have essentially shown similar efficacy in prevention of emesis after a moderate challenge. No adequate trial has been performed to compare the efficacy of oral ondansetron with that of intravenous agents in patients receiving cisplatinbased chemotherapy.
587
CLINICAL THERAPEUTICSm
The results of trials using other 5-HT, receptor antagonists and direct comparisons of intravenous ondansetron and oral granisetron for moderately and highly emetogenic chemotherapy are eagerly awaited.
5. Bunce K, Tyers M, Beranek P. Clinical evaluation of 5-HT, receptor antagonists as anti-emetics. Trends Pharmacol Sci. 1991;12:4U8.
ACKNOWLEDGMENT
7. Soukop M, McQuade B, Hunter E, et al. Ondansetron compared with metoclopramide in the control of emesis and quality of life during repeated chemotherapy for breast cancer. Oncology (Switzerland). 1992;49:295-304.
The data given in this paper were presented in part at a satellite symposium at the 19th European Society of Medical Oncology, Lisbon, Portugal, November 1994.
correspondence to: Edith A. Perez, MD, Division of Hematology/ Oncology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224. Address
REFERENCES Grunberg SM. Potential for combination therapy with the new antiserotonergic agents. Eur J Cancer. 1993;29A(Suppl l):S39-s41. Gralla RJ, Itri LM, Pisko SE, et al. Antiemetic efficacy of high-dose metoclopramide: Randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. NEJM. 1981;305:905-909. Miner WD, Sanger GJ. Inhibition of cisplatin-induced vomiting by selective 5hydroxytryptamine M-receptor antagonism. Br J Pharmacol. 1986;88:497-499. Merrifield KR, Chafee BJ. Recent advances in the management of nausea and vomiting caused by antineoplastic agents. Clin Pharm. 1989;8:187-199.
6. Smyth JF. New directions for anti-emetic research. Ann Oncol. 1994;5:569-570.
8. 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. 1987;5:141-149. 9. Tonato M, Roila F, Del Favero A. Methodology of antiemetic trials: A review. Ann Oncol. 1991;2:107-114. 10. Bleiberg HH, Spielmann M, Falkson G, Romain D. Antiemetic treatment with oral granisetron in patients receiving moderately emetogenic chemotherapy: A doseranging study. Clin Thel: 1995;17:38-51. 11. Hesketh P, Burris H, Cohn J, et al. A double-blind comparison of the efficacy and safety of oral granisetron with oral prochlorperazine in preventing nausea and emesis in patients receiving moderately emetogenic chemotherapy. Cancer J. In press. 12. Ettinger D, Eisenberg P, Fitts D, et al. A double-blind comparison of the efficacy of two dose regimens of oral granisetron in preventing acute emesis in patients receiving moderately emetogenic chemotherapy. Cancel: 1996;78: 144-15 1.
.A. PEREZ
13. Heron JF, Goedhals L, Jordaan JP, et al. Oral granisetron alone and in combination with dexamethasone: A double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis. Ann Oncol. 1994;5:579-584.
21. Marr HE, Davey PT, Boyle EA, Blower PR. Further studies of the antiemetic activity of granisetron against whole body X-irradiation or cisplatin-induced emesis in the ferret. Pharmacology. 1994;48: 283-292.
14. Hacking A, on behalf of the Granisetron Study Group. Oral granisetron-simple and effective: A preliminary report. Eur J Cancel: 1992;28A(Suppl l):S28-S32.
22. Cupissol DR, Serrou B, Caubel M. The efficacy of granisetron as a prophylactic anti-emetic and intervention agent in highdose cisplatin-induced emesis. Eur J Cancer. 1990;26(Suppl l):S23S27.
15. Johnsonbaugh RE, Mason BA, Friedman CJ, Fitts D. Oral granisetron is an effective anti-emetic in patients receiving moderately emetogenic chemotherapy. Proc Am Sot Clin Oncol. 1994;13:437. Abstract.
23. Chevallier B, on behalf of the Granisetron Study Group. The control of acute cisplatin-induced emesis-a comparative study of granisetron and a combination regimen of metoclopramide and dexamethasone. Br J Cancel: 1993;68:176-180.
16. Aapro MS. Controlling emesis related to cancer therapy. Eur J Cancer. 1991;27: 356-361. 17. Seynaeve C, De Mulder PHM, Verweij J, Gralla RJ. Controlling cancer chemotherapy-induced emesis. Pharm Weekbl Sci. 1991;13:189-197. 18. Smith DB, Newlands ES, Rustin GJS, et al. Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatincontaining chemotherapy. Lancer. 1991; 338:487-490. 19. Latreille J, Stewart D, Laberge F, et al. Dexametbasone improves the efficacy of granisetron in the first 24 hours following high dose cisplatin chemotherapy. Proc Am Sot Clin Oncol. 1993;12:133. Abstract. 20. Carmichael J, Bessel1 E, Harris AL, et al. Comparison of granisetron alone and granisetron plus dexamethasone in the prophylaxis of cytotoxic-induced emesis. Br J Cunce,: 1994;70:1161-1164.
24. Navari RM, Kaplan HG, Gralla RJ, et al. Efficacy and safety of granisetron, a highly selective 5-hydroxytryptamine-3 receptor antagonist, in the prevention of nausea and vomiting induced by high-dose cisplatin. J Clin Oncol. 1994;12:22042210. 25. Riviere A, on behalf of the Granisetron Study Group. Dose finding study of granisetron in patients receiving high-dose cisplatin chemotherapy. Br J Cancer 1994;69:967-971. 26. Soukop M, on behalf of the Granisetron Study Group. A dose-finding study of granisetron, a novel antiemetic, in patients receiving high-dose cisplatin. Support Cure Cancel: 1994;2:177-183. 27. Cooke CE, Mehra IV. Oral ondansetron for preventing nausea and vomiting. Am J Hosp Pharm. 1994;51:762-771. 28. Marschner NW, Adler M, Jaenicke F, et al. Langzeitergebnisse der antiemetischen Effectivimt des 5-HTs-Antagonisten Ondansetron. Onkologie. 1990;13:313-315.
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CLINICAL THERAPEUTICS”
29. Campora E, Oliva C, Mammoliti S, et al. Oral ondansetron (GR 38032F) for the control of CMFinduced emesis in the outpatient. Breast Cancer Res Treat. 1991;19: 129-132. 30. Rosso R, Campora E, Cetto G, et al. Oral ondansetron (GR 38032F) for the control of acute and delayed cyclophosphamideinduced emesis. Anticancer Res. 199 1; 11: 937-940. 31. Beck TM, Ciociola AA, Jones SE, et al. Efftcacy of oral ondansetron in the prevention of emesis in outpatients receiving cyclophosphamide-based chemotherapy. Ann Intern Med. 1993;118:407-413. 32. Cubeddu LX, Pendergrass K, Ryan T, et al. Efficacy of oral ondansetron, a selective antagonist of 5-HT, receptors, in the treatment of nausea and vomiting associated with cyclophosphamide-based chemotherapies. Am J Clin Oncol Cancer Clin TriaZs. 1994;17:137-146. 33. Herrstedt J, Sigsgaard T, Boesgaard M, et al. Ondansetron plus metopimazine compared with ondansetron alone in patients receiving moderately emetogenic chemotherapy. NEJM. 1993;328:1076-1080.
590
34. Fraschini G, Ciociolo A, Esparza L, et al. Evaluation of three oral dosages of ondansetron in the prevention of nausea and emesis associated with cyclophosphamide-doxorubicin chemotherapy. J Clin Oncol. 1991;9:1268-1274. 35. Marschner NW, Adler M, Nagel GA, et al. Double-blind randomised trial of the antiemetic efficacy and safety of ondansetron and metoclopramide in advanced breast cancer patients treated with epirubicin and cyclophosphamide. Eur J Cancer: 1991;27:1137-1140. 36. Levitt M, Warr D, Yelle L, et al. Ondansetron compared with dexamethasone and metoclopramide as antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotrexate and fluorouracil. NEJM. 1993;328:1081-1084. 37. Yarker YIE, McTavish D. Granisetron. An update of its therapeutic use in nausea and vomiting induced by antineoplastic therapy. Drugs. 1994;48:761-793. 38. De Bruijn KH. Tropisetron: A review of clinical experience. Drugs. 1992;43(Suppl 3):11-22.