Efficacy of granisetron in the prevention of emesis induced by conditioning chemotherapy for allogeneic bone marrow transplantation

We conducted this study to compare granisetron, 5-HT3 antagonist, with conventional antiemetics in the prophylaxis of emesis induced by conditioning chemotherapy for allogeneic bone marrow transplantation in 41 patients. The conditioning chemotherapy regimen included either cytosine arabinoside 2 g/m2 x 4 and cyclophosphamide 60 mg/kg x 2 (CA, CY), or busulfan 4 mg/kg x 4 and cyclophosphamide 60 mg/kg x 2 (BU, CY). In CA and CY regimen, the clinical effective rate with granisetron against emesis was 94.1% on the 1st day, compared with 7.6% in the control group. On day 2 and 3, the effective rate with granisetron was 58.8% and 23.5%, respectively, compared with 0% in the control group. In the BU and CY regimen, control of emesis with granisetron on day 5 and 6 was 66.7%, against 20.0% in the control group. Based on these data, we concluded granisetron is superior to conventional antiemetics in the prophylaxis of emesis induced by conditioning for allogeneic bone marrow transplantation.     

Control of emesis by intravenous granisetron in breast cancer patients treated with 5-FU, epirubicin and cyclophosphamide

Granisetron, a potent and selective 5-hydroxytryptamine receptor (5-HT3) antagonist was reported to be an effective antiemetic agent both in animal studies and in patients given highly emetogenic chemotherapy. A sample of 43 patients with breast cancer was accrued from September to November 1992 in a phase II study to assess the efficacy of granisetron in patients receiving FEC (5-FU, epirubicin, cyclophosphamide). Each patient received 3 mg intravenous granisetron as a single dose just prior to chemotherapy. Oral metoclopromide was prescribed to each patient as a rescue anti-emetic. The emetic episodes and degree of nausea were evaluated on a daily basis. Good control of emesis (0-2 episodes of vomiting) and nausea (mild or no nausea) was in the range 77%-98% and 77%-93% respectively. There was a complete response (no emetic episodes throughout the 6-day period) in 16 patients (37.2%). Onset of emesis tends to occur on day 1 and tend to subside after day 3; 85% of patients had onset of emesis in the first 2 days after chemotherapy. Control of emesis and nausea tends to improve after day 3, which could be the result of the reduced emetogenicity of the combination FEC with time. Altogether, 77% had good control of acute emesis; control of delayed emesis was better with 84% achieving a major response on day 2 after chemotherapy, which improved to more than 90% after day 4. Granisetron was generally tolerated with headache being the most common side-effect followed by constipation and flushing. This study suggests that granisetron is an effective and well-tolerated anti-emetic agent, which deserves randomised trials to elucidate its efficacy further.     

Generating a normalized geometric liver model using warping

This review discusses the development and use of 5-hydroxytryptamine3 (5-HT3) antagonists, especially granisetron, for the treatment of chemotherapy-induced emesis. Following recent evidence suggesting that high-dose chemotherapy is more effective in increasing tumor response rate and median survival time, more effective antiemetic control is essential. Granisetron, a new 5-HT3, is approximately 400 times more potent than metoclopramide and, unlike metoclopramide, does not produce extrapyramidal side effects. Granisetron has been shown to be effective as a single prophylactic dose, over 5 days and in patients receiving repeated cycles of chemotherapy. Patients with nausea and vomiting within the first 24 h after chemotherapy are more likely to experience delayed symptoms; however, episodes of breakthrough nausea and vomiting can be controlled by intervention with one, and in some cases more, doses of granisetron. The development of granisetron represents an important advance in the control of chemotherapy induced emesis.     

Antiemetic efficacy of granisetron in pediatric cancer treatment--(2). Comparison of granisetron and granisetron plus methylprednisolone as antiemetic prophylaxis

A crossover clinical trial was carried out to compare the effectiveness and safety of granisetron alone (40 micrograms/kg) with that from a combination of granisetron plus methylprednisolone (MPL, 10 mg/kg) for control of emesis and vomiting induced by anticancer drugs in children with cancer. Complete control of emesis and vomiting were achieved in 95% (19/20 cases) of patients receiving the combination compared to 85% (17/20 cases) of patients receiving granisetron alone. There were no clinical toxicities or side effects in either treatment group. These data indicated that the combination of granisetron plus MPL was superior for control of emesis and vomiting in children receiving cytostatic anticancer drugs.     

Review of the preclinical pharmacology and comparative efficacy of 5-hydroxytryptamine-3 receptor antagonists for chemotherapy-induced emesis

PURPOSE: This analysis was undertaken to review published reports of the comparative efficacy and safety of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists in the prophylaxis of acute chemotherapy-induced emesis. METHODS: Comparison data used are the preclinical pharmacology as well as the design and results of clinical trials. Seven comparative studies that used granisetron, ondansetron, or tropisetron in patients who received either moderately or highly emetogenic chemotherapy are reviewed. As the study designs, patient population, chemotherapy, antiemetic doses and schedule, and methods of assessment were slightly different, the results of each study are analyzed independently. Effectiveness is assessed by emetic episodes, nausea, and patient preference. RESULTS: The preclinical pharmacologic profile is different among the 5-HT3 antagonists in terms of potency, selectivity, dose response, and duration of action. The comparative clinical trials show that a single intravenous (i.v.) dose of granisetron 3 mg is as effective as multiple (8 mg x 3) or single (32 mg) i.v. doses of ondansetron for the prevention of acute nausea and emesis due to cisplatin. In the two moderately emetogenic clinical trials, granisetron 3 mg i.v. was at least as effective as ondansetron 8 mg i.v. +/- 24 mg orally and tropisetron 5 mg i.v. Patient preference was evaluated in three of the four crossover trials: granisetron was preferred in three of four, and no preference was reported in the fourth. The one trial to compare ondansetron 0.15 mg/kg x 3 versus granisetron 10 micrograms/kg x 1 or granisetron 40 micrograms/kg i.v. demonstrated equivalent control of nausea and vomiting in patients who received cisplatin-based chemotherapy. CONCLUSION: The 5-HT3 receptor antagonists compared are highly effective antiemetic agents that have now become the standard of care for preventing chemotherapy-induced emesis. Whether the described preclinical differences among these agents are also clinically significant remains to be seen. In the comparative trials analyzed, the 5-HT3 receptor antagonists demonstrated relatively equivalent clinical efficacy. Cost analysis may favor the use of one agent over another depending on the emetogenic challenge, dose of the 5-HT3 antagonists, and number of doses recommended. Patient preference may be an important factor to be considered in future antiemetic trials.     

Modern aspects of antiemetic therapy

We summarized the current knowledge about chemotherapy and radiotherapy-induced nausea and vomiting. Nausea and vomiting are among the most frequent side effects in the treatment of malignancies, and they are very unpleasant for the patient. We reviewed basic aetiological and physiological mechanisms (except that of delayed emesis, which is not enough explored), particularly the role of serotonin in acute chemotherapy and radiotherapy-induced nausea and vomiting. An oncologist cannot make many changes in the treatment of malignancies and patient-related prognostic factors, but he (she) can make changes in the treatment of nausea and vomiting in order to improve the quality of life of patients with malignancies. We also listed some of the most widely used antiemetic drugs with their most important pharmacological properties. Important progress in the control of nausea and vomiting was obtained by the use of selective antagonists of 5-HT3-receptors such as ondansetron, granisetron, tropisetron and dolasetron. Usually ondasetron and granisetron were used. Their clinical activity is similar but better results were obtained with the combination of 5-HT3-antagonists and corticosteroids (complete response was approximately 90%) than by their individual use (complete response was approximately 50%). The problem of delayed emesis has not yet been solved, and best results were obtained with the combination of metoclopramide and corticosteroids. For the control of nausea and vomiting caused by radiotherapy, orally given ondansetron is effective.     

Comparison of single-dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicenter, double-blind, randomized parallel study

PURPOSE: The antiemetic effectiveness and safety of single-dose oral granisetron were compared with intravenous (I.V.) ondansetron in chemotherapy-naive patients who received moderately emetogenic chemotherapy. PATIENTS AND METHODS: In this double-blind, parallel-group study, patients naive to emetogenic chemotherapy (N = 1,085) who were scheduled to receive cyclophosphamide- (500 to 1,200 mg/m2) or carboplatin (> or = 300 mg/m2) based chemotherapy, were randomized to receive either oral granisetron (n = 542) or I.V. ondansetron (n = 543). Efficacy assessments included the proportion of patients in each treatment group with total control over the 24 and 48 hours following chemotherapy initiation, as well as incidence and severity of nausea and emesis and use of antiemetic rescue medication. Prophylactic corticosteroids were allowed. Safety assessment was based on patients' reports of adverse experiences. RESULTS: Approximately 80% of patients received prophylactic corticosteroids. Single-dose oral granisetron (2 mg) and I.V. ondansetron (32 mg) resulted in equivalent levels of total emetic control during the first 48 hours after chemotherapy. The proportion of nausea- and emesis-free patients at 24 and 48 hours were also approximately equivalent. The most commonly reported adverse experiences were headache, asthenia, and constipation. More patients who received ondonsetron than granisetron reported dizziness (9.6% v 5.4%, respectively; P = .011) and abnormal vision (4.2% v 0.6%, respectively; P < .001). CONCLUSION: A single oral dose of granisetron (2 mg) resulted in equivalent levels of antiemetic protection as I.V. ondansetron (32 mg). Both agents were well tolerated, although more dizziness and abnormal vision were reported with ondansetron. Because the two antiemetic regimens exhibited equivalent efficacies, additional factors such as convenience and cost of therapy should be considered.     

Efficacy and safety of two methods of administration of granisetron injection for nausea and vomiting induced by chemotherapy for tumors in hematopoietic organs--a randomized crossover comparison between intravenous drip infusion and intravenous bolus injection]

We investigated the efficacy and safety of two methods of granisetron injection to treat nausea and vomiting induced by chemotherapy for tumors in hematopoietic organs. The methods of administration were intravenous drip infusion over 30 minutes, which is the conventional method, and intravenous bolus injection. In this study, 89.5% of patients in both groups (17/19 for each) were free from vomiting. No serious adverse events were observed in either administration group. Abnormal laboratory test values suspected to be related to granisetron were observed in 3 cases in the bolus injection group and in 2 cases in the drip infusion group. but did not pose any clinical problem. These results demonstrated the safety of both methods of administration. In conclusion, it is considered that granisetron intravenous bolus injection can be considered as the method of choice for the prevention of nausea and vomiting induced by chemotherapy for tumors in hematopoietic organs.     

Computer simulation of changes in nursing productivity from early tracheal extubation of coronary artery bypass graft patients

A total of 530 patients were treated in this multicenter, double-blind, double-dummy, parallel group study to compare the anti-emetic efficacy and safety of a once daily ondansetron oral regimen with a once daily i.v. dosing regimen over a 24 h period, administered to patients prior to receiving cisplatin (50 mg/m2 or greater) chemotherapy. Patients were randomized to receive a single dose of ondansetron plus dexamethasone given either orally (ondansetron 24 mg and dexamethasone 12 mg, n=262) or i.v. (ondansetron 8 mg and dexamethasone 20 mg, n=268). Complete control of emesis (i.e. no emetic episodes, no rescue and no premature withdrawal) was achieved for 85% of patients (224 of 262) in the oral group and 83% (223 of 268) in the i.v. group. No nausea was reported in 70% of patients in the oral group and 68% in the i.v. group. There were no statistically significant differences between the two groups for any of the assessments of efficacy, which included time to first emetic episode, number of emetic episodes and the worst grade of nausea occurring over the 24 h study period. Once daily ondansetron oral and i.v., in combination with dexamethasone, was well tolerated in this study. In conclusion, once daily oral ondansetron 24 mg plus dexamethasone is equally effective in the control of emesis and nausea induced by highly emetogenic chemotherapy as once daily ondansetron 8 mg i.v. plus dexamethasone.     

Oral ondansetron for the control of cisplatin-induced delayed emesis: a large, multicenter, double-blind, randomized comparative trial of ondansetron versus placebo

PURPOSE: To investigate the efficacy and safety of oral ondansetron in the control of cisplatin-induced delayed emesis in patients who do not require rescue antiemetic therapy for acute emesis. PATIENTS AND METHODS: Five hundred thirty-eight chemotherapy-naive patients who received cisplatin chemotherapy (> or = 70 mg/m2), and who were not rescued for acute emesis, were eligible to be randomized to receive one of the three oral regimens to control delayed emesis. Group I received placebo on days 2 to 6; group II received ondansetron 8 mg twice daily on days 2 and 3 and placebo on days 4 to 6; group III received ondansetron 8 mg twice daily on days 2 to 6. All patients received intravenous ondansetron (0.15 mg/kg every 4 hours for three doses) for the control of acute emesis on day 1. The number of emetic episodes on days 2 and 3 combined (days 2/3, when incidence and severity of delayed emesis were expected to be greatest) was considered the primary measure of efficacy. RESULTS: Patients who received odansetron had significantly fewer emetic episodes on days 2/3, 4, and 5 than those who received placebo (P < or = .002 on each day). Additionally, significantly more patients who received ondansetron had a complete plus major response (C+MR; < or = two two emetic episodes) than those who received placebo on days 2/3 (56% v 37%, P = .001), 4 (94% v 85%, P = .005), and 5 (98% v 88%, P = .006). Patients who received ondansetron had significantly less nausea on day 2/3 when day-1 nausea was used as the baseline score (P = .025). Patients who received ondansetron also had significantly less nausea on day 4 (P = .042) and the results approached significance on day 5 (P = .066). CONCLUSION: Oral ondansetron had a significant effect in the control of cisplatin-induced delayed emesis and nausea in patients who had not required rescue antiemetics during the acute emesis period. The control of delayed nausea and vomiting was most notable in the immediate 2 days following cisplatin administration, with the clinical difference narrowing between the two treatment arms on subsequent days.     

Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. L-754,030 Antiemetic Trials Group

BACKGROUND: The localization of substance P in brain-stem regions associated with vomiting, and the results of studies in ferrets, led us to postulate that a neurokinin-1-receptor antagonist would be an antiemetic in patients receiving anticancer chemotherapy. METHODS: In a multicenter, double-blind, placebo-controlled trial involving 159 patients who had not previously received cisplatin, we evaluated the prevention of acute emesis (occurring within 24 hours) and delayed emesis (on days 2 to 5) after a single dose of cisplatin therapy (70 mg or more per square meter of body-surface area). Before receiving cisplatin, all the patients received granisetron (10 microg per kilogram of body weight intravenously) and dexamethasone (20 mg orally). The patients were randomly assigned to one of three treatments in addition to granisetron and dexamethasone: 400 mg of an oral trisubstituted morpholine acetal (also known as L-754,030) before cisplatin and 300 mg on days 2 to 5 (group 1), 400 mg of L-754,030 before cisplatin and placebo on days 2 to 5 (group 2), or placebo before cisplatin and placebo on days 2 to 5 (group 3). Additional medication was available at any time to treat occurrences of vomiting or nausea. RESULTS: In the acute-emesis phase, 93 percent of the patients in groups 1 and 2 combined and 67 percent of those in group 3 had no vomiting (P<0.001). In the delayed-emesis phase, 82 percent of the patients in group 1, 78 percent of those in group 2, and 33 percent of those in group 3 had no vomiting (P<0.001 for the comparison between group 1 or 2 and group 3). The median nausea score in the delayed-emesis phase was significantly lower in group 1 than in group 3 (P=0.003). No serious adverse events were attributed to L-754,030. CONCLUSIONS: The neurokinin-1-receptor antagonist L-754,030 prevents delayed emesis after treatment with cisplatin. Moreover, combining L-754,030 with granisetron plus dexamethasone improves the prevention of acute emesis.     

Patients' self-reported functional status after granisetron or ondansetron therapy to prevent chemotherapy-induced nausea and vomiting at six cancer centers

Patient functional status after administration of either granisetron or ondansetron to prevent acute chemotherapy-induced nausea and vomiting (CINV) was studied. Pharmacists and nurses from six cancer centers distributed Functional Living Index-Emesis (FLIE) questionnaires to 115 outpatients receiving either granisetron or ondansetron for prevention of CINV. The emetogenic potential of each patient's chemotherapy regimen was high, moderately high, or moderate. Immediately before and 72 hours after chemotherapy, each patient rated his or her reaction to each of 18 items on the questionnaire on a 7-point scale. Possible scores ranged from 18 to 126, with higher scores indicating higher levels of functioning. The occurrence of nausea in the granisetron group was 40.0% compared with 43.2% in the ondansetron group; the occurrence of vomiting was 18.8% in the granisetron group and 11.1% in the ondansetron group. Patients who received highly emetogenic chemotherapy had significantly lower scores on the FLIE after chemotherapy than before. Patients with both nausea and vomiting reported a much higher negative impact on functional status after chemotherapy than those with nausea only. The mean prechemotherapy and postchemotherapy FLIE scores were 124.2 and 110.4 for granisetron and 124.9 and 111.9 for ondansetron. Granisetron and ondansetron did not differ significantly in their effect on functional status reported by patients before and 72 hours after receiving cancer chemotherapy.     

A lymphoma cell line resistant to 4-piperidinopiperidine was less sensitive to CPT-11

The purpose of the study was to assess the toxicity and efficacy of an oral, combination antiemetic regimen including granisetron (Kytril; SmithKline Beecham Pharmaceuticals, Philadelphia, PA, USA) in the setting of highly emetogenic conditioning chemotherapy for stem cell transplantation. Antiemetic prophylaxis consisted of oral granisetron 2 mg once daily, oral prochlorperazine 10 mg q 6 h and oral dexamethasone 4 mg q 6 h, beginning 1 h prior to chemotherapy on each of the 4 days of chemotherapy and continuing until 24 h after the completion of high-dose chemotherapy (HDC). Patients received either CVP (cyclophosphamide 6 g/m2, VP-16 1800 mg/m2 and carboplatin 1200 mg/m2) or CTP (thiotepa 500 mg/m2 in place of VP-16) in four daily doses given over 4 h from days -4 to -1. Previously mobilized and cryopreserved peripheral blood stem cells (PBSC) were reinfused on day +1. Evaluation of nausea, emetic episodes (EE), adverse events, and rescue medications were recorded on a daily patient diary. Thirty-six patients were entered. Fifty-three percent (95% CI = 37-75%) of patients achieved complete response for emesis (CR = 0 EE/24 h) and 75% (95% CI = 58-90%) had combined complete and major response (CR+MR = 0-3 EE/24 h) during all 5 of the treatment days. During the 5 study days, the average number of patient-days with no emesis was 3.7 (74%) and with 1-3 EE was 4.3 (86%). On days -4, -3, -2, -1 and 0, the combined CR+MR rate for emesis was 97, 92, 86, 78 and 75%, respectively. Nausea was absent or mild on all 5 study days in 57% (95% CI = 37-75%). Eight patients had severe late-onset emesis occurring on days +1 to +3 after reinfusion of stem cells. No clinically significant toxicities attributable to the antiemetic regimen were observed. An all oral antiemetic regimen of granisetron, prochlorperazine and dexamethasone appears to be safe and highly effective in patients receiving multiple, daily, high-dose chemotherapy regimens. This regimen offers the advantage of cost-savings, a low side-effect profile and ease of administration in the predominately outpatient setting of HDC with peripheral blood stem cell transplant (PBSCT).     

A randomized cross-over study of high-dose metoclopramide plus dexamethasone versus granisetron plus dexamethasone in patients receiving chemotherapy with high-dose cisplatin

We carried out a randomized, single-blind, cross-over trial to compare the antiemetic effect, for both acute and delayed emesis, of granisetron plus dexamethasone (GRN+Dx) with that of high-dose metoclopramide plus dexamethasone (HDMP+Dx). Fifty-four patients with primary or metastatic lung cancer, given single-dose cisplatin (> 80 mg/m2) chemotherapy more than twice, were enrolled in this study. They were treated with both HDMP+Dx and GRN+Dx in two consecutive chemotherapy courses. On day 1, patients experienced a mean of 2.5 (SD = 4.3) and 0.1 (SD = 0.4) episodes of vomiting in the HDMP+Dx and the GRN+Dx groups, respectively (P = 0.0008). Complete response rate on day 1 was 45 and 90% in the HDMP+Dx and the GRN+Dx groups, respectively (P = 0.0001). Patients treated with GRN+Dx had a tendency to suffer more episodes of vomiting than the HDMP+Dx group on days 2-5, but it was not statistically significant. Twenty-four patients (57%) preferred the GRN+Dx treatment and 14 patients (33%), HDMP+Dx. In the HDMP+Dx group, nine patients (21%) had an extrapyramidal reaction, and 5 patients (12%) had constipation that lasted for at least two days. In contrast, no patients had extrapyramidal reactions, and 18 patients (43%) had constipation in the GRN+Dx group (P < 0.01). GRN+Dx was more effective than HDMP+Dx only in preventing the acute emesis induced by cisplatin. An effective treatment for delayed emesis is still needed.     

Dolasetron. A review of its pharmacology and therapeutic potential in the management of nausea and vomiting induced by chemotherapy, radiotherapy or surgery

Dolasetron (dolasetron mesilate) is a pseudopelletierine-derived 5-HT3 antagonist which has recently become available for clinical use. It is rapidly converted in vivo to its active major metabolite, hydrodolasetron, which appears to be largely responsible for its pharmacological activity. In clinical trials, single intravenous or oral doses of dolasetron were effective in preventing acute chemotherapy-induced nausea and vomiting (CINV). Intravenous doses of 1.8 mg/kg achieved complete suppression of vomiting in approximately 50% of patients receiving highly emetogenic cisplatin-containing chemotherapy and in approximately 60 to 80% of patients receiving moderately emetogenic chemotherapy. In the latter setting, oral doses of 200 mg achieved similar response rates. In comparative studies, intravenous dolasetron 1.8 mg/kg was as effective as intravenous granisetron 3 mg or ondansetron 32 mg after highly emetogenic chemotherapy, and oral dolasetron 200 mg was equivalent to multiple oral doses of ondansetron (3 or 4 doses of 8 mg) after moderately emetogenic chemotherapy. Dolasetron 1.8 mg/kg was superior to metoclopramide in preventing emesis induced by high dose cisplatin or by moderately emetogenic chemotherapy in high risk subgroups. Dolasetron has also shown efficacy in preventing radiotherapy-induced nausea and vomiting (RINV) in preliminary studies. Single intravenous or oral dolasetron doses ranging from 12.5 to 100 mg and 25 to 200 mg, respectively, were significantly more effective than placebo in preventing postoperative nausea and vomiting (PONV) in female surgical patients. A 50 mg intravenous dose was as effective in preventing PONV as ondansetron 4 mg in a mixed-gender group. Intravenously administered dolasetron was also effective in treating established PONV, although complete suppression of vomiting was achieved in < 40% of patients. Dolasetron has a tolerability profile characteristic of this class of compounds, with headache, dizziness and diarrhoea being the most commonly occurring adverse events in clinical trials. Diarrhoea is not thought to be related to dolasetron administration, being experienced mostly by patients receiving chemotherapy. Dolasetron and other 5-HT3 receptor antagonists have been associated with minor changes in ECG intervals, but these generally do not appear to be clinically important. Thus, available evidence suggests that dolasetron will provide an alternative to other 5-HT3 receptor antagonists for the management of CINV and PONV. Further studies are required to determine whether it offers any advantages over other agents in these settings and to determine the optimum dosage for preventing RINV.     

Effects of granisetron and its combination with dexamethasone on cisplatin-induced delayed emesis in the ferret

1. Granisetron and its combination with dexamethasone for the treatment of delayed emesis following cisplatin (CDDP) administration were investigated using ferrets. 2. CDDP-induced emesis was significantly inhibited in both the granisetron group and the combined granisetron and dexamethasone group during the acute and delayed phase in terms of total emesis, latency to first emesis and duration of emesis. 3. Food and water consumption in the combined group of ferrets was significantly increased as compared with the CDDP control group. 4. 5-Hydroxytryptamine (5-HT) level was increased in the ileum and the 5-hydroxyindole acetic acid (5-HIAA) level was increased in the area postrema of ferrets after 3 days of CDDP administration. It is suggested that the antiemetic activity of granisetron and/or dexamethasone is not related to 5-HT levels in delayed emesis. 5. Both granisetron and its combination with dexamethasone are effective in CDDP-induced emesis, but combination treatment is more effective than granisetron alone for the duration of emesis in the delayed phase.     

Immunoglobulin production by human peripheral B cells against Staphylococcus aureus

Patterns of antiemetic therapy and its outcomes in patients undergoing high-dose antineoplastic therapy were studied. The study, conducted at a cancer center, included both a retrospective evaluation of patients undergoing highly emetogenic high-dose chemotherapy with peripheral blood stem-cell rescue between November 1994 and December 1995 and a concurrent evaluation of patients treated between January and May 1996. During the study period the recommended antiemetic regimen for highly emetogenic chemotherapy was a single dose of granisetron 1 mg i.v. daily 30 minutes before treatment on days of chemotherapy. Severity of nausea and vomiting during both the acute phase (from day 1 of chemotherapy to 24 hours after its completion) and delayed phase (from 24 hours to five days after the end of chemotherapy) was graded according to the Common Toxicity Criteria Grading Scale. A total of 59 patients were evaluable; 41 were reviewed retrospectively, and 18 were reviewed concurrently. On day 1 of the acute phase, 53 patients (90%) had no vomiting and 51 patients (86%) had no nausea. The frequency and severity of nausea and vomiting increased on successive acute-phase days, and it was necessary to add other antiemetics. Nausea and vomiting continued to be significant problems throughout the delayed phase; 32 (54%) of the patients had a maximum of grade 3 nausea, and 29 patients (49%) had a maximum of grade 2 vomiting. Substantial numbers of patients who received selective serotonin type 3 receptor antagonists before high-dose antineoplastic agents had significant nausea and vomiting that required the addition of other antiemetics.     

Effect of concurrent use of ondansetron hydrochloride and dexamethasone against nausea and vomiting in lung cancer patients receiving cisplatin

We examined the efficacy of concurrent use of ondansetron hydrochloride and dexamethasone, and the effective dose of dexamethasone against nausea and vomiting in lung cancer patients receiving chemotherapy including single high dose cisplatin. The study was carried out on total of 44 courses of chemotherapy in either initial onset or recurrence of lung cancer. The patients were given 4 mg of ondansetron injection on the day of cisplatin injection (Day 1), and 4 mg/day of ondansetron tablet for Days 2 to 4. These patients were randomly allocated into 2 groups, i.e., those who, on Day 2, concomitantly received 10 mg of dexamethasone (D10 Group, 22 courses) or 20 mg (D20 Group, 22 courses), for comparing the antiemetic effects in a different concomitant dose of dexamethasone. An efficacy rate of 70% or more was achieved in each group for acute emesis on Day 1. The efficacy rate was 80% or above for emesis on Day 2 when dexamethasone was concurrently administered, and Days 3 and 4 in both groups. No significant difference was observed between the groups. A higher complete suppression rate against nausea was seen in D20 Group even though the difference from D10 Group was not significant. Furthermore, food intake rate on Day 2 was significantly better in D20 Group. However, in the cases that were graded effective or markedly effective for acute emesis on Day 1, the efficacy rate was also high in both groups through Days 2-4. It was notable that the efficacy rate of Days 2-4 was 100% in D2 Group. The high efficacy rate was shown in male patients regardless of which dose of dexamethasone was used. However, control of emesis was unfavorable in female patients on Day 1 and was still unfavorable even though dexamethasone was combined from Day 2. We considered from the above results that 10 mg/day of concurrent dexamethasone is sufficient in suppression of delayed emesis on Day 2. However, in order to improve nausea or food intake, or to suppress emesis in patients who are highly likely to show unfavorable control for Day 2 and onward, 20 mg/day should also be effective.     

Randomized, double blind, dose-response trial across four oral doses of dolasetron for the prevention of acute emesis after moderately emetogenic chemotherapy. Oral Dolasetron Dose-Response Study Group

BACKGROUND: This double blind parallel group study assessed the acute antiemetic efficacy of four oral doses of dolasetron mesylate in cancer patients receiving their first course of intravenous chemotherapy with doxorubicin and/or cyclophosphamide. METHODS: Patients were randomized to receive 25, 50, 100, or 200 mg of dolasetron mesylate 30 minutes prior to chemotherapy and were monitored for nausea and emetic episodes for the next 24 hours. RESULTS: Three hundred and nineteen cancer patients at 32 sites completed the study. Most patients were female (81%); of this group, 69% had breast carcinoma. A highly statistically significant linear trend demonstrating improved response with higher doses was detected for complete response (no emetic episodes and no rescue medication) (P < 0.001), for complete plus major response (0-2 emetic episodes and no rescue medication) (P < 0.001), and for patient visual analog scale assessments of nausea (P = 0.001) and general satisfaction with antiemetic therapy (P = 0.001). No serious adverse events were noted. The most frequent adverse event was mild, self-limiting headache, which has been reported with other drugs in this class. CONCLUSIONS: Single oral doses of dolasetron mesylate were found to be effective in preventing acute emesis in cancer patients receiving moderately emetogenic chemotherapy.     

Initial high anti-emetic efficacy of granisetron with dexamethasone is not maintained over repeated cycles

We have reported previously that the anti-emetic efficacy of single agent 5HT3 antagonists is not maintained when analysed with the measurement of cumulative probabilities. Presently, the most effective anti-emetic regimen is a combination of a 5HT3 antagonist plus dexamethasone. We, therefore, assessed the sustainment of efficacy of such a combination in 125 patients, scheduled to receive cisplatin > or = 70 mg m(-2) either alone or in combination with other cytotoxic drugs. Anti-emetic therapy was initiated with 10 mg of dexamethasone and 3 mg of granisetron intravenously, before cisplatin. On days 1-6, patients received 8 mg of dexamethasone and 1 mg of granisetron twice daily by oral administration. Protection was assessed during all cycles and calculated based on cumulative probability analyses using the method of Kaplan-Meier and a model for transitional probabilities. Irrespective of the type of analysis used, the anti-emetic efficacy of granisetron/dexamethasone decreased over cycles. The initial complete acute emesis protection rate of 66% decreased to 30% according to the method of Kaplan-Meier and to 39% using the model for transitional probabilities. For delayed emesis, the initial complete protection rate of 52% decreased to 21% (Kaplan-Meier) and to 43% (transitional probabilities). In addition, we observed that protection failure in the delayed emesis period adversely influenced the acute emesis protection in the next cycle. We conclude that the anti-emetic efficacy of a 5HT3 antagonist plus dexamethasone is not maintained over multiple cycles of highly emetogenic chemotherapy, and that the acute emesis protection is adversely influenced by protection failure in the delayed emesis phase.