| Japanese Journal of Clinical Oncology | Pages |
Navoban (Tropisetron, ICS 205-930) and Dexamethasone Combination in the Prevention of Vomiting for Patients Receiving Preconditioning High-dose Chemotherapy Before Marrow Transplantation
Introduction
Patients And Methods
Patients
Preconditioning Regimen
Anti-emetic Combination
Response Evaluation
Adverse Effects
Statistical Analysis
Results
Preconditioning Regimen
Anti-emetic Efficacy
Adverse Effects
Discussion
References
Navoban (Tropisetron, ICS 205-930) and Dexamethasone Combination in the Prevention of Vomiting for Patients Receiving Preconditioning High-dose Chemotherapy Before Marrow Transplantation
The anti-emetic efficacy of a combination of tropisetron and dexamethasone was studied in 33 patients who underwent bone marrow transplantation. Another 50 patients receiving conventional anti-emetic therapies in bone marrow transplantation served as control. On the first and second days of preconditioning chemotherapy, 51% and 36% respectively of patients in the tropisetron and dexamethasone group did not experience vomiting, compared with only 12% and 10% of control group patients (P < 0.001). The mean number of episodes of vomiting in the tropisetron and dexamethasone group was also significantly lower than in the control group (0.97 ± 1.65 vs 3.50 ± 2.45 and 1.30 ± 1.40 vs 4.44 ± 2.91 respectively, both P < 0.001). Control of vomiting in the two groups was not significantly different during days 3-6. Analysis of patients receiving busulfan and cyclophosphamide as the preconditioning regimen still showed better anti-emetic control in the tropisetron and dexamethasone group than in the control group on the first two days of treatment (total control rate 33.3% vs 6.5% and 44.4% vs 12.9% respectively, P < 0.001). Patients given tropisetron and dexamethasone combination more frequently suffered from dizziness and burning sensation of the chest. However, diarrhea and extrapyramidal symptoms were the most frequent adverse effects seen after using conventional anti-emetic combination. The combination of tropisetron and dexamethasone was thus superior to conventional anti-emetic combinations in preventing vomiting during preconditioning period of bone marrow transplantation. The adverse effects of this combination were minimal and well tolerated by patients.
INTRODUCTION
Vomiting and nausea are side effects dreaded by patients receiving chemotherapy, especially those patients who receive highly emetogenic drugs such as cisplatin, or those who received high dose chemotherapy, or total body irradiation (TBI) during preconditioning for bone marrow transplantation (BMT). These side effects can be very distressing for patients, and may jeopardize the success of treatment by disturbing nutritional intake or important drug administration.
Metoclopramide, one of the dopamine antagonists, is most frequently used to manage vomiting and nausea during preconditioning for BMT, either singly or in combination with other drugs. However, these drugs must be used in high doses in order to prevent nausea and vomiting by blocking 5-hydroxytryptamine-3 (5-HT3, serotonin) receptors (1). However, administration of metoclopramide in such a high dose will produce strong dopamine receptor blockage, causing extrapyramidal symptoms (EPS) (2,3).
In recent years, several drugs have been found, such as ondansetron (4) (ZofranR), granisetron (5) (KytrilR) and tropisetron (6-8) (NavobanR), which block only 5-HT3 receptors and can thus effectively prevent chemotherapy-induced vomiting and nausea. A single use of a 5-HT3 receptor antagonist can achieve at least the same, or better, control of vomiting than conventional anti-emetics. Also, the side effects which are often produced by conventional anti-emetic drugs, such as extrapyramidal reactions and severe sedation, are greatly reduced because only 5-HT3 receptors are blocked. Tropisetron (6-8) (NavobanR) has shown good results in preventing vomiting induced by chemotherapy or radiotherapy. It is a long-acting drug and its once a day administration makes it a good choice for anti-emetic therapy.
Among conventional anti-emetics, dexamethasone has an important place in combination therapy. Prior to the availability of 5-HT3 receptor antagonists, use of dexamethasone in combination with high dosage metoclopramide showed good results in anti-emetic therapy. Recent research reports also noted evidence that the effectiveness of ondansetron was greatly increased when used in combination with dexamethasone (9,10). In this study we investigate the effect of the use of tropisetron in combination with dexamethasone (TROP/DEX) in the prevention of preconditioning-induced vomiting, and its possible adverse effects.
PATIENTS AND METHODS
Patients
Thirty-three patients who received bone marrow transplantation in Veterans General Hospital-Taipei during the period from February 1993 to February 1994 were subjects of this study. They all received the TROP/DEX anti-emetic combination during treatment. For the purpose of evaluating the effectiveness of this combination, we compared these 33 patients with another group of 50 patients who underwent bone marrow transplantation at this hospital in the previous year. This second group of patients, defined as the control group, received conventional anti-emetic combinations that did not include 5-HT3 receptor antagonists. Clinical characteristics of both groups of patients are summarized in Table 1.
Preconditioning Regimen
Most of our cases received one of two preconditioning regimens. The first was the BuCy regimen, under which the patient is given busulfan 4 mg/kg/day orally for four days, followed by cyclophosphamide 60 mg/kg/day given intravenously for two days. The second was the Cytoxan + TBI regimen, under which the patient is given cyclophosphamide 60 mg/kg/day for two days, followed by total body irradiation at a total dose of 1200 cGy, given in six fractions over a four-day period. The rest of the patients received the BEAM protocol or other regimens (Table 2).
Anti-emetic Combination
All patients in the TROP/DEX group were given anti-emetics over a six-day period in accordance with the following regimen. On the first day of high dose intravenous chemotherapy, 5 mg of tropisetron in 100 ml 5% dextrose in normal saline was administered over 20 minutes before chemotherapy. From day 2 to day 6, a daily dose of 5 mg of tropisetron was given orally. In addition, 20 mg of dexamethasone was given intravenously on each day when intravenous high dose chemotherapy was given.
Patients in the control group received anti-emetic combinations which included metoclopramide 1-2 mg/kg of body weight, plus diazepam 10 mg or lorazepam 1 mg given daily from the first day of high dose intravenous chemotherapy for six days. Dexamethasone 20 mg was also given intravenously on each day that the patient was given high dose intravenous chemotherapy.
Response Evaluation
Vomiting was defined as an episode of expulsion of any stomach content or a period of retching. Patients were monitored by nursing staff and the vomiting occurrences were recorded every four hours. Mean episodes of vomiting of each group during each day of treatment were also calculated. We defined the degree of control during a day as follows: total control, complete absence of vomiting; partial control, 1-4 attacks of vomiting; failure, more than 4 attacks of vomiting.
Table 1
| Characteristic | TROP/DEX | Control |
| Total | 33 | 50 |
| Male/Female | 18/15 | 31/19 |
| Age (median) (years) | 32.8 (8-57) | 25.6 (5-48) |
| Disease | ||
| AML | 14 | 11 |
| CML | 3 | 14 |
| ALL | 4 | 4 |
| ML | 5 | 4 |
| SAA | 6 | 12 |
| Others | 1 | 5 |
| Stem cell source | ||
| Allogeneic BMT | 21 | 37 |
| Autologous BMT | 11 | 13 |
| PBSCT | 1 | |
Table 2
| Preconditioning regimen | TROP/DEX (n = 33) | Control (n = 50) | P value |
| BuCy | 54.5% | 62.0% | NS |
| Cytoxan+TBI | 27.3% | 26.0% | NS |
| BEAM | 15.2% | 6.0% | NS |
| Others | 3.0% | 6.0% | NS |
Adverse Effects
In addition to recording occurrences of vomiting, any adverse effects within either group were also recorded, especially those affecting the central nervous system and the gastrointestinal tract.
Statistical Analysis
The [chi]2 test was used to compare the two groups of patients receiving different preconditioning regimens, both for the degree of emetic control and for adverse effects. The independent t test was used to analyze the difference between the mean episodes of vomiting on each day in the two groups.
RESULTS
Preconditioning Regimen
Most of the patients received either BuCy or Cytoxan + TBI as the preconditioning regimen. As shown in Table 2, there was no significant difference between the two groups with respect to the proportions of patients receiving different preconditioning regimens.
Anti-emetic Efficacy
The degree of vomiting control in both groups is summarized in Table 3. On the first and second days, 42% and 58% respectively of patients in the control group suffered from severe vomiting (more than four episodes per day). However, in the TROP/DEX group, on the first and on the second day only 6% of patients experienced severe vomiting. Furthermore, on the first and second days of chemotherapy, 52% and 36% respectively of patients in the TROP/DEX group did not have any vomiting at all. In comparison, on the first and second days of chemotherapy, only 12% and 10% respectively of the patients in the control group did not experience vomiting. The differences between the two groups were statistically significant (P < 0.001).
In order to avoid possible bias due to arbitrary definition of `control' of vomiting, we compared the number of episodes of vomiting on each day between the two groups. In Table 4 we can see that on day 1 and day 2, the mean ± SD episodes of vomiting were 0.97 ± 1.65 and 1.30 ± 1.40 respectively for the TROP/DEX group, and were 3.50 ± 2.45 and 4.44 ± 2.91 respectively for the control group. The mean number of attacks was significantly lower in the TROP/DEX group (P < 0.001). The differences of vomiting control between the two groups were not, however, significant from days 3-6 (Tables 3 and 4).
Most of the patients in this study received BuCy as the preconditioning regimen, so we analyzed this group of patients separately. In Table 5 we can see that in this subgroup, those who received the TROP/DEX combination still achieved better emetic control than those who received conventional anti-emetic combinations on the first two days of treatment (total control 33.3% vs 6.5% and 44.4% vs 12.9% respectively, P < 0.001), but these differences were not significant from days 3-6, either (Table 5).
Table 3
| Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 | |
| TROP/DEX (n = 33) | ||||||
| Total control | 17 (52%) | 12 (36%) | 12 (36%) | 16 (48%) | 15 (45%) | 19 (57%) |
| Partial control | 14 (42%) | 19 (58%) | 15 (45%) | 12 (36%) | 13 (39%) | 9 (27%) |
| Failure | 2 (6%) | 2 (6%) | 6 (19%) | 5 (16%) | 5 (16%) | 5 (16%) |
| Control (n = 50) | ||||||
| Total control | 6 (12%) | 5 (10%) | 10 (20%) | 20 (40%) | 26 (52%) | 25 (50%) |
| Partial control | 23 (46%) | 16 (32%) | 24 (48%) | 18 (36%) | 15 (30%) | 20 (40%) |
| Failure | 21 (42%) | 29 (58%) | 16 (32%) | 12 (24%) | 9 (18%) | 5 (10%) |
| P | <0.001 | <0.001 | NS | NS | NS | NS |
Table 4
| Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 | |
| TROP/DEX (n = 33) | 0.97 ± 1.65 | 1.30 ± 1.40 | 2.36 ± 3.63 | 1.58 ± 2.18 | 1.45 ± 1.86 | 1.59 ± 2.75 |
| Control (n = 50) | 3.50 ± 2.45 | 4.44 ± 2.91 | 2.70 ± 2.46 | 1.94 ± 2.14 | 1.58 ± 2.13 | 1.60 ± 2.54 |
| P | <0.001 | <0.001 | NS | NS | NS | NS |
Table 5
| Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | Day 6 | |
| TROP/DEX (n = 18) | ||||||
| Total control | 6 (33.3%) | 8 (44.4%) | 7 (38.9%) | 12 (66.7%) | 10 (55.5%) | 12 (66.7%) |
| Partial control | 10 (55.5%) | 9 (50%) | 7 (38.9%) | 5 (27.8%) | 7 (38.9%) | 4 (22.21%) |
| Failure | 2 (11.1%) | 1 (5.5%) | 4 (22.2%) | 1 (5.5%) | 1 (5.5%) | 2 (11.1%) |
| Control (n = 31) | ||||||
| Total control | 2 (6.5%) | 4 (12.9%) | 9 (29.0%) | 21 (67.7%) | 20 (64.5%) | 22 (71.0%) |
| Partial control | 16 (51.6%) | 11 (35.5%) | 16 (51.6%) | 7 (22.6%) | 10 (32.2%) | 7 (22.6%) |
| Failure | 13 (41.9%) | 16 (51.6%) | 6 (19.4%) | 3 (9.7%) | 1 (3.2%) | 2 (6.4%) |
| P | <0.001 | <0.001 | NS | NS | NS | NS |
Table 6
| Adverse effects | TROP/DEX (n = 33) | Control (n = 50) | P value |
| Headache* | 12.1% | 16.0% | NS |
| Dizziness* | 30.3% | 6.0% | 0.002 |
| Heartburn | 21.2% | 2.0% | 0.003 |
| Constipation* | 3.0% | 0.0% | NS |
| Diarrhea[dagger] | 6.1% | 18.0% | NS |
| Extrapyramidal symptoms | 3.0% | 28.0% | 0.005 |
Adverse Effects
The most commonly experienced adverse effects are summarized in Table 6. In the TROP/DEX group the adverse effects which occurred most frequently were dizziness and burning sensations of the chest. The occurrence of both was significantly higher than that in the control group. The headaches were mild and easily controlled by the use of acetaminophen and similar medication. There were no patients who decided to stop treatment due to adverse effects. Extrapyramidal symptoms (EPS) were seen in one patient on the second day with the onset of heart palpitations and involuntary movements of neck and oral muscles. These symptoms disappeared after administration of akineton. Subsequent use of tropisetron and dexamethasone did not induce any similar adverse reactions. EPS occurred more frequently in the control group (28% vs 3%, P = 0.005).
DISCUSSION
The preconditioning regimen, with or without TBI, which is used in bone marrow or peripheral stem cell transplantation, is highly emetogenic. Conventional anti-emetic combinations, usually metoclopramide-based, could not effectively prevent vomiting in these patients. Most reports have indicated that using conventional anti-emetic combinations, a major control rate (less than four vomiting episodes per day) of about 50-60%, and a total control rate (no vomiting) of about 5-25%, could be attained during the first 24 hours (11-12). In our study, the control group achieved a major control rate of 58% and a total control rate of 12% of emesis during the first 24 hours of chemotherapy, which are not far from the rates reported by other studies.
There are many reports about the use of ondansetron or granisetron in anti-emetic therapy in stem cell transplantation. Ondansetron is the most often studied drug. Hewittet al. (13)report an 80% major control rate and 60% total control rate of vomiting by using ondansetron during the first 24 hours of preconditioning therapy in 15 children who underwent BMT. In the study of Schwellaet al. (14), 88% of patients suffered fewer than three episodes of vomiting during the first 24 hours of TBI after taking ondansetron. In the randomized trials of Aguraet al. (15), ondansetron, either low dose or high dose, provided better emesis control than metoclopramide plus droperidol.
In studies on granisetron, Hunteret al. (16) showed that a single intravenous dose of granisetron could offer a total protection from vomiting in 56.3% of patients and major control of emesis in 40.3% of the patients under TBI. Prenticeet al. (17) also showed superior control of vomiting by granisetron over the combination of metoclopramide, lorazepam and dexamethasone (total control rate 53% vs 13% during the first 24 hours). Recently, in a randomized study, Okamoto et al. (12) not only found that granisetron could achieve better control of emesis during the first 24 hours of preconditioning therapy than could be achieved by conventional anti-emetic treatment, but also maintained this superiority throughout the whole preconditioning period.
There have been fewer studies using tropisetron in anti-emetic treatment during preconditioning for BMT. Or et al. (18) have shown that nine out of 11 patients (81%) could achieved complete or major control of vomiting by using tropisetron while receiving the preconditioning regimen.
In the current study, we gave one intravenous injection of tropisetron on the first day when intravenous high dose chemotherapy was given, and from day 2 to day 6, the drug was administered in oral form. Dexamethasone was given on the days the patient received intravenous chemotherapy. The study showed a total control of vomiting in 51% of patients during the first 24 hours of intravenous high dose chemotherapy and only 6% of patients failed to control emesis. The result is far better than the situation in the control group (Table 3). We also compared the mean episodes of vomiting on each day between the two groups, in order to avoid possible bias due to an arbitrary definition of vomiting control. These results, too, showed much better anti-emetic control in patients of the TROP/DEX group (Table 4).
However, the differences of emesis control from day 3 to day 6 between two groups were not significant (Tables 2 and 3). This is in contrast to the study of granisetron by Okamoto et al. (12). A possible explanation is that most of our patients received busulfan and cytoxan alone as the preconditioning regimen (the `BuCy' regimen). Only about 26% of patients received high dose cytoxan plus TBI (Table 2). In the analysis of the subgroup of those patients who received the BuCy regimen, although the TROP/DEX combination achieved better emetic control in the first two days, the conventional combination could achieve a major emesis control rate ([le]4 episodes of vomiting per day) of around 70-80% from day 3 to day 6 of preconditioning therapy, which is not different from that of the TROP/DEX group (Table 5). In the study of Okamotoet al. (12), more than 70% of their patients received high dose chemotherapy and TBI. TBI is highly emetogenic. Most of the studies have shown that 5-HT antagonists are efficient and superior to conventional combination in the control of TBI-induced emesis (14,16,17). This might explain why in the study of Okamotoet al. (12) the granisetron group could maintain significant antiemetic superiority over the control group during the whole preconditioning period.
The combination of dexamethasone and ondansetron could produce better anti-emetic control in patients receiving chemotherapy than ondansetron alone (9,10). In the study of Hulstaert et al. (19), the addition of dexamethasone significantly increased the control rate of both acute and delayed emesis in patients who had incomplete control of vomiting when tropisetron was used alone. In our study, we also used the combination of tropisetron and dexamethasone, hoping that maximum anti-emetic control could be achieved.
The most frequently observed side effects after receiving the TROP/DEX combination were dizziness and a burning sensation in the chest, though these were not severe and were usually transient. Also, some patients had headaches and a change of bowel movement (Table 6). These reactions have all been reported in other studies of 5-HT3 receptor antagonists (8-19). Those receiving conventional anti-emetic combinations had more frequent occurrence of EPS (Table 6).
In summary, we demonstrated the superiority of the combination of tropisetron and dexamethasone over conventional anti-emetic combinations in preventing vomiting during the preconditioning period of BMT. Their adverse effects are minimal and well tolerated by patients.
References
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Last modification: 19 May 1998
Copyright© Japanese Journal of Clinical Oncology, 1998.
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