Comparing different antiemetic regimens for chemotherapy induced nausea and vomiting.
Cancer is increasing at an alarming rate globally. Chemotherapy is the primary treatment for cancer and in some cases the only resort. Most of the chemotherapeutic drugs have been found to cause release of large amounts of serotonin from enterochromaffin cells in the gut, (1) serotonin acts on 5-[HT.sub.3] receptors in the gut and brain stem and stimulate vagal affarents to initiate the vomiting reflex. Chemotherapy induced nausea and vomiting (CINV) remains a significant problem for cancer patients, having a long lasting effect on their quality of life.
There is evidence that emesis control during chemotherapy acts on the quality and cost of treatment by allowing a better compliance to scheduled drug dose. It improves the quality of life of patients by reducing the intensity and number of side effects and thereby reducing the length of hospitalization and treatment related expenditure. (2)
5-[HT.sub.3] receptor antagonists or serotonin antagonists suppress nausea and vomiting by inhibiting serotonin binding to the 5-[HT.sub.3] receptors. Serotonin antagonists are found to be very effective in controlling CINV and are used along with dexamethasone as a potent antiemetic regimen in chemotherapy. (3-6)
Nowadays the stores in India are flooded with many options of serotonin antagonists coming at different prices. So comparison of their relative efficacies and safeties in Indian patients against their prices is needed before prescribing them indiscriminately. Hence we have performed a double blind, randomized controlled trial to compare the relative efficacies of ondansetron, granisetron and palonosetron for both acute and delayed onset emesis, in moderately and highly emetogenic chemotherapy against their respective prices in Indian market.
Patients and methods
Eligible patients for this double blind, randomized controlled trial were men and women
aged 15 years or above with confirmed malignant disease and admitted to any department of Bankura Sammilani Medical College and Hospital, India from November 05, 2007 to September 30, 2009 for the purpose of receiving either one day of moderately or highly emetogenic chemotherapy or moderately or highly emetogenic chemotherapy for Day 1 and lower emetogenic drugs on the subsequent days. Emetogenic levels of common chemotherapy and biotherapy agents are given in Figure 1. (7-9)
Exclusion criteria included: severe, uncontrolled, concurrent illness other than neoplasia; asymptomatic metastases to the brain; seizure disorder needing anticonvulsants unless clinically stable; intestinal obstruction; concurrent intake of any other emetogenic drug or radiotherapy or a known hypersensitivity to 5-[HT.sub.3]-receptor antagonists or dexamethasone.
1213 patients were found to be eligible for the study, among them 487 were on highly emetogenic and 726 were on moderately emetogenic chemotherapy. The study was approved by the ethical board of institute and all patients provided written informed consent before enrolment. Patients were randomly assigned to receive ondansetron or granisetron or palonosetron. All study personnel and patients were blinded to the treatment assignment for the duration of the study and the nursing staffs injecting the drugs were prohibited from divulging any information on drug assignment even to the doctors giving the chemotherapeutic drugs.
Ondansetron 8 mg or granisetron 3 mg were given on Day 1 and Day 2 or palonosetron 0.75 mg was given on Day 1, intravenously, 30 min before chemotherapy, along with 16 mg of intravenous dexamethasone on Day 1 and 4 mg on Day 2 and Day 3. Patients were followed for 5 days for the efficacy endpoints and 8 days for the safety endpoints.
The primary efficacy endpoints of this study were the proportion of patients with a complete response during the acute phase (0-24 hours post chemotherapy). Secondary efficacy endpoints included complete response during successive 24 h time periods (i.e., 24-48 h, 48-72 h, 72-96 h, and 96-120 h) and for the overall chronic phase (24-120 hours post chemotherapy).
Complete response was defined as no emetic episodes, no rescue medication use, and no more than mild nausea. People having 0-1 vomits and/or moderate nausea for a maximum of 4 hours were termed as partial response. Failure delineated [greater than or equal to] 2 vomits, or severe nausea or nausea lasting more than 4 hours.
All data were analyzed using SAS software, version 9.1. Chi-square test or Fisher's exact test was used to compare the proportions. A both sided p value of [less than or equal to] 0.05 was considered statistically significant.
In the group receiving highly emetogenic chemotherapy, 287 (58.9%) were females and 200 (41.1%) were males and in the group receiving moderately emetogenic chemotherapy, 370 (50.9%) were females and 356 (49.1%) were males. Overall, previous history of chemotherapy was present in 916 patients (75.5%), while 297 (24.5%) were chemotherapy-naive. Highly emetogenic regimens chiefly had cisplatin (96.3%), and as a part of antiemetic therapy 237 patients were prescribed ondansetron, 186 granisetron and 64 palonosetron. While the moderately emetogenic regimens consisted of lower dose (<1500 mg/[m.sup.2]) cyclophosphamide (85.8%) and doxorubicin (12.8%) and for combating the emesis 379 patients were put on ondansetron, 254 on granisetron and 93 on palonosetron. Baseline and demographic characteristics of the patients are given in Table 1.
The doses of the serotonin antagonists were administered as per previous research data regarding their optimal dose related efficacy. Ondansetron 8 mg is found to be equally efficacious to ondansetron 32 mg for both highly and moderately emetogenic chemotherapy. (10-11) Although United States Food and Drug Administration deemed that the 10 [micro]g/kg dose for granisetron was fully effective, results suggest that there is some benefit to the higher 40 [micro]g/kg (3mg) dose in certain patient groups, (12) hence the higher dose was used. A clear dose-response relation was noted over a 120 h study period when 0.075 mg, 0.25 mg, and 0.75 mg doses of palonosetron were given with dexamethasone to prevent CINV associated with highly emetogenic chemotherapy, indicating a significant difference in response with the 0.075 mg dose compared with the two higher doses. (13) Also another study with moderately emetogenic regimen revealed dose-dependent increases in complete response with more than a 10% difference in the highest complete response recorded in the 0.75 mg dose group compared with the 0.25 mg, in both delayed and overall phases. (14) Three doses of palonosetron were well-tolerated and did not show any increase in adverse effects related to dose. The better efficacy with the 0.75 mg dose than with the lower doses and the similar safety profile suggested that palonosetron 0.75 mg be the recommended dose for use in this trial.
Overall, irrespective of the emetogenicity of the regimens, palonosetron is found to be the best acting drug followed by granisetron, although the difference in the efficacies of the drugs was not huge. 472 patients (76.6%) in ondansetron group, 340 (77.27%) in granisetron group and 138 (87.8%) in palonosetron group showed complete response in the acute phase (0-24 hours) (p value = 0.021); compared to 350 patients (56.8%) in ondansetron group, 279 (63.4%) in granisetron group and 106 (67.5%) in palonosetron group in chronic phase (24-120 hours) (p value= 0.013). Complete responses obtained for each drug on daily basis is illustrated in Figure 2. All the responses obtained for each drug from Day 1 to 5 have been given in Table 2.
For highly emetogenic regimens it was postulated that palonosetron is superior to ondansetron, which was found to be false, as p values were > 0.05. 52 patients (81.2%) had complete response during the acute phase (0-24 hours) in palonosetron group compared with 181 patients (76.4%) in the ondansetron group and 130 patients (69.9%) in granisetron group (p value = 0.246). During the overall chronic phase (24-120 hours), 41 patients (64%) had complete response in the palonosetron group compared with 133 patients (56.1%) in the ondansetron group and 114 patients (61.2%) in granisetron group (p value = 0.461). Complete responses obtained for each drug on a 24 hourly basis is illustrated in Figure 3. Responses of each drug in the highly emetogenic regimen, from Day 1 to 5 have been given in Table 3.
For moderately emetogenic regimens it was postulated that palonosetron is superior to granisetron which was superior to ondansetron, which was found to be true, as p values were [less than or equal to] 0.05. 86 patients (92.5%) had complete response during the acute phase (0-24 hours) in palonosetron group compared with 291 patients (76.8%) in the ondansetron group and 210 patients (82.6%) in granisetron group (p value = 0.01). During the delayed phase (24-120 hours), 63 patients (67.7%) had complete response in the palonosetron group compared with 216 patients (57%) in the ondansetron group and 162 patients (63.8%) in granisetron group (p value = 0.05). Complete responses obtained for each drug on a 24 hourly basis is illustrated in Figure 4. Responses of each drug in the moderately emetogenic regimen, from Day 1 to 5 have been given in Table 4.
There were no clinically relevant differences between groups with regard to overall incidence of side effects (p value = 0.99998). As was expected, headache and constipation were the most common side effects (6) occurring in 11 (1.8%) and 26 (4.2%) patients respectively among ondansetron users; while it was 8 (1.8%) and 19 (4.3%) for granisetron users and 3 (1.9%) and 8 (5.1%) for palonosetron users. Hypokalemia occurred in 9 (1.5%) ondansetron users, 7 (1.6%) granisetron users and 2 (1.3%) palonosetron users. Elevation of liver enzymes alanine transaminase (ALT) and aspartate transaminase (AST) was also noted, although none of the patients reported increase in serum bilirubin. Table 5 has details of the treatment related side effects.
Nausea and vomiting are still the major distressing health issues in patients undergoing chemotherapy. Although 5-[HT.sub.3]-receptor antagonists along with a corticosteroid are proved to be the key treatment regimen against CINV (3-6), the standard serotonin antagonist to be used in various chemotherapy regimens is yet to be known.
There are some differences in metabolism and receptor specificities among the different serotonin antagonists. (15) Palonosetron is a highly potent, selective, second-generation 5-[HT.sub.3] receptor antagonist with a receptor binding affinity higher than other 5-[HT.sub.3] receptor antagonists (pKi 10.5 compared with 8.91 for granisetron, 8.39 for ondansetron). (16-17) Palonosetron shows a 40 h half life 18-19 which is significantly longer than others in its class [ondansetron, 4 h; (20) tropisetron, 7.3 h; (21) dolasetron, 7.5 h; (22) granisetron, 8.9 h]. (23) It shows both competitive binding and allosteric interactions with the 5-[HT.sub.3]-receptor and requires only a single dosing contrary to ondansetron and granisetron, which show strictly competitive antagonism. As the allosteric interactions can induce changes in the receptor conformation; it is speculated that palonosetron's dual action induces amplification of its inhibitory effect at the primary receptor binding site. (24)
In our study when considered irrespective of the emetogenicity of the regimens, palonosetron is found to be the best acting drug followed by granisetron more so from Day 2 onwards, i.e. the period after the initial 24 hours. But in highly emetogenic regimens no momentous difference was found between the efficacies of the drugs, contrary to previous studies. (25, 26) In moderately emetogenic regimens the superiority of palonosetron was clearly established in the acute phase (0-24 h), (27) although apparent, much difference was not found in the subsequent hours (24-120 h).
All the patients were observed till Day 8 for the occurrence of any side effects. Side effect profiles of the drugs were found to be similar (26) (p value = 0.99998), with no life threatening adverse effects occurring (see Figure 5). 39 (6.3%) patients in ondansetron group, 28 (6.4%) in granisetron group and 17 (10.8%) in palonosetron group were found to be having at least one antiemetic drug related side effect (p value= 0.118). The incidence of prolongation of the heart-rate-corrected QT interval (QTc) was found in 5 (0.8%) patients on ondansetron, although caused no further complications. 3 patients on ondansetron and 2 patients on granisetron died within Day 5-8 of chemotherapy initiation, although the cause of the deaths were found to be due to the malignant processes itself and unrelated to the antiemetic treatment.
There are several brand names for a given 5[HT.sub.3] receptor antagonists in India. The cost of drug expenditure was based on the mean price of all parenteral combinations available in Indian market as in December 2009. In our study, ondansetron and granisetron were given on Day 1 and 2, whereas palonosetron was given only on Day 1. Calculations of expenses for each drug/cycle are given in Table 6. Palonosetron was found to be the most expensive drug, followed by granisetron, also supply of palonosetron in the medicine shops is inadequate in lieu of its cost. The cost of dexamethasone was not included in analysis, since it is the same for the 3 arms of treatment. Information available was not sufficient for a detailed cost analysis and hence there should be further research regarding the detailed cost analysis of the drugs.
Our study is the first one to compare the efficiency and cost of 5-[HT.sub.3] receptor antagonists in Indian patients. It suggests that ondansetron, granisetron and palonosetron have similar efficacy and side-effect profiles in prophylaxis of CINV secondary to moderately or highly emetogenic chemotherapy. Preference among them must be based on other parameters such as cost, ease of administration, patient preferences, co morbid illnesses and drug interactions.
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Acknowledgment: Dr. Partha Bhowmik, Statistician, AIIH & PH, Kolkata, India.
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Bankura Sammilani Medical College, India Email: firstname.lastname@example.org
Bankura Sammilani Medical College, India
Tables Table 1: Demographic characteristics of patients Characteristics Ondasetron Granisetron Palonosetron n % n % n % Patient number 616 50.8 440 36.3 157 12.9 Age (median, year) 48 49 47 Sex distribution Male 275 44.6 210 47.7 71 45.2 Female 341 55.4 230 52.3 86 54.8 Prior chemotherapy 459 74.5 337 76.6 120 76.4 Table 2: Overall responses of each drug from Day 1 to 5 DAY THERAPY ONDANSETRON GRANISETRON PALONOSETRON P RESPONSE value Day 1 Complete 472 (76.63%) 340 (77.27%) 138 (87.89%) 0.02 Response Partial 104 (16.88%) 65 (14.77%) 14 (8.92%) Response Failure 40 (6.49%) 35 (7.96%) 5 (3.19%) Day 2 Complete 355 (57.63%) 284 (64.55%) 108 (68.78%) 0.04 Response Partial 209 (33.92%) 121 (27.49%) 38 (24.21%) Response Failure 52 (8.45%) 35 (7.96%) 11 (7.01%) Day 3 Complete 355 (57.63%) 269 (61.13%) 107 (68.15%) 0.0002 Response Partial 218 (35.39%) 116 (26.36%) 35 (22.29%) Response Failure 43 (6.98%) 55 (12.51%) 15 (9.56%) Day 4 Complete 344(55.85%) 282 (64.01%) 103 (65.60%) 0.013 Response Partial 218 (35.39%) 115 (26.27%) 42 (26.76%) Response Failure 54 (8.76%) 43 (9.72%) 12 (7.64%) Day 5 Complete 347 (56.33%) 281 (63.87%) 106 (67.52%) 0.006 Response Partial 217 (35.23%) 116 (26.36%) 43 (27.39%) Response Failure 52 (8.44%) 43 (9.77%) 8 (5.09%) Table 3: Overall responses of each drug for highly emetogenic chemotherapy from Day 1 to 5 DAY THERAPY ONDANSETRON GRANISETRON PALONOSETRON P RESPONSE value Day 1 Complete 181 (76.35%) 130 (69.89%) 52 (81.26%) 0.24 Response Partial 40 (16.89%) 35 (18.82%) 9 (14.06%) Response Failure 16 (6.76%) 21 (11.29%) 3 (4.68%) Day 2 Complete 138 (58.23%) 118 (63.45%) 44 (68.76%) 0.42 Response Partial 75 (31.65%) 55 (29.57%) 17 (26.56%) Response Failure 24 (10.12%) 13 (6.98%) 3 (4.68%) Day 3 Complete 135 (56.97%) 109 (58.61%) 43 (67.19%) 0.0014 Response Partial 88 (37.13%) 47 (25.27%) 15 (23.44%) Response Failure 14 (5.90%) 30 (16.12%) 6 (9.37%) Day 4 Complete 130 (54.86%) 120 (64.52%) 38 (59.38%) 0.15 Response Partial 85 (35.86%) 45 (24.19%) 20 (31.25%) Response Failure 22 (9.28%) 21 (11.29%) 6 (9.37%) Day 5 Complete 132 (55.69%) 117 (62.90%) 39 (60.93%) 0.63 Response Partial 79 (33.34%) 53 (28.49%) 18 (28.13%) Response Failure 26 (10.97%) 16 (8.61%) 7 (10.94%) Table 4: Overall responses of each drug for moderately emetogenic chemotherapy from Day 1 to 5 DAY THERAPY ONDANSETRON GRANISETRON PALONOSETRON P value RESPONSE Day 1 Complete 291 (76.78%) 210 (82.67%) 86 (92.47%) 0.01 Response Partial 64 (16.88%) 30 (11.81%) 5 (5.37%) Response Failure 24 (6.34%) 14 (5.52%) 2 (2.16%) Day 2 Complete 217 (57.25%) 166 (65.35%) 64 (68.81%) 0.05 Response Partial 134 (35.36%) 66 (25.98%) 21 (22.58%) Response Failure 28 (7.39%) 22 (8.67%) 8 (8.61%) Day 3 Complete 220 (58.04%) 160 (63.00%) 64 (68.81%) 0.09 Response Partial 130 (34.30%) 69 (27.16%) 20 (21.51%) Response Failure 29 (7.66%) 25 (9.84%) 9 (9.68%) Day 4 Complete 214 (56.46%) 162 (63.77%) 65 (69.89%) 0.09 Response Partial 133 (35.09%) 70 (27.56%) 22 (23.65%) Response Failure 32 (8.45%) 22 (8.67%) 6 (6.46%) Day 5 Complete 215 (56.72%) 164 (64.56%) 67 (72.04%) 0.0006 Response Partial 138 (36.41%) 63 (24.81%) 25 (26.88%) Response Failure 26 (6.87%) 27 (10.63%) 1 (1.08%) Table 5: Details of the treatment related side effects DRUG Headache Constipation Hypokalemia Elevation of ALT ONDANSETRON 11 (1.8%) 26 (4.2%) 9 (1.5%) 10 (1.6%) GRANISETRON 8 (1.8%) 19 (4.3%) 7 (1.6%) 8 (1.8%) PALONOSETRON 3 (1.9%) 8 (5.1%) 2 (1.3%) 3 (1.9%) DRUG Elevation of AST ONDANSETRON 8 (1.3%) GRANISETRON 5 (1.1%) PALONOSETRON 2 (1.3%) Table 6: Calculations of expenses for each 5HT3 receptor antagonists used for one cycle (costs of the drugs given are mean costs of all the brands available in Indian market) Cost Total Cost Required Number of Drug Dose (INR = Indian doses (INR = Indian Rupee) required/cycle Rupee) ONDANSETRON 8 mg 32 INR 2 64 INR GRANISETRON 3 mg 57 INR 2 114 INR PALONOSETRON 0.75 mg 430 INR 1 430 INR Figure 1: List of chemotherapeutic agents according to their emetogenicity (7-9) High (> 90% frequency of emesis) Low (10%-30% frequency of emesis) Cetuximab Carmustine > 250 mg/ [m.sup.2] Cisplatin > 50 mg/ [m.sup.2] Cytarabine 100-200 mg/ [m.sup.2] Cyclophosphamide > Docetaxel 1,500 mg/ [m.sup.2] Etoposide Dacarbazine 5-fluorouracil Mechlorethamine Gemcitabine Procarbazine (oral) Methotrexate > 50 mg/ [m.sup.2] Streptozocin Mitomycin Mitoxantrone Paclitaxel Moderate (30%-90% frequency Minimal (< 10% frequency of emesis) of emesis) Carboplatin Bevacizumab Cyclophosphamide < Bleomycin 1,500 mg/ [m.sup.2] Bortezomib Cyclophosphamide (oral) Busulfan Cytarabine > 1 g/ [m.sup.2] Fludarabine Daunorubicin Gefitinib Doxorubicin Hydroxyurea (oral) Epirubicin Rituximab Etoposide (oral) Trastuzumab Idarubicin 2-chlorodeoxyadenosine Ifosfamide Vinblastine Imatinib (oral) Vincristine Irinotecan Vinorelbine Oxaliplatin > 75 mg/ [m.sup.2] Temozolomide (oral) Vinorelbine (oral)
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|Author:||Ghosh, Sayantani; Dey, Saugat|
|Publication:||International Journal of Collaborative Research on Internal Medicine & Public Health (IJCRIMPH)|
|Date:||May 1, 2010|
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