(2011) 46, 784 789 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11 www.nature.com/bmt ORIGINAL ARTICLE The NK-1 receptor-antagonist aprepitant in high-dose chemotherapy (highdose melphalan and high-dose T-ICE: paclitaxel, ifosfamide, carboplatin, etoposide): efficacy and safety of a triple antiemetic combination K Jordan 1, F Jahn 1, P Jahn 2, T Behlendorf 1, A Stein 1, J Ruessel 1, T Kegel 1 and H-J Schmoll 1 1 Department of Internal Medicine IV Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany and 2 Institute for Health and Nursing Science, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany Complete protection from nausea/vomiting is currently achieved in a minority of patients receiving high-dose chemotherapy (HDC). Currently the use of 5-HT 3 -antagonists and dexamethasone (DEX) represents the standard of care. The role of the NK-1-antagonist aprepitant in HDC remains to be better defined. A total of 64 patients undergoing multiple days of HDC received granisetron, DEX plus aprepitant during chemotherapy. After the end of chemotherapy aprepitant plus DEX was given for a further 2 days. Primary end point was CR defined as no vomiting and no use of rescue medication in the overall phase (day 1 until 5 days after end of chemotherapy). Acute/delayed and overall CR were achieved in 83%/70% and 63%, respectively. Acute and delayed nausea were observed in 20 and 38% of the patients. The tolerability of the aprepitant regimen over 4 5 days was comparable with the 3-day antiemetic regimen. In our study, aprepitant demonstrated good tolerability. Taking into account the methodological constraints of comparing our results with those from the available literature, the addition of aprepitant to the antiemetic treatment regimen may provide improved prevention of chemotherapy-induced nausea and vomiting during HDC. (2011) 46, 784 789; doi:10.1038/bmt.2010.205; published online 13 September 2010 Keywords: chemotherapy-induced nausea and vomiting; NK-1-receptor-antagonist; aprepitant; high dose chemotherapy; risk factors receptor antagonists (5-HT 3 -RA) improved emetic control dramatically. The inclusion of dexamethasone (DEX) 3 into the antiemetic regimen resulted in further improvement in controlling CINV. However, complete response from vomiting is currently achieved in a minority of patients receiving high-dose chemotherapy (HDC). In SCT CRs between 15 50% occur in patients receiving a 5-HT 3 -RA alone or in combination with DEX. Cross comparisons of studies are difficult because of the varied regimens and different patient populations. 3 Since 2005, the guidelines for antiemesis published by the leading societies (ASCO, MASCC, ESMO, NCCN) define the triple combination composed of 5-HT 3 -RA, DEX and the neurokinin-1-receptor antagonist (NK-1-RA), aprepitant, to be the standard in 1-day high or moderate emetogenic (that is, based on anthracycline and CY) chemotherapy. 4,5 Owing to a lack of study data, no evidence-based recommendations for the treatment of CINV in HDC can be given for this triple combination so far. The expert panel creating the updated 2009 MASCC/ESMO guidelines proposes for HDC the use of a 5-HT 3 -RA in combination with DEX for acute CINV, and DEX alone for delayed CINV. 5 The reported results from existing studies looking at the triple antiemetic combination including a NK-1-RA in the HDC setting are limited. 6 8 Thus, the role of the NK-1-RA aprepitant in HDC remains to be better defined. Patients and methods Introduction Chemotherapy-induced nausea and vomiting (CINV) remains one of the most aggravating adverse drug reactions associated with chemotherapy. 1,2 The advent of 5-HT 3 - Correspondence: Dr K Jordan, Department of Internal Medicine IV, Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Street 40, Halle/Saale 06120, Germany. E-mail: Karin.jordan@medizin.uni-halle.de Received 15 March 2010; revised and accepted 16 June 2010; published online 13 September 2010 This non-randomized single-centre observational trial of the triple combination of aprepitant, granisetron and DEX in HDC was conducted at the university hospital in Halle, Germany, between March 2007 and September 2009. It was conducted in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. Inclusion criteria Patients were included if they received a HDC at least for 2 days with autologous PBSCT, had a Karnofsky index 470% and were aged 18 80 years. HDC had to reach at least a moderate emetogenic level at each treatment day.
Other antiemetics (for example, metoclopramide, neuroleptics) were not permitted during the study. Benzodiazepines were allowed as a soporific. End points Primary end point was CR in the overall phase (day 1 until 5 days after end of chemotherapy), defined as no vomiting and no use of rescue therapy in this period. Other end points were acute (during days of HDC) and delayed (day 1 until 5 days after end of HDC) CR, acute and delayed nausea as well as safety of the triple combination. For efficacy assessment, nausea and vomiting were recorded daily on a special documentary chart. All adverse events (AE) were recorded to evaluate the tolerability and were graded according to the common terminology criteria for AE (CTC-AE). All drugs administered during the study, especially cytochrome P 450 (CYP 3A4) interacting drugs, and co-emetic stimuli (that is, opioides or antibiotics) were recorded. Treatments Concerning the two HDC regimen, melphalan was given at day 1 and day 2 before PBSCT in a dosage of 100 mg/m 2 each day if patients were aged 18 60 years, or in a dosage of 70 mg/m 2 each day if they were 460 years. Details of the second HDC regimen composed of paclitaxel, carboplatin, etoposide and ifosfamide are given in Table 1. HDC was followed by a break of one day before reinfusion of stem cells. To prevent CINV, patients received aprepitant, granisetron and DEX as shown in Table 2. who received the whole study drug regimen and had efficacy assessment completed. Data were analyzed by descriptive statistics and by test statistics. Group differences were judged by simple t-test and w 2 -test. P-values o0.05 were considered statistically significant (type I error probability ¼ 5%). Results Patient characteristics and treatment In the study period, 64 patients, 52 men and 12 women, with various types of cancers were included. Details of patient characteristics are given in Table 3. In all, 43 patients (67.2%) received high-dose T-ICE (paclitaxel, ifosfamide, carboplatin, etoposide), and 21 patients (32.8%) high-dose melphalan. Mean duration of HDC was 2.67 days with a s.d. of 0.47 days, the median duration of chemotherapy was 2.9 days. Antiemetic efficacy For the overall evaluation phase the primary end point of CR was achieved in 40 (63%) of patients. For the acute phase (during days of HDC) CR was achieved in 53 patients (83%). For the delayed phase (day 1 through to day 5 after the end of HDC) CR was seen in 45 patients (70%). Acute nausea was observed in 13 patients (20%), delayed nausea in 24 patients (24%) and overall nausea by 30 patients (47%; Table 4 and Figures 1 and 2). The CR rates for the melphalan and T-ICE regimens are also listed separately in Figures 1 and 2. At the day of 785 Statistics According to the protocol-defined exclusion criteria, the per-protocol efficacy population consisted of all patients Table 3 Parameter Patient characteristics Absolute and relative counts Table 1 HDC regimen Day 1 Day 2 Day 3 Day 5 High-dose T-ICE Paclitaxel 200 mg/m 2 Carboplatin 330 mg/m 2 330 mg/m 2 330 mg/m 2 Etoposide 330 mg/m 2 330 mg/m 2 330 mg/m 2 Ifosfamide 3300 mg/m 2 3300 mg/m 2 3300 mg/m 2 PBSCT High-dose melphalan Age 18 60 years 100 mg/m 2 100 mg/m 2 PBSCT (day 4) Age 60 70 years 70 mg/m 2 70 mg/m 2 PBSCT (day 4) Abbreviations: HDC¼ high-dose chemotherapy; T-ICE ¼ paclitaxel, ifosfamide, carboplatin, etoposide. Table 2 Antiemetic treatment regimen Day 1 Other days of HDC Days 1, 2 after HDC Aprepitant 125 mg p.o. 80 mg p.o. 80 mg p.o. Granisetron 1 mg i.v. 1 mg i.v. Dexamethasone 8 mg i.v. 8 mg i.v. 8 mg i.v. Abbreviation: HDC ¼ high-dose chemotherapy. No. of patients observed 64 Age (mean (min max)) 42.3 (21 67) No. of women/men 12 (18.8%)/ 52 (81.2%) Age o35 years 18 (28.1%) Karnofsky index 100% 9 (14.1%) 90% 39 (60.9%) 80% 13 (20.3%) 70% 3 (4.7%) Type of malignancy: Multiple myeloma 21 (32.8%) Thymic carcinoma 4 (6.3%) Testicular cancer 23 (35.9%) Sarcoma 15 (23.4%) Cancer of unknown primary 1 (1.6%) Previous gastrointestinal surgery 6 (9.4%) Alcohol abuse: Yes 5 (7.8%) No 44 (68.8%) Refused to answer 15 (23.4%) Pre-existing loss of appetite 5 (7.8%) Pre-existing nausea 4 (6.3%) Pre-existing dizziness 1 (1.6%) Anxious type of personality 9 (14.1%)
786 Table 4 Number of patients with CR and incidence of nausea by phase Phase Day CR, all (n ¼ 64) CR, HD melphalan (n ¼ 21) CR, HD T-ICE (n ¼ 43) Nausea, all (n ¼ 64) Acute phase 1 61 (95%) 21 (100%) 40 (93%) 4 (6%) 2 59 (92%) 19 (91%) 40 (93%) 6 (9%) 3 37 (88%) 37 (88%) 6 (9%) 1 3 53 (83%) 19 (91%) 34 (81%) 13 (20%) Delayed phase 1 55 (86%) 18 (86%) 37 (88%) 12 (19%) 2 a 54 (84%) 16 (76%) 36 (88%) 12 (19%) 3 59 (92%) 17 (81%) 42 (98%) 5 (8%) 4 57 (89%) 16 (76%) 42 (98%) 8 (13%) 5 55 (86%) 14 (67%) 41 (95%) 11 (17%) 1 5 45 (70%) 11 (52%) 34 (79%) 24 (24%) Overall 40 (63%) 11 (52%) 29 (67%) 30 (47%) Abbreviations: HD melphalan ¼ high-dose melphalan; T-ICE ¼ paclitaxel, ifosfamide, carboplatin, etoposide. a Retransfusion of the stem cells. Relative no. of patients [%] 100 80 60 40 20 83 81 91 70 retransfusion of stem cells (second day of delayed phase in all HDC groups), the CR rate was 84% and the rate of nausea was 19%. Safety No grade 3 or 4 CTC-AE occurred before or during HDC. Within the observational period after HDC, grade 3 CTC- AE mucositis occurred in o10% of all patients. Singultus occurred in 6.3% of patients. One patient suffered from a severe loss of appetite. Details are given in Table 5. Ifosfamide was administered to 42 patients (66%). Of these, 11 (26%) patients developed an ifosfamide encephalopathy. Toxicity concerning significant blood parameters was: neutropenia grade 4 CTC-AE during 6.5 days in the mean, with a spread of 2 11 days, and thrombocytopenia grade 4 CTC-AE during 5.1 days in the mean with a spread of 0 13 days. Risk analysis For several categorical or continuous variables (Table 6), risk factor analyses were performed, comparing non-cr vs CR. Differences between the two groups did not reach statistical significance. An effect could only be demonstrated with concomitant medications patients 79 52 63 67 52 0 CR acute CR delayed CR overall All HDC (N=64) HD T-ICE (N =43) HD Melphalan (N=21) Figure 1 Frequency of CR in the acute (during HDC), delayed (day 1 to 5 days after the end of HDC) and overall phase in patients with HDC. Relative no. of patients [%] 100 80 60 40 20 0 taking opiates had a significantly higher risk (P ¼ 0.02) of not achieving CR with the administered prophylactic regime (Table 6). Discussion 20 23 12 24 23 All HDC (N=64) HD T-ICE (N=43) HD Melphalan (N =21) Following HDC, CINV remains one of the most devastating adverse drug reactions. There is still very little data on the effective use of modern antiemetics for patients treated with HDC with stem cell support. Currently, 5-HT 3 -RA plus DEX are recommended as the standard therapy preventing CINV in this setting. 6,9 However, the level of control with this antiemesis prophylaxis is still suboptimal. In order to improve on these results, the addition of a NK- 1-RA in HDC seems to be the next logical step to enhance emetic control in this setting. In our study we evaluated the role of the NK-1-RA aprepitant when added to the standard antiemetic regimen of the 5-HT 3 -RA granisetron and DEX in HDC. The variable definitions of response in the few existing studies, which combine a 5-HT 3 -RA and steroid are the main reason for differences to our results presented here. Our primary end point was to achieve CR with no vomiting at 67 47 37 Nausea acute Nausea delayed Nausea overall Figure 2 Relative frequency of acute (during HDC), delayed (day 1 5 after HDC) and overall nausea in patients with HDC. 67
Table 5 Overview of adverse events by HDC treatment phase and CTC-AE grades (no grade 4 toxicity was detected) 787 CTC-AE grade Before HDC During HDC After HDC (o10 day) After HDC (410 day) 0 1 0 1 2 0 1 2 3 0 1 2 3 Adverse event: Hiccups 64 63 1 61 3 64 Loss of appetite 59 5 31 32 1 27 29 8 40 14 9 1 Headache 63 1 61 2 1 56 7 1 59 4 1 Constipation 64 63 1 58 6 60 4 Mucositis 63 1 60 3 1 39 12 8 5 37 10 11 6 Diarrhoea 64 58 6 49 11 4 47 15 2 Abbreviations: CTC-AE ¼ common terminology criteria for adverse events; HDC ¼ high-dose chemotherapy. Table 6 Risk factor analysis for categorical and continuous individual parameters, and for comedications including CYP-inducing medications: intergroup comparison non-cr vs CR Non-CR CR RR 95% CI P-value a Categorial values No. of patients 24 (37%) 40 (63%) Patients with HD-melphalan 10 (48%) 11 (52%) 1.46 0.79 2.72 0.24 No. of women 7 (58%) 5 (42%) 1.78 0.96 3.31 0.10 Patients with alcohol abuse 2 (3%) 3 (5%) 1.17 0.37 3.70 0.79 Anxious personality 5 (56%) 4 (44%) 1.61 0.81 3.20 0.23 Non-CR CR DBM 95% CI P-value b Continuous values No. of patients 24 (37%) 40 (63%) Age (years) (mean (s.d.)) 41.2 (13.9) 42.9 (12.0) 1.69 4.88 8.26 0.61 Karnofsky index (mean (s.d.)) 88.8 (6.8) 88.3 (7.5) 0.50 4.23 3.23 0.78 Duration of HDC (days) (mean (s.d.)) 2.6 (0.1) 2.7 (0.1) 0.14 0.10 0.39 0.25 Non-CR CR RR 95% CI P-value a Comedications/CYP-inducing medications Opiates 9 (64%) 5 (35%) 2.14 1.21 3.81 0.02 c Imipenem 0 (0%) 1 (100%) 0.44 Moxifloxacin 1 (25%) 3 (75%) 0.65 0.12 3.67 0.59 Ciprofloxacin 20 (40%) 30 (60%) 1.40 0.57 3.43 0.44 Abbreviations: CI ¼ confidence interval; CR ¼ complete response; CYP ¼ cytochrome P; DBM ¼ difference between means; HDC ¼ high-dose chemotherapy; Non-CR ¼ non-complete response; RR ¼ relative risk. a Pearson s w 2 -test. b t-test. c Statistically significant (type I-error probability ¼ 5%). all, and no use of rescue therapy during the acute and the delayed phase of HDC. In contrast, in most studies cited here, patients were considered complete responders, even when having had one or more episodes of emesis. 10,11 Separate studies in HDC are difficult to evaluate and compare because of several factors: (1) other causes for nausea and vomiting including antibiotics, analgesics and possible emetogenic potential of the cryo-preservatives, in which stem cells have been suspended; (2) concomitant use of total-body irridiation; (3) varied chemotherapy regimens, different patient populations and tumor types; (4) non-chemotherapy naive patients and (5) significantly different definitions of response and complete response, which makes cross-comparison extremely difficult. 3,5,6 Monotherapy with 5-HT 3 -RA: Former single-arm studies with 5-HT 3 -RA covered only small numbers of patients, 12 and led especially to late-onset delayed emesis. 11,13 With a similar chemotherapy regime, a total of 33 myeloma patients treated with high-dose melphalan (140 200 mg/m 2 /day i.v.) were given the 5-HT 3 -RA ondansetron in the study by Viner et al. 10 Emetic episodes were abolished in only 15% of the patients over a 7 day period. Similar findings were reported in an observational study in 100 consecutive transplant patients. 14 In this study, Lopez-Jimenez et al. reported a CR rate of only 20% of patients with the use of a 5-HT 3 -RA. These results and similar studies led to the conclusion that single-agent use of a 5-HT 3 -RA had a poor antiemetic effect, and that optimized therapies would be needed. Combination antiemetic therapies: An all oral antiemetic regimen 13 (2 mg granisetron once daily, 4 mg DEX every 6 h and 10 mg prochlorperazine) during and one day after HDC (6 g/m 2 CY, 1.8 g/m 2 VP-16 or 500 mg/m 2 thiotepa,
788 1.2 g/m 2 carboplatin in four daily doses over 4 days) for conditioning PBSCT, was administered to 36 patients. Acute CR for emesis (no emetic episodes during 4 treatment days) was achieved by 53% of the patients. Severe cases of late onset during the delayed phase, defined as more than three emetic episodes, occurred in 8 of 27 patients (29.6%) who had not failed during the acute phase. Although the study results are difficult to compare (different end point, therapeutic regimen and broad variation in patient populations), our results showed better antiemetic control with 83% CR in the acute phase and 70% CR in the delayed phase, especially when considering our strict response criterias. Climent et al. 15 presented results of a study in 30 patients with breast cancer, who received HDC with CY 1500 mg/ m 2 /day, thiotepa 125 mg/m 2 /day and carboplatin 200 mg/ m 2 /day all over 4 days. The CINV prophylaxis regime consisted of granisetron (3 mg/12 h i.v.), DEX (12 mg/24 h i.v.), haloperidol (0.5 mg/12 h per os (p.o.)) and lorazepam (1 mg/24 h p.o.). Acute (day 1 4) and overall (day 1 8) prevention of emesis were achieved in 10.7 and 6% of the patients, respectively. On the day of the stem cell retransfusion, protection of emesis was achieved in 53.3% of the patients. This compares to a CR of 84% in our study. So far, no valid data has been published with regard to the emetogenic potential of the cryo-preservatives, in which stem cells have been suspended. These results are not suitably comparable in the study by Climent et al., 15 the antiemetics were given on the transplantation day on an as needed basis, whereas all patients in our study received the protocol mandated antiemetic therapy. Furthermore, in our study it is not possible to distinguish whether the high CR rates on the day of the stem cell reinfusion are related to a sufficient antiemetic prophylaxis or a possible low emetogenic potential of the cryo-preservatives. The additional use and value of aprepitant in HDC were presented in several posters, but these results are currently not fully published and will therefore not be discussed here. 16 20 In a very recent study the efficacy of the triple combination therapy with aprepitant in 42 patients receiving HDC was evaluated. 8 Eight different chemotherapeutic regimens with varying duration and emetogenic potentials including total body irradiaton were used. The application of aprepitant was comparable to our study, but the 5-HT 3 -RA and DEX was only given on day 1 in the study by Paul et al. 8 The median duration of the HDC was not specified. The CR rate (no emesis, none-to-mild nausea, and no breakthrough medication) on the worst day was 42.9%. On average, 54% of the patients had CR from the beginning of the HDC until day 7 after HDC in the study by Paul et al. Our results, with a CR of 83% for the acute phase and an overall efficacy of 63% were superior to the study by Paul et al. These results cannot be easily compared due to differing patient populations, chemotherapeutic regimens and antiemetic regimens used in the two studies. However, the application of the 5-HT 3 -RA and DEX on day 1 only in the Paul study may be one reason for the difference in results. Safety: Concerning the prolonged use of aprepitant combined with 5-HT 3 -RA and steroid, a good tolerability profile was stated in the available studies. 8,21 The tolerability profile of the triple combined regimen in our study patients corresponds to former findings concerning antiemetic treatment with 5-HT 3 -RA and steroids in patients receiving HDC. 6,10,13 Interestingly, in our patient population the incidence of hiccups was 6.3%, which compares well with the incidence in the approval studies for aprepitant, 22,23 was much lower than in the study by Paul et al. with a singultus incidence of 33%. 8 A suspected interaction between aprepitant and ifosfamide is reported and discussed in a case report. 24 In general, ifosfamide-induced encephalopathy is described in 10 30% of patients. Our finding of 26% of ifosfamide-induced encephalopathy under the triple combination therapy lies within the range reported for high-dose ifosfamide without aprepitant. This, of course, cannot exclude an interrelationship between the two agents. 25 Risk factors: In our study, patients taking opiates had a significantly higher risk (P ¼ 0.02) of not completely responding to the administered prophylaxis. This observation highlights the role of confounding factors in patients receiving HDC and should be considered when planning a randomized trial. 3 In conclusion, in our study aprepitant has demonstrated good tolerability. There is no augmentation of the toxicity profile compared with data published elsewhere. Considering the methodological limitations of comparing our results with those from literature, it appears that the addition of aprepitant to the standard antiemetic treatment regimen may afford improved prevention from CINV during multiple-day HDC administration. Randomized studies will be necessary to possibly implement the NK-1-RA into the guidelines on antiemetic therapy during HDC. Conflict of interest K Jordan and H-J Schmoll have received compensation as members of the scientific advisory board of MSD Merck Sharp and Dohme. The remaining authors declare no conflict of interest Acknowledgements We thank Dr H-J Olbert for assistance in preparing the paper. References 1 Coates A, Abraham S, Kaye SB, Sowerbutts T, Frewin C, Fox RM et al. On the receiving end patient perception of the sideeffects of cancer chemotherapy. Eur J Cancer Clin Oncol 1983; 19: 203 208. 2 Griffin AM, Butow PN, Coates AS, Childs AM, Ellis PM, Dunn SM et al. On the receiving end V: patient perceptions of the side effects of cancer chemotherapy in 1993. Ann Oncol 1996; 7: 189 195. 3 Einhorn LH, Rapoport B, Koeller J, Grunberg SM, Feyer P, Rittenberg C et al. Antiemetic therapy for multiple-day chemotherapy and high-dose chemotherapy with stem cell transplant: review and consensus statement. Support Care Cancer 2005; 13: 112 116.
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