The NK-1 Receptor-Antagonist Aprepitant in High-Dose Chemotherapy

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ORIGINAL ARTICLE The NK-1 receptor-antagonist aprepitant in high-dose chemotherapy (high- dose melphalan and high-dose T-ICE: paclitaxel, ifosfamide, carboplatin, etoposide): efﬁcacy and safety of a triple antiemetic combination

K Jordan1, F Jahn1, P Jahn2, T Behlendorf1, A Stein1, J Ruessel1, T Kegel1 and H-J Schmoll1

1Department of Internal Medicine IV Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany and 2Institute for Health and Nursing Science, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany

Complete protection from nausea/vomiting is currently receptor antagonists (5-HT3-RA) improved emetic control achieved in a minority of patients receiving high-dose dramatically. The inclusion of dexamethasone (DEX)3 chemotherapy (HDC). Currently the use of 5-HT3-anta- into the antiemetic regimen resulted in further improve- gonists and dexamethasone (DEX) represents the standard ment in controlling CINV. However, complete response of care. The role of the NK-1-antagonist aprepitant in from vomiting is currently achieved in a minority of HDC remains to be better deﬁned. A total of 64 patients patients receiving high-dose chemotherapy (HDC). In undergoing multiple days of HDC received granisetron, SCT CRs between 15–50% occur in patients receiving a

DEX plus aprepitant during chemotherapy. After the end 5-HT3-RA alone or in combination with DEX. Cross of chemotherapy aprepitant plus DEX was given for a comparisons of studies are difficult because of the varied further 2 days. Primary end point was CR defined as no regimens and different patient populations.3 vomiting and no use of rescue medication in the overall Since 2005, the guidelines for antiemesis published by the phase (day 1 until 5 days after end of chemotherapy). leading societies (ASCO, MASCC, ESMO, NCCN) define

Acute/delayed and overall CR were achieved in 83%/70% the triple combination composed of 5-HT3-RA, DEX and and 63%, respectively. Acute and delayed nausea were the neurokinin-1-receptor antagonist (NK-1-RA), aprepi- observed in 20 and 38% of the patients. The tolerability tant, to be the standard in 1-day high or moderate of the aprepitant regimen over 4–5 days was comparable emetogenic (that is, based on anthracycline and CY) with the 3-day antiemetic regimen. In our study, aprepi- chemotherapy.4,5 Owing to a lack of study data, no tant demonstrated good tolerability. Taking into account evidence-based recommendations for the treatment of the methodological constraints of comparing our results CINV in HDC can be given for this triple combination with those from the available literature, the addition of so far. The expert panel creating the updated 2009 aprepitant to the antiemetic treatment regimen may provide MASCC/ESMO guidelines proposes for HDC the use of improved prevention of chemotherapy-induced nausea and a 5-HT3-RA in combination with DEX for acute CINV, vomiting during HDC. and DEX alone for delayed CINV.5 The reported results Bone Marrow Transplantation (2011) 46, 784–789; from existing studies looking at the triple antiemetic doi:10.1038/bmt.2010.205; published online 13 September 2010 combination including a NK-1-RA in the HDC setting Keywords: chemotherapy-induced nausea and vomiting; are limited.6–8 Thus, the role of the NK-1-RA aprepitant NK-1-receptor-antagonist; aprepitant; high dose chemo- in HDC remains to be better deﬁned. therapy; risk factors

Patients and methods

Introduction This non-randomized single-centre observational trial of the triple combination of aprepitant, granisetron and DEX Chemotherapy-induced nausea and vomiting (CINV) in HDC was conducted at the university hospital in Halle, remains one of the most aggravating adverse drug reactions Germany, between March 2007 and September 2009. It was 1,2 associated with chemotherapy. The advent of 5-HT3- conducted in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice.

Correspondence: Dr K Jordan, Department of Internal Medicine IV, Inclusion criteria Oncology/Hematology, Martin-Luther-University Halle-Wittenberg, Patients were included if they received a HDC at least for Ernst-Grube-Street 40, Halle/Saale 06120, Germany. E-mail: [email protected] 2 days with autologous PBSCT, had a Karnofsky index Received 15 March 2010; revised and accepted 16 June 2010; published 470% and were aged 18–80 years. HDC had to reach at online 13 September 2010 least a moderate emetogenic level at each treatment day. Addition of NK-1 receptor antagonist in high-dose chemotherapy K Jordan et al 785 Other antiemetics (for example, metoclopramide, neuro- who received the whole study drug regimen and had leptics) were not permitted during the study. Benzodiaze- efficacy assessment completed. Data were analyzed by des- pines were allowed as a soporific. criptive statistics and by test statistics. Group differences were judged by simple t-test and w2-test. P-values o0.05 End points were considered statistically significant (type I—error Primary end point was CR in the overall phase (day 1 until probability ¼ 5%). 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 Results (day 1 until 5 days after end of HDC) CR, acute and delayed nausea as well as safety of the triple combination. Patient characteristics and treatment For efficacy assessment, nausea and vomiting were In the study period, 64 patients, 52 men and 12 women, recorded daily on a special documentary chart. All adverse with various types of cancers were included. Details of events (AE) were recorded to evaluate the tolerability and patient characteristics are given in Table 3. were graded according to the common terminology criteria In all, 43 patients (67.2%) received high-dose T-ICE for AE (CTC-AE). All drugs administered during the (paclitaxel, ifosfamide, carboplatin, etoposide), and 21 study, especially cytochrome P 450 (CYP 3A4) interacting patients (32.8%) high-dose melphalan. Mean duration of drugs, and co-emetic stimuli (that is, opioides or anti- HDC was 2.67 days with a s.d. of 0.47 days, the median biotics) were recorded. duration of chemotherapy was 2.9 days.

Treatments Antiemetic efﬁcacy Concerning the two HDC regimen, melphalan was given at For the overall evaluation phase the primary end point day 1 and day 2 before PBSCT in a dosage of 100 mg/m2 of CR was achieved in 40 (63%) of patients. For the each day if patients were aged 18–60 years, or in a dosage of acute phase (during days of HDC) CR was achieved in 53 70 mg/m2 each day if they were 460 years. Details of the patients (83%). For the delayed phase (day 1 through to second HDC regimen composed of paclitaxel, carboplatin, day 5 after the end of HDC) CR was seen in 45 patients etoposide and ifosfamide are given in Table 1. HDC was (70%). Acute nausea was observed in 13 patients (20%), followed by a break of one day before reinfusion of stem delayed nausea in 24 patients (24%) and overall nausea cells. by 30 patients (47%; Table 4 and Figures 1 and 2). The To prevent CINV, patients received aprepitant, granise- CR rates for the melphalan and T-ICE regimens are tron and DEX as shown in Table 2. also listed separately in Figures 1 and 2. At the day of

Statistics According to the protocol-deﬁned exclusion criteria, the per-protocol efﬁcacy population consisted of all patients Table 3 Patient characteristics Parameter Absolute and relative counts

No. of patients observed 64 Table 1 HDC regimen Age (mean (min–max)) 42.3 (21–67) No. of women/men 12 (18.8%)/ Day 1 Day 2 Day 3 Day 5 52 (81.2%) High-dose T-ICE Age o35 years 18 (28.1%) Paclitaxel 200 mg/m2 Carboplatin 330 mg/m2 330 mg/m2 330 mg/m2 Karnofsky index Etoposide 330 mg/m2 330 mg/m2 330 mg/m2 100% 9 (14.1%) Ifosfamide 3300 mg/m2 3300 mg/m2 3300 mg/m2 90% 39 (60.9%) PBSCT 80% 13 (20.3%) High-dose melphalan 70% 3 (4.7%) Age 18–60 years 100 mg/m2 100 mg/m2 PBSCT (day 4) Age 60–70 years 70 mg/m2 70 mg/m2 PBSCT (day 4) Type of malignancy: Multiple myeloma 21 (32.8%) Thymic carcinoma 4 (6.3%) Abbreviations: HDC ¼ high-dose chemotherapy; T-ICE ¼ paclitaxel, ifosfamide, Testicular cancer 23 (35.9%) carboplatin, etoposide. Sarcoma 15 (23.4%) Cancer of unknown primary 1 (1.6%) Previous gastrointestinal surgery 6 (9.4%) Table 2 Antiemetic treatment regimen Alcohol abuse: Day 1 Other days Days 1, 2 Yes 5 (7.8%) of HDC after HDC No 44 (68.8%) Refused to answer 15 (23.4%) Aprepitant 125 mg p.o. 80 mg p.o. 80 mg p.o. Pre-existing loss of appetite 5 (7.8%) Granisetron 1 mg i.v. 1 mg i.v. Pre-existing nausea 4 (6.3%) Dexamethasone 8 mg i.v. 8 mg i.v. 8 mg i.v. Pre-existing dizziness 1 (1.6%) Anxious type of personality 9 (14.1%) Abbreviation: HDC ¼ high-dose chemotherapy.

Bone Marrow Transplantation Addition of NK-1 receptor antagonist in high-dose chemotherapy K Jordan et al 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%) 2a 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. aRetransfusion of the stem cells.

100 91 100 83 81 79 80 70 67 63 80 67 67 52 60 52 60 47 40 37 40 24 20 20 23 23 12 20 0

Relative no. of patients [%] CR acute CR delayed CR overall

Relative no. of patients [%] 0 All HDC (N=64) HD T-ICE (N =43) HD Melphalan Nausea acute Nausea delayed Nausea overall (N=21)

Figure 1 Frequency of CR in the acute (during HDC), delayed (day 1 to All HDC (N=64) HD T-ICE (N=43) HD Melphalan 5 days after the end of HDC) and overall phase in patients with HDC. (N =21) Figure 2 Relative frequency of acute (during HDC), delayed (day 1–5 after HDC) and overall nausea in patients with HDC.

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%. taking opiates had a signiﬁcantly higher risk (P ¼ 0.02) of not achieving CR with the administered prophylactic regime (Table 6). Safety No grade 3 or 4 CTC-AE occurred before or during HDC. Within the observational period after HDC, grade 3 CTC- Discussion AE mucositis occurred in o10% of all patients. Singultus occurred in 6.3% of patients. One patient suffered from a Following HDC, CINV remains one of the most devastat- severe loss of appetite. Details are given in Table 5. ing adverse drug reactions. There is still very little data on Ifosfamide was administered to 42 patients (66%). Of the effective use of modern antiemetics for patients treated these, 11 (26%) patients developed an ifosfamide encepha- with HDC with stem cell support. Currently, 5-HT -RA lopathy. 3 plus DEX are recommended as the standard therapy Toxicity concerning signiﬁcant blood parameters was: preventing CINV in this setting.6,9 However, the level of neutropenia grade 4 CTC-AE during 6.5 days in the mean, control with this antiemesis prophylaxis is still suboptimal. with a spread of 2–11 days, and thrombocytopenia grade 4 In order to improve on these results, the addition of a NK- CTC-AE during 5.1 days in the mean with a spread of 1-RA in HDC seems to be the next logical step to enhance 0–13 days. emetic control in this setting. In our study we evaluated the role of the NK-1-RA Risk analysis aprepitant when added to the standard antiemetic regimen

For several categorical or continuous variables (Table 6), of the 5-HT3-RA granisetron and DEX in HDC. The risk factor analyses were performed, comparing non-CR variable deﬁnitions of response in the few existing studies,

vs CR. Differences between the two groups did not which combine a 5-HT3-RA and steroid are the main reach statistical signiﬁcance. An effect could only be reason for differences to our results presented here. Our demonstrated with concomitant medications—patients primary end point was to achieve CR with no vomiting at

Bone Marrow Transplantation Addition of NK-1 receptor antagonist in high-dose chemotherapy K Jordan et al 787 Table 5 Overview of adverse events by HDC treatment phase and CTC-AE grades (no grade 4 toxicity was detected)

CTC-AE grade Before HDC During HDC After HDC (o10 day) After HDC (410 day)

0101201230123

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-valuea

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-valueb

Continuous values No. of patients 24 (37%) 40 (63%) Age (years) (mean (s.d.)) 41.2 (13.9) 42.9 (12.0) 1.69 À4.88–8.26 0.61 Karnofsky index (mean (s.d.)) 88.8 (6.8) 88.3 (7.5) 0.50 À4.23–3.23 0.78 Duration of HDC (days) (mean (s.d.)) 2.6 (0.1) 2.7 (0.1) 0.14 À0.10–0.39 0.25

Non-CR CR RR 95% CI P-valuea

Comedications/CYP-inducing medications Opiates 9 (64%) 5 (35%) 2.14 1.21–3.81 0.02c 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. aPearson’s w2-test. bt-test. cStatistically signiﬁcant (type I-error probability ¼ 5%).

all, and no use of rescue therapy during the acute and the led especially to late-onset delayed emesis.11,13 With a similar delayed phase of HDC. In contrast, in most studies cited chemotherapy regime, a total of 33 myeloma patients treated here, patients were considered complete responders, even with high-dose melphalan (140–200 mg/m2/day i.v.) were 10,11 when having had one or more episodes of emesis. given the 5-HT3-RA ondansetron in the study by Viner Separate studies in HDC are difficult to evaluate and et al.10 Emetic episodes were abolished in only 15% of the compare because of several factors: (1) other causes for patients over a 7 day period. Similar findings were reported nausea and vomiting including antibiotics, analgesics and in an observational study in 100 consecutive transplant possible emetogenic potential of the cryo-preservatives, in patients.14 In this study, Lopez-Jimenez et al. reported a CR which stem cells have been suspended; (2) concomitant use rate of only 20% of patients with the use of a 5-HT3-RA. of total-body irridiation; (3) varied chemotherapy regi- These results and similar studies led to the conclusion that mens, different patient populations and tumor types; (4) single-agent use of a 5-HT3-RA had a poor antiemetic effect, non-chemotherapy naive patients and (5) significantly and that optimized therapies would be needed. different definitions of response and complete response, Combination antiemetic therapies: An all oral antiemetic which makes cross-comparison extremely difficult.3,5,6 regimen13 (2 mg granisetron once daily, 4 mg DEX every 6 h

Monotherapy with 5-HT3-RA: Former single-arm studies and 10 mg prochlorperazine) during and one day after 12 2 2 2 with 5-HT3-RA covered only small numbers of patients, and HDC (6 g/m CY, 1.8 g/m VP-16 or 500 mg/m thiotepa,

Bone Marrow Transplantation Addition of NK-1 receptor antagonist in high-dose chemotherapy K Jordan et al 788 1.2 g/m2 carboplatin in four daily doses over 4 days) for patients corresponds to former ﬁndings concerning antie-

conditioning PBSCT, was administered to 36 patients. metic treatment with 5-HT3-RA and steroids in patients Acute CR for emesis (no emetic episodes during 4 treat- receiving HDC.6,10,13 Interestingly, in our patient popula- ment days) was achieved by 53% of the patients. Severe tion the incidence of hiccups was 6.3%, which compares cases of late onset during the delayed phase, defined as well with the incidence in the approval studies for more than three emetic episodes, occurred in 8 of 27 aprepitant,22,23 was much lower than in the study by Paul patients (29.6%) who had not failed during the acute phase. et al. with a singultus incidence of 33%.8 Although the study results are difficult to compare A suspected interaction between aprepitant and ifosfa- (different end point, therapeutic regimen and broad mide is reported and discussed in a case report.24 In general, variation in patient populations), our results showed better ifosfamide-induced encephalopathy is described in 10–30% antiemetic control with 83% CR in the acute phase and of patients. Our finding of 26% of ifosfamide-induced 70% CR in the delayed phase, especially when considering encephalopathy under the triple combination therapy lies our strict response criterias. within the range reported for high-dose ifosfamide without Climent et al.15 presented results of a study in 30 patients aprepitant. This, of course, cannot exclude an interrelation- with breast cancer, who received HDC with CY 1500 mg/ ship between the two agents.25 m2/day, thiotepa 125 mg/m2/day and carboplatin 200 mg/ Risk factors: In our study, patients taking opiates had m2/day all over 4 days. The CINV prophylaxis regime a significantly higher risk (P ¼ 0.02) of not completely consisted of granisetron (3 mg/12 h i.v.), DEX (12 mg/24 h responding to the administered prophylaxis. This observa- i.v.), haloperidol (0.5 mg/12 h per os (p.o.)) and lorazepam tion highlights the role of confounding factors in patients (1 mg/24 h p.o.). Acute (day 1–4) and overall (day 1–8) receiving HDC and should be considered when planning a prevention of emesis were achieved in 10.7 and 6% of the randomized trial.3 patients, respectively. On the day of the stem cell retrans- In conclusion, in our study aprepitant has demon- fusion, protection of emesis was achieved in 53.3% of the strated good tolerability. There is no augmentation of the patients. This compares to a CR of 84% in our study. So toxicity profile compared with data published elsewhere. far, no valid data has been published with regard to the Considering the methodological limitations of compa- emetogenic potential of the cryo-preservatives, in which ring our results with those from literature, it appears that stem cells have been suspended. These results are not the addition of aprepitant to the standard antiemetic suitably comparable—in the study by Climent et al.,15 the treatment regimen may afford improved prevention from antiemetics were given on the transplantation day on an CINV during multiple-day HDC administration. Rando- as needed basis, whereas all patients in our study received mized studies will be necessary to possibly implement the protocol mandated antiemetic therapy. Furthermore, the NK-1-RA into the guidelines on antiemetic therapy in our study it is not possible to distinguish whether the during HDC. 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. Conflict of interest The additional use and value of aprepitant in HDC were presented in several posters, but these results are currently K Jordan and H-J Schmoll have received compensation not fully published and will therefore not be discussed as members of the scientific advisory board of MSD here.16–20 In a very recent study the efficacy of the triple Merck Sharp and Dohme. The remaining authors declare combination therapy with aprepitant in 42 patients receiving no conflict of interest HDC was evaluated.8 Eight different chemotherapeutic regimens with varying duration and emetogenic potentials including total body irradiaton were used. The application of Acknowledgements aprepitant was comparable to our study, but the 5-HT3-RA 8 and DEX was only given on day 1 in the study by Paul et al. We thank Dr H-J Olbert for assistance in preparing the paper. 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% References 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 1 Coates A, Abraham S, Kaye SB, Sowerbutts T, Frewin C, Fox a CR of 83% for the acute phase and an overall efficacy of RM et al. On the receiving end–patient perception of the side- 63% were superior to the study by Paul et al. These results effects of cancer chemotherapy. Eur J Cancer Clin Oncol 1983; cannot be easily compared due to differing patient popula- 19: 203–208. tions, chemotherapeutic regimens and antiemetic regimens 2 Griffin AM, Butow PN, Coates AS, Childs AM, Ellis PM, used in the two studies. However, the application of the Dunn SM et al. On the receiving end V: patient perceptions of Ann Oncol 5-HT -RA and DEX on day 1 only in the Paul study may be the side effects of cancer chemotherapy in 1993. 3 1996; 7: 189–195. one reason for the difference in results. 3 Einhorn LH, Rapoport B, Koeller J, Grunberg SM, Feyer P, Safety: Concerning the prolonged use of aprepitant Rittenberg C et al. Antiemetic therapy for multiple-day combined with 5-HT3-RA and steroid, a good tolerability chemotherapy and high-dose chemotherapy with stem cell profile was stated in the available studies.8,21 The toler- transplant: review and consensus statement. Support Care ability profile of the triple combined regimen in our study Cancer 2005; 13: 112–116.

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