Journal of the Egyptian National Cancer Institute xxx (2017) xxx–xxx

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Journal of the Egyptian National Cancer Institute

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Full length article Addition of 3-day aprepitant to ondansetron and dexamethasone for prophylaxis of -induced nausea and vomiting among patients with diffuse large B cell lymphoma receiving 5-day -based chemotherapy ⇑ Raafat Abdel-Malek, Noha Abbas, Kyrillus S. Shohdy , Mohamed Ismail, Radwa Fawzy, Dalal S. Salem, Ezzat Safwat a Clinical Oncology Department, Kasr Alainy Center of Clinical Oncology & Nuclear Medicine (NEMROCK), Kasr Alainy School of Medicine, Cairo, University, Cairo University Hospitals, Al-Saray St., El-Maniel, 11451 Cairo, Egypt article info abstract

Article history: Background: Neurokinin-1 receptor antagonists, such as aprepitant are currently emerging as powerful Received 4 November 2016 prophylactic agents for chemotherapy-induced nausea and vomiting (CINV). Therefore, it is important Received in revised form 26 April 2017 to adjust the anti-emetic regimens based on personal risk factors of the patient, duration of the Accepted 1 May 2017 and cost-effectiveness. Available online xxxx Purpose: To determine the efficacy of the 3-day aprepitant along with ondansetron and dexamethasone in controlling CINV in patients with large B cell lymphoma receiving multiday-cisplatin regimen Keywords: chemotherapy. Aprepitant Methods: This is a pilot prospective cross-over trial. Patients were allocated to either aprepitant 125 mg Lymphoma Multi-day cisplatin on day 1 and 80 mg on days 2 & 3 or placebo in the first 2 cycles, with crossover to the opposite treatment Nausea in the 3rd and 4th cycles. The primary end point was complete response (CR) of both acute (days 1–5) and Vomiting delayed (days 6–8) CINV. CR means neither to develop emetic episodes nor to use rescue anti-emetics medication. Results: Twelve of the 15 patients recruited for the study were fully evaluable and completed 4 cycles of ESHAP regimen with a total of 48 cycles given. In the cycles with aprepitant and those without the CR were 83.3% and 0% respectively (p < 0.05). Patients receiving aprepitant in the first 2 cycles recorded less nausea in subsequent cycles that were given without aprepitant. This was not statistically significant. Conclusion: This triple anti-emetic regimen showed efficacy in controlling the multi-day cisplatin- induced nausea and vomiting. Further randomized controlled trials are needed to compare between 3- day and 7-day aprepitant for multi-day cisplatin regimens. Ó 2017 Production and hosting by Elsevier B.V. on behalf of National Cancer Institute, Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/).

Introduction apy regimen and cost-effectiveness especially in developing coun- tries. Optimizing the dosage of NK1RA is a crucial step now as it Chemotherapy-induced nausea and vomiting (CINV) is still was with metoclopramide that once yielded a favorable effect among the most distressing adverse effects of chemotherapy. The against CINV only when the dose was escalated massively. introduction of neurokinin-1 receptor antagonists (NK1RA), such Since their fortuitous discovery in the 1960s, platinum based- as aprepitant achieves a major advance in the prevention of CINV compounds, such as cisplatin have sprouted vastly in the arma- especially the delayed type. The next era of anti-emetic research mentarium of anti-cancer drugs. Nowadays, multi-day cisplatin is shall aim to tailor the prophylactic anti-emetic regimens based the cornerstone in treatment of germ cell tumors. Moreover, a reg- on personal risk factors of the patient, duration of the chemother- imen entailing multi-day cisplatin along with , methyl- prednisolone, high-dose , known as ESHAP, has been shown to be active against refractory or relapsed non-Hodgkin’s Peer review under responsibility of The National Cancer Institute, Cairo University. ⇑ Corresponding author. lymphoma (NHL) [1,2]. E-mail address: [email protected] (K.S. Shohdy). http://dx.doi.org/10.1016/j.jnci.2017.05.001 1110-0362/Ó 2017 Production and hosting by Elsevier B.V. on behalf of National Cancer Institute, Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Abdel-Malek R et al. Addition of 3-day aprepitant to ondansetron and dexamethasone for prophylaxis of chemotherapy- induced nausea and vomiting among patients with diffuse large B cell lymphoma receiving 5-day cisplatin-based chemotherapy. J Egyptian Nat Cancer Inst (2017), http://dx.doi.org/10.1016/j.jnci.2017.05.001 2 R. Abdel-Malek et al. / Journal of the Egyptian National Cancer Institute xxx (2017) xxx–xxx

The evidence mounts that triple anti-emetic regimen including Statistical analysis NK1-RA, 5-hydroxytryptamine-3 receptor antagonist (5HT3-RA) and dexamethasone is the standard of care for prevention of CINV Statistical analyses of the data were conducted using small stata in patients receiving highly emetogenic chemotherapy with single- 12.1 software for windows. The comparison of the rate of emetic day cisplatin combination chemotherapy [3]. Despite this signifi- episodes in the placebo and aprepitant cycles was done by Chi- cant progress, CINV continues to represent a challenge with squared test. P-value of <0.05 was considered statistically multi-day cisplatin settings with a handful of studies that has been significant. conducted till now [4,5]. Therefore, we conducted a pilot cross- over study that compared aprepitant to placebo combined with standard antiemetic prophylaxis (a 5HT3-RA and dexamethasone) Results in patients receiving 5 days of cisplatin combination chemotherapy for relapsed/refractory NHL aiming to assess the effect of addition Fifteen patients were randomly assigned to one of the two of the 3-day aprepitant in preventing delayed CINV. treatment groups. The median age was 45 years (range 38– 56 years) with 8 males and 7 females. Twelve of the 15 patients who entered the study were fully evaluable and completed 4 cycles Patients and methods of ESHAP chemotherapy regimen with a total of 48 cycles given, three patients were excluded due to loss of follow up or protocol Study design violation. The complete response (CR) was 83.3% in the treatment group This prospective placebo-controlled cross-over study was con- and 0% in the control group. During the 24 cycles received with ducted in the Clinical Oncology department, Faculty of Medicine, aprepitant, nausea was recorded in 3 times (12.5%) compared to Cairo University between January 2015 and June 2015, after 14 times (58.3%) in the cycles without (p = 0.001). The median approval by institutional review board. This is a single-blinded duration was the same between the 2 groups (2 days, range 1–4). double arm trial. Eligible patients were those with relapsed/refrac- Patients receiving aprepitant in the first 2 cycles recorded less nau- tory NHL receiving ESHAP combination chemotherapy. Antiemetic sea in subsequent cycles given without aprepitant compared to the prophylaxis with ondansetrone 8 mg and dexamethasone 8 mg other group without reaching statistical significance (relative risk was administered once daily on days 1 to 5. Patients were ran- of 0.75, 95% Confidence interval 0.37 to 1.49). As regarding vomit- domly assigned to either aprepitant 125 mg on day 1 and 80 mg ing, it was recorded once during the cycles with aprepitant (8.3%) on days 2 & 3 or placebo in the first 2 cycles, with crossover to compared to 10 times (41.6%) during cycles without aprepitant the opposite treatment in the 3rd and 4th cycles. Treatment group (p = 0.002). Moreover, all participants showed a preference to the assignments were made by block randomization. Patients served cycles with aprepitant. as their own controls with cross-over after two chemotherapy cycles. Cross-over was allowed on systematic basis. The primary end point of the trial is to reach complete response (CR) of both Discussion acute (days 1 through 5) and delayed (days 6 through 8) CINV. This means neither to develop any emetic episodes nor to use any of Diffuse large B-cell lymphoma (DLBCL) is one of the most com- rescue anti-emetics medication. Secondary end point was mon malignancies among the non-Hodgkin’s lymphoma spectrum patient-stated preference after the 4th cycle. and is the most common in Egypt. Addition of Rituximab to stan- dard anthracycline-containing regimen significantly improved the disease free as well as overall survival [6]. Nevertheless, one- Patients third of patients still have a disease that is either refractory to ini- tial therapy or relapses after standard therapy [7]. Inclusion criteria comprised patients age 18 years or older with From a patient’s perspective, nausea and vomiting are one of a diagnosis of relapsed/refractory NHL receiving ESHAP the most distressing adverse effects of chemotherapy [8]. The com- chemotherapy regimen. ESHAP is administered as follows: Etopo- bination of Dexamethasone, with Ondansetron increased the effi- side 40 mg/m2/day as a 1 h intravenous infusion from day 1 to 4; cacy of Ondansetron in preventing acute CINV by 10–15% in Cisplatin 25 mg/m2/day as a continuous infusion from day 1 to 4; randomized trials but with less success for delayed CINV [9–11]. Solumedrol 500 mg/day as a 15 min intravenous infusion from Aprepitant demonstrated efficacy against both acute and delayed day 1 to day 5, Cytarabine 2 g/m2 given as a 2 h intravenous infu- emesis [12]. sion on day 5. Patients must have had no nausea or vomiting for Nowadays, the expedition for abrogation of emetogenic effect of 24 h before study entry and no antiemetic use for 72 h before study cisplatin does not only include addition of new drugs or herbals entry. Adequate full blood count, Kidney and Liver functions were with anti-emetic effect, such as olanzapine and Zingiber officinale required. [13] but also tailoring the already-validated regimens along with introducing non-pharmacologic solutions, such as acupuncture [14]. This study evaluated the addition of Aprepitant administered Response evaluation on days 1–3 of chemotherapy for acute and delayed CINV prophy- laxis in multiday highly emetogenic chemotherapy regimen with A patient diary was given to the members of the study group on standard antiemetic prophylaxis in a randomized, cross-over study cycles 1–4. The diary encompassed days 1 through 8 of their design. The study accomplished its primary objective of showing chemotherapy cycle. Each member accomplished a daily record that 3-day aprepitant combined with ondansetron and dexametha- of his/her episodes of nausea and vomiting and the time. Adequate sone resulting in a significant improvement in control of CINV in training was provided to participants based on the CTCAE criteria patients receiving 5-day cisplatin-based chemotherapy regimens to assess Nausea and Vomiting events. Moreover, any medication for relapsed/refractory NHL. Further investigations are needed to taken to control established nausea or emesis i.e. rescue therapy prove cost-effectiveness of this regimen and that 3-day aprepitant was also recorded. The rescue therapy was determined based on is non-inferior to 5-day aprepitant. Moreover, patients showed a the investigator’s choice. preference for cycles with aprepitant as it was well tolerated with Please cite this article in press as: Abdel-Malek R et al. Addition of 3-day aprepitant to ondansetron and dexamethasone for prophylaxis of chemotherapy- induced nausea and vomiting among patients with diffuse large B cell lymphoma receiving 5-day cisplatin-based chemotherapy. J Egyptian Nat Cancer Inst (2017), http://dx.doi.org/10.1016/j.jnci.2017.05.001 R. Abdel-Malek et al. / Journal of the Egyptian National Cancer Institute xxx (2017) xxx–xxx 3

Table 1 Studies on NK1-RAs in patients receiving multi-day cisplatin-based chemotherapy. Proper comparison between these studies is difficult as they assume different anti-emetic regimen and study design.

Author Study design Anti-emetic regimen Evaluable CR (%) Malignancy (Intervention/Comparsion) cycles/patients (Treatment regimen) Albany 2012 [16] Cross-over, Phase III 5D-Apr* 35 42 GCT Placebo 34 13 Olver, 2013 [4] Single arm phase II 7D-Apr 50 82 GCT Hamada, 2014 [17] Single arm, open label 5D-Apr 30 90 GCT Adra, 2016 [5] Phase II 2D-fosapr 54 24.1 GCT Current study Pilot prospective, cross-over 3D-Apr 24 83.4 DLBCL (ESHAP) Placebo 24 41.6

5D-APR = five days aprepitant regimen, *Apr 125 mg D3; Apr 80 mg D4-7. GCT: germ cell tumor, DLBCL: diffuse large B cell lymphoma.

no increased adverse effects. It reduced the need for rescue anti- aprepitant was maintained with no emetic episodes reported by emetics medications. over 80% of patients at any given day. Before NK1RA, the results of clinical trials of 5HT3RA and dex- The main limitation of our study was relatively small size of the amethasone on patients undergoing multiday cisplatin were not followed patients and a high dropout rate. However, the follow-up auspicious, the 5-day overall complete response was ranging 30– for 4 cycles permit better assessment of individuals and mitigation 55% (reviewed in [15]). The studies that added NK1RA showed of personal risk factors rather than single-cycle studies. Another promising results. To the best of our knowledge, there are four limitation is that this was a single- institution study. Further stud- studies that evaluated the efficacy of NK1RA in a multi-day cis- ies are needed before generalizing the results to other settings. platin regimen (see Table 1). In 2012, Albany et al. [16] were the Nevertheless, this is the first study to assess 3-day aprepitant in first to conduct a randomized controlled cross-over study assessing patients with NHL. the triple anti-emetic regimen (aprepitant, 5HT3 antagonists and dexamethasone) in patients on 5-day cisplatin for germ cell tumors Conclusion (GCT). This study along with another single arm study [17] advo- cated 5-day aprepitant regimen. Meanwhile, Olver et al. [4] in sin- Addition of Aprepitant for 3 days to Ondansetron effectively gle arm open label phase II study showed that 7-day aprepitant controlled acute and delayed CINV in patients receiving multiday resulted in overall CR of 82%. The heterogeneity of these studies highly emetogenic chemotherapy regimen. However, a larger makes the comparison daunting. study is needed to confirm these observations. Moreover, this Given that fosaprepitant was deemed to be as effective as oral study demonstrated that 3-day aprepitant was not inferior to aprepitant in the single day cisplatin chemotherapy [18,19], Adra 7 day aprepitant or 2 shots of fosaprepitant for treating CINV of et al. [5] have evaluated fosaprepitant in multi-day cisplatin regi- multiday cisplatin. men for GCT. Two shots of fosaprepitant 150 mg were received on days 3 and 5. The factual complete response, 24.1%, was lower than what the investigators had expected for substitution of fos- Funding aprepitant for aprepitant. Besides these discouraging results, the use of multiple injections fosaprepitant bear higher risk of infusion None to declare. site adverse events compared with aprepitant [20]. The notion that aprepitant regimens with more than 3 days intake is as effective as Conflict of interest single shot fosaprepitant or 3-day aprepitant for single day HEC [18] needs further assessment. For instance, in a retrospective None. study [21], 100% of 11 patients receiving multiday cisplatin regi- men with 3-day aprepitant required rescue medications. This study was designed to be cross-over, so that every individ- References ual response is assessed either with aprepitant or without. The cross-over design helps in mitigation of some of personal risk fac- [1] Velasquez WS, McLaughlin P, Tucker S, Hagemeister FB, Swan F, Rodriguez MA, et al. ESHAP–an effective chemotherapy regimen in refractory and relapsing tors [16]. One study [22] classified patients receiving adjuvant lymphoma: a 4-year follow-up study. J Clin Oncol 1994;12:1169–76. chemotherapy for breast cancer according to personal risk factors [2] Wang WS, Chiou TJ, Liu JH, Fan FS, Yen CC, Tung SL, et al. ESHAP as salvage into 4 levels from low to high risk. Throughout the chemotherapy therapy for refractory non-Hodgkin’s lymphoma: Taiwan experience. Jpn J Clin Oncol 1999;29:33–7. cycles the anti-emetic regimen is upgraded where level 0 received [3] Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, et al. ondansetron and dexamethasone, aprepitant was added for level 1, Antiemetics: American Society of Clinical Oncology clinical practice guideline extended-duration dexamethasone was added for level 2, low-dose update. J Clin Oncol 2011;29:4189–98. [4] Olver IN, Grimison P, Chatfield M, Stockler MR, Toner GC, Gebski V, et al. olanzapine was finally added to level 3. Not any of these added reg- Results of a 7-day aprepitant schedule for the prevention of nausea and imens could achieve better nausea control in those with high risk vomiting in 5-day cisplatin-based germ cell tumor chemotherapy. Support for CINV due to personal risk factors. Care Cancer 2013;21:1561–8. The continuance of the initial high anti-emetic effects of 5HT3 [5] Adra N, Albany C, Brames MJ, Case-Eads S, Johnson CS, Liu Z, et al. Phase II study of fosaprepitant + 5HT3 receptor antagonist + dexamethasone in and dexamethasone is sometimes declined through subsequent patients with germ cell tumors undergoing 5-day cisplatin-based cycles [23]. However, the effect of aprepitant seems to be main- chemotherapy: a Hoosier Cancer Research Network study. Support Care tained as in cross-over studies (this study and that of Albany Cancer 2016;24:2837–42. [6] Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, Gill K, Klasa R, et al. et al. [16]), the patients receiving aprepitant recorded less nausea Introduction of combined CHOP plus rituximab therapy dramatically improved in subsequent cycles that were given without Aprepitant reflecting outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol decrease in the anticipatory nausea. Moreover, when Olver et al. 2005;23:5027–33. [7] Friedberg J. Rituximab for early-stage diff use large-B-cell lymphoma. Lancet [4] followed his 50 patients for 4 cycles, the efficacy of 7-day Oncol 2006;7:357–9. Please cite this article in press as: Abdel-Malek R et al. Addition of 3-day aprepitant to ondansetron and dexamethasone for prophylaxis of chemotherapy- induced nausea and vomiting among patients with diffuse large B cell lymphoma receiving 5-day cisplatin-based chemotherapy. J Egyptian Nat Cancer Inst (2017), http://dx.doi.org/10.1016/j.jnci.2017.05.001 4 R. Abdel-Malek et al. / Journal of the Egyptian National Cancer Institute xxx (2017) xxx–xxx

[8] Hesketh PJ. Treatment of chemotherapy-induced emesis in the 1990s: impact antagonist and dexamethasone in patients with germ cell tumors receiving 5- of the 5-HT3 receptor antagonists. Support Care Cancer 1994;2:286–92. day cisplatin co. J Clin Oncol 2012;30:3998–4003. [9] Latreille J, Pater J, Johnston D, Laberge F, Stewart D, Rusthoven J, et al. Use of [17] Hamada S, Hinotsu S, Kawai K, Yamada S, Narita S, Kamba T, et al. Antiemetic dexamethasone and granisetron in the control of delayed emesis for patients efficacy and safety of a combination of palonosetron, aprepitant, and who receive highly emetogenic chemotherapy. National Cancer Institute of dexamethasone in patients with testicular germ cell tumor receiving 5-day Canada Clinical Trials Group. J Clin Oncol 1998;16:1174–8. cisplatin-based combination chemotherapy. Support Care Cancer [10] Goedhals L, Heron JF, Kleisbauer JP, Pagani O, Sessa C. Control of delayed 2014;22:2161–6. nausea and vomiting with granisetron plus dexamethasone or dexamethasone [18] Ando Y, Hayashi T, Ito K, Suzuki E, Mine N, Miyamoto A, et al. Comparison alone in patients receiving highly emetogenic chemotherapy: a double-blind, between 5-day aprepitant and single-dose fosaprepitant meglumine for placebo-controlled, comparative study. Ann Oncol 1998;9:661–6. preventing nausea and vomiting induced by cisplatin-based chemotherapy. [11] Tsukada H, Hirose T, Yokoyama A, Kurita Y. Randomised comparison of Support Care Cancer 2016;24:871–8. ondansetron plus dexamethasone with dexamethasone alone for the control of [19] Saito H, Yoshizawa H, Yoshimori K, Katakami N, Katsumata N, Kawahara M, delayed cisplatin-induced emesis. Eur J Cancer 2001;37:2398–404. et al. Efficacy and safety of single-dose fosaprepitant in the prevention of [12] Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, et al. The oral chemotherapy-induced nausea and vomiting in patients receiving high-dose neurokinin-1 antagonist aprepitant for the prevention of chemotherapy- cisplatin: a multicentre, randomised, double-blind, placebo-controlled phase 3 induced nausea and vomiting: a multinational, randomized, double-blind, trial. Ann Oncol 2013;24:1067–73. placebo-controlled trial in patients receiving high-dose cisplatin–the [20] Tsuda T, Kyomori C, Mizukami T, Taniyama T, Izawa N, Horie Y, et al. Infusion Aprepitant Protocol 052 Study Gr. J Clin Oncol 2003;21:4112–9. site adverse events in breast cancer patients receiving highly emetic [13] Ullah I, Subhan F, Ayaz M, Shah R, Ali G, Haq IU, et al. Anti-emetic mechanisms chemotherapy with prophylactic anti-emetic treatment with aprepitant and of Zingiber officinale against cisplatin induced emesis in the pigeon; fosaprepitant: a retrospective comparison. Mol Clin Oncol 2016;4:603–6. behavioral and neurochemical correlates. BMC Complement Altern Med [21] Freve J-FO, Soulieres D, Blais N, LeTart N. Aprepitant in multiple-day cisplatin- 2015;15:34. based chemotherapy. J Clin Oncol 2012;30:e19591. [14] Cui Y, Wang L, Shi G, Liu L, Pei P, Guo J. Electroacupuncture alleviates cisplatin- [22] Dranitsaris G, Mazzarello S, Smith S, Vandermeer L, Bouganim N, Clemons M. induced nausea in rats. Acupunct Med 2016;34:120–6. Measuring the impact of guideline-based antiemetic therapy on nausea and [15] Ranganath P, Einhorn L, Albany C. Management of chemotherapy induced vomiting control in breast cancer patients with multiple risk factors. Support nausea and vomiting in patients on multiday cisplatin based combination Care Cancer 2016;24:1563–9. chemotherapy. Biomed Res Int 2015;2015:943618. [23] de Wit R, van den Berg H, Burghouts J, Nortier J, Slee P, Rodenburg C, et al. [16] Albany C, Brames MJ, Fausel C, Johnson CS, Picus J, Einhorn LH. Randomized, Initial high anti-emetic efficacy of granisetron with dexamethasone is not double-blind, placebo-controlled, phase III cross-over study evaluating the maintained over repeated cycles. Br J Cancer 1998;77:1487–91. oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor

Please cite this article in press as: Abdel-Malek R et al. Addition of 3-day aprepitant to ondansetron and dexamethasone for prophylaxis of chemotherapy- induced nausea and vomiting among patients with diffuse large B cell lymphoma receiving 5-day cisplatin-based chemotherapy. J Egyptian Nat Cancer Inst (2017), http://dx.doi.org/10.1016/j.jnci.2017.05.001