- Email: [email protected]
Efficacy of aprepitant for CHOP chemotherapy-induced nausea, vomiting, and anorexia
Author’s Accepted Manuscript Efficacy of aprepitant for CHOP chemotherapyinduced nausea, vomiting and anorexiaAprepitant in CHOP chemotherapy Mihoko Morita, Shinji Kishi, Miyuki Ookura, Yasufumi Matsuda, Katsunori Tai, Takahiro Yamauchi, Takanori Ueda www.elsevier.com/locate/cpcancerv
PII: DOI: Reference:
S0147-0272(17)30140-X http://dx.doi.org/10.1016/j.currproblcancer.2017.09.001 YMCN350
To appear in: Current Problems in Cancer Cite this article as: Mihoko Morita, Shinji Kishi, Miyuki Ookura, Yasufumi Matsuda, Katsunori Tai, Takahiro Yamauchi and Takanori Ueda, Efficacy of aprepitant for CHOP chemotherapy-induced nausea, vomiting and anorexiaAprepitant in CHOP chemotherapy, Current Problems in Cancer, http://dx.doi.org/10.1016/j.currproblcancer.2017.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Efficacy of aprepitant for CHOP chemotherapy-induced nausea, vomiting and anorexia
Mihoko Morita1), Shinji Kishi1), 2), Miyuki Ookura1), Yasufumi Matsuda1), Katsunori Tai1), Takahiro Yamauchi1) and Takanori Ueda1)
1) Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Fukui 910-1193, Japan 2) Department of Health and Nutrition, Faculty of Human Life Studies, Jin-ai University, 3-1-1 Ohde-cho, Echizen, Fukui 915-8586, Japan
Key Words: aprepitant, CHOP chemotherapy, CINV, substance P, malignant lymphoma
Running Head: Aprepitant in CHOP chemotherapy
Correspondence to: Shinji Kishi, Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3, Shimoaizuki, Matsuoka, Eiheiji, Fukui 910-1193, Japan. Tel: +81776613111, Fax: +81776618109, e-mail: [email protected]
1
ABSTRACT The objective of this study was to evaluate whether aprepitant in addition to 5-HT3 receptor antagonist is useful for preventing chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients receiving CHOP therapy, and to evaluate the relationship between in vivo kinetics of plasma substance P and these adverse events. Patients with malignant lymphoma who received CHOP chemotherapy or THP (THP-ADR)-COP therapy were investigated CINV and anorexia for 5 days after start of chemotherapy. With the first course of chemotherapy, all patients received only granisetron on day1 as an antiemetic. Patients who experienced nausea, vomiting or anorexia exceeding grade 1 in the first course received aprepitant for 3 days in addition to granisetron with the second course of CHOP chemotherapy. Plasma substance P concentrations at 24 and 72 h after chemotherapy were measured. Nineteen patients were evaluated. Nausea, vomiting or anorexia was observed with the first course in 7 of 19 patients. During the second course with aprepitant, no patients experienced vomiting, and the toxicity grade of nausea, vomiting or anorexia was decreased compared with those in the first course. Substance P concentrations showed no differences after chemotherapy, in patients with nausea, vomiting or anorexia and in patients without. Addition of aprepitant to 5-HT3 receptor antagonist appears effective for CINV or anorexia for patients who received CHOP chemotherapy.
2
INTRODUCTION Chemotherapy-induced nausea and vomiting (CINV) is one of the most major non-hematological toxicities associated with cancer chemotherapy, and can significantly affect quality of life [1, 2], leading to poor compliance. The management of CINV is thus crucial to successful cancer chemotherapy. Chemotherapy agents and regimens are divided into four categories to manage CINV: highly emetogenic chemotherapy (HEC) with >90% risk; moderately emetic chemotherapy with 30-90% risk of emesis; low emetic chemotherapy with10-30% risk; and minimally emetic chemotherapy with <10% risk of emesis [3, 4]. Although antiemetic therapy using a combination of a 5-HT3 receptor antagonist, dexamethasone, and a neurokinin-1 (NK1) receptor antagonist is recommended for patients receiving HEC, NK1 receptor antagonists have not generally been administered for patients receiving CHOP chemotherapy in clinical settings, as the necessity for NK1 receptor antagonists has remained unclear. Aprepitant is an NK1 receptor antagonist that selectively blocks the binding of substance P at the NK1 receptor in the central nervous system [5]. While aprepitant has robust antiemetic effects against CINV, whether plasma substance P levels influence the effects of NK1 receptor antagonists is unclear [6]. The objective of this study was to evaluate whether aprepitant in addition to 5-HT3 receptor antagonist is useful for CINV or anorexia in patients receiving CHOP therapy, and to evaluate the relationship between the in vivo kinetics of substance P in plasma and CINV.
3
PATIENTS AND METHODS Patients Eligible patients were 18 years old who had histologically confirmed malignant lymphoma and were naïve to chemotherapy. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and normal renal function. All study protocols were approved by the institutional review board at University of Fukui Hospital and were conducted in accordance with the Helsinki Declaration. Written informed consent was obtained from all participants prior to enrolment.
Design and treatment All patients received CHOP chemotherapy or THP-COP therapy. Chemotherapy consisted of 750 mg/m2 of cyclophosphamide, 50 mg/m2 of doxorubicin or THP-doxorubicin, 1.4 mg/m2 of vincristine for 1 day and 100 mg/body of prednisolone for 5 days. For the observation period, patients wrote an assessment dairy of CINV and anorexia for 5 days after the start of chemotherapy. Patients also filled separate questionnaires to assess their alcohol intake higher than once a week, history of motion sickness, anxiety regarding chemotherapy and history of pregnancy-associated emesis. The grading of nausea, vomiting and anorexia was defined according to toxicity terminology criteria for adverse events (CTCAE) version 4.0. As the first course of chemotherapy, all patients received only the 5-HT3 receptor antagonist (3 or 6 mg of granisetron) as an antiemetic on day1 of CHOP chemotherapy. Steroid
4
was given as a part of CHOP chemotherapy, as mentioned above. Patients showing nausea, vomiting, or anorexia of more than grade 1 with the first course of CHOP chemotherapy received aprepitant for 3 days in addition to granisetron from the second CHOP chemotherapy. Additional aprepitant treatment was not considered for patients who reported no nausea or vomiting with the second course of CHOP chemotherapy. The dose of aprepitant was 125 mg/body on day 1 and 80 mg/body on days 2 and 3. Patients who had CINV allowed to use rescue medication of domperidone or metoclopramide.
Measurement of plasma substance P concentrations For evaluation of plasma concentrations of substance P, blood samples were collected before the first CHOP chemotherapy, and 24 h and 72 h after starting chemotherapy. After plasma separation, an exclusive stabilizer was added and substance P levels were measured by Kyowa Medics (Shizuoka, Japan) using the enzyme-linked immunosorbent assay [7].
Statistical analysis All statistical analyses (t-test, chi-square test) were performed using EZR software, version 1.26 (Saitama Medical Center, Jichi Medical University) [8].
RESULTS Twenty patients provided written informed consent between February 2012 and August 2013. One patient withdrew consent before data collection. We therefore analyzed 19 patients. All patients had lymphoid malignancies and
5
received CHOP (17 patients) or THP-COP (2 patients) chemotherapy. Two patients had mild hepatic dysfunction related to tumor invasion. The demographic characteristics of patients are listed in Table 1. In THP-COP chemotherapy, THP-doxorubicin of the equivalent dose was given as a substitute for doxorubicin in CHOP. Nausea, vomiting or anorexia was observed with the first course of chemotherapy in 7 of the 19 patients (39%). All patients who had nausea suffered from anorexia. Six patients with nausea, one patient with vomiting and 7 patients with anorexia were observed. In the acute phase (within 24 h after starting chemotherapy), two of these patients had nausea or anorexia. These patients also showed delayed-phase CINV (24 h after chemotherapy). Toxicity over grade 4 was not seen in any patients. Female sex and habitual alcohol intake were identified as significantly associated with these adverse events (Table 2). Age was unrelated to nausea, vomiting or anorexia. Patients who had nausea, vomiting or anorexia received additional aprepitant for the second course of CHOP chemotherapy. During the second course, no patients vomited, and 5 patients showed nausea or anorexia. The number and grade of CINV were decreased, compared with the first course (Table 3). Nausea and anorexia were significantly reduced (P < 0.05). No adverse events possibly related to aprepitant administration were encountered. Plasma substance P concentrations before chemotherapy (control) and 24 and 72 h after chemotherapy were evaluated in 9 patients. Four of these patients experienced nausea, vomiting or anorexia in the first course of chemotherapy. No significant differences in substance P concentrations were seen among these
6
points (Figure 1). Substance P concentrations did not differ between patients with nausea, vomiting or anorexia and those without. Substance P concentrations also showed no significant changes among time points for individual patients.
DISCUSSION CINV is associated with significant deteriorations in global quality of life [9] for patients with cancer, including malignant lymphoma. Approximately 80% of patients treated with CHOP and 5-HT3 receptor antagonists have been retrospectively reported to achieve complete remission (CR) of CINV [10, 11]. In our study, 6 of the 19 patients (32%) had CINV and 7 of the 19 patients (37%) had anorexia; these patients then received CHOP chemotherapy with 5-HT3 receptor antagonist (granisetron). The greater percentage of CINV in our study compared with the previous study may be due to the detailed prospective questionnaire survey used in our study. It was reported that a single dose of palonosetron that is second generation of 5-HT3 receptor antagonists and has a prolonged half-life and higher binding affinity showed good control of CHOP related CINV [12, 13]. Using granisetron as 5-HT3 receptor antagonist only on day1 in our study might cause the higher incidence of CINV and anorexia. Prognostic factors for CINV have been reported as young age, female gender, limited or no regular alcohol intake, pregnancy-associated morning sickness, motion thickness, and anxiety [14 - 16]. Our results showed similar results (Table 2), although some of them were not significant, probably due to the small number of patients.
7
Additional NK1 receptor antagonists to 5-HT3 antagonists and steroids have been reported as more effective for CINV compared to HEC or MEC regimens in RCT trials [17, 18] and a meta-analysis [19], although most studies have not focused on hematologic malignancy. Nasu et al reported the efficacy of aprepitant for hematological malignancy [20]. That report referred to intensive regimens such as those for acute leukemia, preparative regimens for autologous hematopoietic stem cell transplantation or platinum-containing regimens for resistant/refractory malignant lymphoma. The efficacy of NK1 receptor antagonists for lymphoma patients who received CHOP therapy has not been elucidated. CHOP therapy comprised 750 mg/m2 of cyclophosphamide, 50 mg/m2 of doxorubicin, 1.4 mg/m2 of vincristine and 100 mg/body of prednisolone, almost equivalent to the dose in AC therapy (600 mg/m 2 of cyclophosphamide, 60 mg/m2 of doxorubicin) for breast cancer. In breast cancer patients receiving AC, addition of aprepitant to 5-HT3 receptor antagonist and dexamethasone has been reported to offer improved antiemetic outcomes [18, 21]. Tamura et al reported that among HEC regimens, the incidence of CINV and the degree of nausea with combined anthracycline and cyclophosphamide therapy was higher than with a cisplatin-based regimen in a Japanese patient [22]. We showed the efficacy of adding aprepitant in this prospective trial. While 5-HT3 receptor antagonists have proven largely effective against acute emesis, aprepitant as NK1 receptor antagonist offers anti-emetic efficacy for both acute and delayed CINV [23, 24]. Although only 2 patients showed acute CINV in the first course of CHOP with administration of 5-HT3 receptor antagonist in our study, addition of aprepitant in the second course of CHOP
8
appears effective for both acute- and delayed-phase CINV. We studied whether aprepitant is useful against anorexia, which constitutes an important component of supportive care because loss of appetite induces not only malnutrition, but also dysfunction of the gut that leads to higher incidence of general infection and cannot be circumvented by parenteral nutrition [25]. In this study, all patients who had nausea suffered from anorexia, and anorexia was related to nausea as shown in a previous report [20]. Plasma substance P concentration has been suggested to be related to CINV [6, 26]. Substance P has been shown to be localized in enterochromaffin cells in the gastrointestinal tract and crosses the blood–brain barrier in animals [27]. Substance P is widely distributed in the central and peripheral nervous systems and is the preferred ligand for NK-1 receptors. While aprepitant may exert its antiemetic effect during chemotherapy, by inhibiting the binding of substance P to the NK1 receptor in the vomiting center, a few studies have been conducted to investigate the relationship between the blood pharmacokinetics of substance P and nausea/vomiting during treatment with chemotherapeutic agents in humans. We showed that substance P concentration did not differ between 24 and 72 h after CHOP chemotherapy compared with that before chemotherapy. Moreover, substance P concentrations of patients who had CINV or anorexia did not differ from those of patients who had no CINV. Takahashi et al reported that substance P concentration increased on days 2-4, compared with controls, and was significantly increased in patients with delayed nausea/vomiting [6]; Higa reported similar findings [26]. These reports were conducted using cisplatin-based chemotherapy, which commonly causes delayed nausea and
9
vomiting [28]. The differences with our results might be due to the fact that we evaluated patients with a non-platinum-containing regimen, although the number of evaluated patients was small. It is still unclear whether the co-morbidities which could have affected baseline gut motility, and accordingly substance P levels, and exocytotic release of substance P from enterochromaffin cells in the gastrointestinal tract occurs after administration of emetogenic agents. In conclusion, addition of aprepitant to 5-HT3 receptor antagonist appears effective for CINV or anorexia for patients who received CHOP chemotherapy.
Conflict of interest All authors declare no potential conflicts of interest.
REFERENCES [1] Ballatori E, Roila F. Impact of nausea and vomiting on quality of life in cancer patients during chemotherapy. Health Qual Life Outcomes. 2003;1:46. [2] Grunberg SM, Boutin N, Ireland A, Miner S, Silveira J, Ashikaga T. Impact of nausea/vomiting on quality of life as a visual analogue scale-derived utility score. Support Care Cancer. 1996;4:435-9. [3] Roila F, Molassiotis A, Herrstedt J, Aapro M, Gralla RJ, Bruera E, et al. 2016 MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27:v119-v33. [4] Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol. 2008;5:32-43. [5] Aapro M, Carides A, Rapoport BL, Schmoll HJ, Zhang L, Warr D. Aprepitant and fosaprepitant: a 10-year review of efficacy and safety. Oncologist. 2015;20:450-8. [6] Takahashi T, Nakamura Y, Tsuya A, Murakami H, Endo M, Yamamoto N. Pharmacokinetics of aprepitant and dexamethasone after administration of chemotherapeutic agents and effects of plasma substance P concentration on 10
chemotherapy-induced nausea and vomiting in Japanese cancer patients. Cancer Chemother Pharmacol. 2011;68:653-9. [7] Otsuka K, Niimi A, Matsumoto H, Ito I, Yamaguchi M, Matsuoka H, et al. Plasma substance P levels in patients with persistent cough. Respiration. 2011;82:431-8. [8] Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48:452-8. [9] Osoba D, Zee B, Warr D, Latreille J, Kaizer L, Pater J. Effect of postchemotherapy nausea and vomiting on health-related quality of life. The Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group. Support Care Cancer. 1997;5:307-13. [10] Jorgensen M, Victor MA. Antiemetic efficacy of ondansetron and metoclopramide, both combined with corticosteroid, in malignant lymphoma patients receiving non-cisplatin chemotherapy. Acta Oncol. 1996;35:159-63. [11] Takahashi T, Kumanomidou S, Takami S, Okada T, Adachi K, Jo Y, et al. A retrospective study of R-CHOP/CHOP therapy-induced nausea and vomiting in non-Hodgkin's lymphoma patients: a comparison of intravenous and oral 5-HT3 receptor antagonists. International journal of hematology. 2016. [12] Di Renzo N, Montanini A, Mannina D, Dondi A, Muci S, Mancuso S, et al. Single-dose palonosetron for prevention of chemotherapy-induced nausea and vomiting in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy containing steroids: results of a phase II study from the Gruppo Italiano per lo Studio dei Linfomi (GISL). Support Care Cancer. 2011;19:1505-10. [13] Miyata Y, Yakushijin K, Inui Y, Imamura Y, Goto H, Mizutani Y, et al. A prospective study of the antiemetic effect of palonosetron in malignant lymphoma patients treated with the CHOP regimen. International journal of hematology. 2016;104:682-91. [14] Lopez-Jimenez J, Martin-Ballesteros E, Sureda A, Uralburu C, Lorenzo I, del Campo R, et al. Chemotherapy-induced nausea and vomiting in acute leukemia and stem cell transplant patients: results of a multicenter, observational study. Haematologica. 2006;91:84-91. [15] Warr D. Prognostic factors for chemotherapy induced nausea and vomiting. European journal of pharmacology. 2014;722:192-6. [16] Lorusso V. Management of chemotherapy-induced nausea and vomiting by risk profile: role of netupitant/palonosetron. Ther Clin Risk Manag. 2016;12:917-25. [17] Arpornwirat W, Albert I, Hansen VL, Levin J, Bandekar RR, Grunberg SM. Phase 2 trial results with the novel neurokinin-1 receptor antagonist casopitant in combination with ondansetron and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting in cancer patients receiving moderately emetogenic chemotherapy. Cancer. 11
2009;115:5807-16. [18] Hesketh PJ, Sanz-Altamira P. Aprepitant, dexamethasone, and palonosetron in the prevention of doxorubicin/cyclophosphamide-induced nausea and vomiting. Support Care Cancer. 2012;20:653-6. [19] dos Santos LV, Souza FH, Brunetto AT, Sasse AD, da Silveira Nogueira Lima JP. Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting: a systematic review. J Natl Cancer Inst. 2012;104:1280-92. [20] Nasu R, Nannya Y, Kurokawa M. A randomized controlled study evaluating the efficacy of aprepitant for highly/moderately emetogenic chemotherapies in hematological malignancies. International journal of hematology. 2015;101:376-85. [21] Hesketh PJ, Younger J, Sanz-Altamira P, Hayden M, Bushey J, Trainor B, et al. Aprepitant as salvage antiemetic therapy in breast cancer patients receiving doxorubicin and cyclophosphamide. Support Care Cancer. 2009;17:1065-70. [22] Tamura K, Aiba K, Saeki T, Nakanishi Y, Kamura T, Baba H, et al. Testing the effectiveness of antiemetic guidelines: results of a prospective registry by the CINV Study Group of Japan. Int J Clin Oncol. 2015;20:855-65. [23] Rojas C, Raje M, Tsukamoto T, Slusher BS. Molecular mechanisms of 5-HT(3) and NK(1) receptor antagonists in prevention of emesis. European journal of pharmacology. 2014;722:26-37. [24] Hargreaves R, Ferreira JC, Hughes D, Brands J, Hale J, Mattson B, et al. Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Ann N Y Acad Sci. 2011;1222:40-8. [25] Rubinsky MD, Clark AP. Early enteral nutrition in critically ill patients. Dimens Crit Care Nurs. 2012;31:267-74. [26] Higa GM, Auber ML, Altaha R, Piktel D, Kurian S, Hobbs G, et al. 5-Hydroxyindoleacetic acid and substance P profiles in patients receiving emetogenic chemotherapy. J Oncol Pharm Pract. 2006;12:201-9. [27] Freed AL, Audus KL, Lunte SM. Investigation of substance P transport across the blood-brain barrier. Peptides. 2002;23:157-65. [28] Hesketh PJ, Kris MG, Grunberg SM, Beck T, Hainsworth JD, Harker G, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15:103-9.
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FIGURE LEGEND Fig 1. Plasma concentrations of substance P before chemotherapy (control), at 24 h after starting chemotherapy, and at 72 h after starting chemotherapy in patients who had CINV or anorexia (solid line) after chemotherapy and those who did not (dotted line). Data from 1 patient without CINV at 72 h were not included. Table 1. Patient characteristics and chemotherapies
Patients
19
Gender male/female Median age (range), years
11/8 59 (28-70)
Lymphoma subtype follicular lymphoma (FL)
8
diffuse large B-cell lymphoma (DLBCL)
9
lymphoplasmacytic lymphoma (LPL)
1
small lymphocytic lymphoma (SLL)
1
Performance status 0
18
2
1
Chemotherapy CHOP*
17
THP-COP
2
*Two patients received a 75% dose of CHOP
13
Table 2. Risk of nausea, vomiting, or anorexia after CHOP chemotherapy
CINV or anorexia*1 +
-
female
6
2
male
1
10
yes
1
8
no
6
4
yes
2
1
no
5
11
yes
7
8
no
0
4
yes
4
1
no
2
1
p*2
Sex < 0.005
Habitual alcohol intake < 0.05
History of motion sickness 0.24
Anxiety for chemotherapy History of
0.086
pregnancy-associated emesis
0.67
*1 chemotherapy-induced nausea, vomiting or anorexia over grade 1 *2 chi-square test
14
Table 3. Comparison of CINV patients with CHOP therapy with or without aprepitant
First CHOP (no aprepitant) Grade
nausea
vomiting
Second CHOP (with aprepitant)
anorexia
nausea*
vomiting
anorexia*
0
1
6
0
4
7
2
1
1
0
0
2
0
2
2
4
1
6
1
0
3
3
1
0
1
0
0
0
* grade was defined according to NCCN CTCAE v 4.0 * P < 0.05 with paired t test
15
PII: DOI: Reference:
S0147-0272(17)30140-X http://dx.doi.org/10.1016/j.currproblcancer.2017.09.001 YMCN350
To appear in: Current Problems in Cancer Cite this article as: Mihoko Morita, Shinji Kishi, Miyuki Ookura, Yasufumi Matsuda, Katsunori Tai, Takahiro Yamauchi and Takanori Ueda, Efficacy of aprepitant for CHOP chemotherapy-induced nausea, vomiting and anorexiaAprepitant in CHOP chemotherapy, Current Problems in Cancer, http://dx.doi.org/10.1016/j.currproblcancer.2017.09.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Efficacy of aprepitant for CHOP chemotherapy-induced nausea, vomiting and anorexia
Mihoko Morita1), Shinji Kishi1), 2), Miyuki Ookura1), Yasufumi Matsuda1), Katsunori Tai1), Takahiro Yamauchi1) and Takanori Ueda1)
1) Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Fukui 910-1193, Japan 2) Department of Health and Nutrition, Faculty of Human Life Studies, Jin-ai University, 3-1-1 Ohde-cho, Echizen, Fukui 915-8586, Japan
Key Words: aprepitant, CHOP chemotherapy, CINV, substance P, malignant lymphoma
Running Head: Aprepitant in CHOP chemotherapy
Correspondence to: Shinji Kishi, Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, 23-3, Shimoaizuki, Matsuoka, Eiheiji, Fukui 910-1193, Japan. Tel: +81776613111, Fax: +81776618109, e-mail: [email protected]
1
ABSTRACT The objective of this study was to evaluate whether aprepitant in addition to 5-HT3 receptor antagonist is useful for preventing chemotherapy-induced nausea and vomiting (CINV) and anorexia in patients receiving CHOP therapy, and to evaluate the relationship between in vivo kinetics of plasma substance P and these adverse events. Patients with malignant lymphoma who received CHOP chemotherapy or THP (THP-ADR)-COP therapy were investigated CINV and anorexia for 5 days after start of chemotherapy. With the first course of chemotherapy, all patients received only granisetron on day1 as an antiemetic. Patients who experienced nausea, vomiting or anorexia exceeding grade 1 in the first course received aprepitant for 3 days in addition to granisetron with the second course of CHOP chemotherapy. Plasma substance P concentrations at 24 and 72 h after chemotherapy were measured. Nineteen patients were evaluated. Nausea, vomiting or anorexia was observed with the first course in 7 of 19 patients. During the second course with aprepitant, no patients experienced vomiting, and the toxicity grade of nausea, vomiting or anorexia was decreased compared with those in the first course. Substance P concentrations showed no differences after chemotherapy, in patients with nausea, vomiting or anorexia and in patients without. Addition of aprepitant to 5-HT3 receptor antagonist appears effective for CINV or anorexia for patients who received CHOP chemotherapy.
2
INTRODUCTION Chemotherapy-induced nausea and vomiting (CINV) is one of the most major non-hematological toxicities associated with cancer chemotherapy, and can significantly affect quality of life [1, 2], leading to poor compliance. The management of CINV is thus crucial to successful cancer chemotherapy. Chemotherapy agents and regimens are divided into four categories to manage CINV: highly emetogenic chemotherapy (HEC) with >90% risk; moderately emetic chemotherapy with 30-90% risk of emesis; low emetic chemotherapy with10-30% risk; and minimally emetic chemotherapy with <10% risk of emesis [3, 4]. Although antiemetic therapy using a combination of a 5-HT3 receptor antagonist, dexamethasone, and a neurokinin-1 (NK1) receptor antagonist is recommended for patients receiving HEC, NK1 receptor antagonists have not generally been administered for patients receiving CHOP chemotherapy in clinical settings, as the necessity for NK1 receptor antagonists has remained unclear. Aprepitant is an NK1 receptor antagonist that selectively blocks the binding of substance P at the NK1 receptor in the central nervous system [5]. While aprepitant has robust antiemetic effects against CINV, whether plasma substance P levels influence the effects of NK1 receptor antagonists is unclear [6]. The objective of this study was to evaluate whether aprepitant in addition to 5-HT3 receptor antagonist is useful for CINV or anorexia in patients receiving CHOP therapy, and to evaluate the relationship between the in vivo kinetics of substance P in plasma and CINV.
3
PATIENTS AND METHODS Patients Eligible patients were 18 years old who had histologically confirmed malignant lymphoma and were naïve to chemotherapy. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and normal renal function. All study protocols were approved by the institutional review board at University of Fukui Hospital and were conducted in accordance with the Helsinki Declaration. Written informed consent was obtained from all participants prior to enrolment.
Design and treatment All patients received CHOP chemotherapy or THP-COP therapy. Chemotherapy consisted of 750 mg/m2 of cyclophosphamide, 50 mg/m2 of doxorubicin or THP-doxorubicin, 1.4 mg/m2 of vincristine for 1 day and 100 mg/body of prednisolone for 5 days. For the observation period, patients wrote an assessment dairy of CINV and anorexia for 5 days after the start of chemotherapy. Patients also filled separate questionnaires to assess their alcohol intake higher than once a week, history of motion sickness, anxiety regarding chemotherapy and history of pregnancy-associated emesis. The grading of nausea, vomiting and anorexia was defined according to toxicity terminology criteria for adverse events (CTCAE) version 4.0. As the first course of chemotherapy, all patients received only the 5-HT3 receptor antagonist (3 or 6 mg of granisetron) as an antiemetic on day1 of CHOP chemotherapy. Steroid
4
was given as a part of CHOP chemotherapy, as mentioned above. Patients showing nausea, vomiting, or anorexia of more than grade 1 with the first course of CHOP chemotherapy received aprepitant for 3 days in addition to granisetron from the second CHOP chemotherapy. Additional aprepitant treatment was not considered for patients who reported no nausea or vomiting with the second course of CHOP chemotherapy. The dose of aprepitant was 125 mg/body on day 1 and 80 mg/body on days 2 and 3. Patients who had CINV allowed to use rescue medication of domperidone or metoclopramide.
Measurement of plasma substance P concentrations For evaluation of plasma concentrations of substance P, blood samples were collected before the first CHOP chemotherapy, and 24 h and 72 h after starting chemotherapy. After plasma separation, an exclusive stabilizer was added and substance P levels were measured by Kyowa Medics (Shizuoka, Japan) using the enzyme-linked immunosorbent assay [7].
Statistical analysis All statistical analyses (t-test, chi-square test) were performed using EZR software, version 1.26 (Saitama Medical Center, Jichi Medical University) [8].
RESULTS Twenty patients provided written informed consent between February 2012 and August 2013. One patient withdrew consent before data collection. We therefore analyzed 19 patients. All patients had lymphoid malignancies and
5
received CHOP (17 patients) or THP-COP (2 patients) chemotherapy. Two patients had mild hepatic dysfunction related to tumor invasion. The demographic characteristics of patients are listed in Table 1. In THP-COP chemotherapy, THP-doxorubicin of the equivalent dose was given as a substitute for doxorubicin in CHOP. Nausea, vomiting or anorexia was observed with the first course of chemotherapy in 7 of the 19 patients (39%). All patients who had nausea suffered from anorexia. Six patients with nausea, one patient with vomiting and 7 patients with anorexia were observed. In the acute phase (within 24 h after starting chemotherapy), two of these patients had nausea or anorexia. These patients also showed delayed-phase CINV (24 h after chemotherapy). Toxicity over grade 4 was not seen in any patients. Female sex and habitual alcohol intake were identified as significantly associated with these adverse events (Table 2). Age was unrelated to nausea, vomiting or anorexia. Patients who had nausea, vomiting or anorexia received additional aprepitant for the second course of CHOP chemotherapy. During the second course, no patients vomited, and 5 patients showed nausea or anorexia. The number and grade of CINV were decreased, compared with the first course (Table 3). Nausea and anorexia were significantly reduced (P < 0.05). No adverse events possibly related to aprepitant administration were encountered. Plasma substance P concentrations before chemotherapy (control) and 24 and 72 h after chemotherapy were evaluated in 9 patients. Four of these patients experienced nausea, vomiting or anorexia in the first course of chemotherapy. No significant differences in substance P concentrations were seen among these
6
points (Figure 1). Substance P concentrations did not differ between patients with nausea, vomiting or anorexia and those without. Substance P concentrations also showed no significant changes among time points for individual patients.
DISCUSSION CINV is associated with significant deteriorations in global quality of life [9] for patients with cancer, including malignant lymphoma. Approximately 80% of patients treated with CHOP and 5-HT3 receptor antagonists have been retrospectively reported to achieve complete remission (CR) of CINV [10, 11]. In our study, 6 of the 19 patients (32%) had CINV and 7 of the 19 patients (37%) had anorexia; these patients then received CHOP chemotherapy with 5-HT3 receptor antagonist (granisetron). The greater percentage of CINV in our study compared with the previous study may be due to the detailed prospective questionnaire survey used in our study. It was reported that a single dose of palonosetron that is second generation of 5-HT3 receptor antagonists and has a prolonged half-life and higher binding affinity showed good control of CHOP related CINV [12, 13]. Using granisetron as 5-HT3 receptor antagonist only on day1 in our study might cause the higher incidence of CINV and anorexia. Prognostic factors for CINV have been reported as young age, female gender, limited or no regular alcohol intake, pregnancy-associated morning sickness, motion thickness, and anxiety [14 - 16]. Our results showed similar results (Table 2), although some of them were not significant, probably due to the small number of patients.
7
Additional NK1 receptor antagonists to 5-HT3 antagonists and steroids have been reported as more effective for CINV compared to HEC or MEC regimens in RCT trials [17, 18] and a meta-analysis [19], although most studies have not focused on hematologic malignancy. Nasu et al reported the efficacy of aprepitant for hematological malignancy [20]. That report referred to intensive regimens such as those for acute leukemia, preparative regimens for autologous hematopoietic stem cell transplantation or platinum-containing regimens for resistant/refractory malignant lymphoma. The efficacy of NK1 receptor antagonists for lymphoma patients who received CHOP therapy has not been elucidated. CHOP therapy comprised 750 mg/m2 of cyclophosphamide, 50 mg/m2 of doxorubicin, 1.4 mg/m2 of vincristine and 100 mg/body of prednisolone, almost equivalent to the dose in AC therapy (600 mg/m 2 of cyclophosphamide, 60 mg/m2 of doxorubicin) for breast cancer. In breast cancer patients receiving AC, addition of aprepitant to 5-HT3 receptor antagonist and dexamethasone has been reported to offer improved antiemetic outcomes [18, 21]. Tamura et al reported that among HEC regimens, the incidence of CINV and the degree of nausea with combined anthracycline and cyclophosphamide therapy was higher than with a cisplatin-based regimen in a Japanese patient [22]. We showed the efficacy of adding aprepitant in this prospective trial. While 5-HT3 receptor antagonists have proven largely effective against acute emesis, aprepitant as NK1 receptor antagonist offers anti-emetic efficacy for both acute and delayed CINV [23, 24]. Although only 2 patients showed acute CINV in the first course of CHOP with administration of 5-HT3 receptor antagonist in our study, addition of aprepitant in the second course of CHOP
8
appears effective for both acute- and delayed-phase CINV. We studied whether aprepitant is useful against anorexia, which constitutes an important component of supportive care because loss of appetite induces not only malnutrition, but also dysfunction of the gut that leads to higher incidence of general infection and cannot be circumvented by parenteral nutrition [25]. In this study, all patients who had nausea suffered from anorexia, and anorexia was related to nausea as shown in a previous report [20]. Plasma substance P concentration has been suggested to be related to CINV [6, 26]. Substance P has been shown to be localized in enterochromaffin cells in the gastrointestinal tract and crosses the blood–brain barrier in animals [27]. Substance P is widely distributed in the central and peripheral nervous systems and is the preferred ligand for NK-1 receptors. While aprepitant may exert its antiemetic effect during chemotherapy, by inhibiting the binding of substance P to the NK1 receptor in the vomiting center, a few studies have been conducted to investigate the relationship between the blood pharmacokinetics of substance P and nausea/vomiting during treatment with chemotherapeutic agents in humans. We showed that substance P concentration did not differ between 24 and 72 h after CHOP chemotherapy compared with that before chemotherapy. Moreover, substance P concentrations of patients who had CINV or anorexia did not differ from those of patients who had no CINV. Takahashi et al reported that substance P concentration increased on days 2-4, compared with controls, and was significantly increased in patients with delayed nausea/vomiting [6]; Higa reported similar findings [26]. These reports were conducted using cisplatin-based chemotherapy, which commonly causes delayed nausea and
9
vomiting [28]. The differences with our results might be due to the fact that we evaluated patients with a non-platinum-containing regimen, although the number of evaluated patients was small. It is still unclear whether the co-morbidities which could have affected baseline gut motility, and accordingly substance P levels, and exocytotic release of substance P from enterochromaffin cells in the gastrointestinal tract occurs after administration of emetogenic agents. In conclusion, addition of aprepitant to 5-HT3 receptor antagonist appears effective for CINV or anorexia for patients who received CHOP chemotherapy.
Conflict of interest All authors declare no potential conflicts of interest.
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chemotherapy-induced nausea and vomiting in Japanese cancer patients. Cancer Chemother Pharmacol. 2011;68:653-9. [7] Otsuka K, Niimi A, Matsumoto H, Ito I, Yamaguchi M, Matsuoka H, et al. Plasma substance P levels in patients with persistent cough. Respiration. 2011;82:431-8. [8] Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant. 2013;48:452-8. [9] Osoba D, Zee B, Warr D, Latreille J, Kaizer L, Pater J. Effect of postchemotherapy nausea and vomiting on health-related quality of life. The Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group. Support Care Cancer. 1997;5:307-13. [10] Jorgensen M, Victor MA. Antiemetic efficacy of ondansetron and metoclopramide, both combined with corticosteroid, in malignant lymphoma patients receiving non-cisplatin chemotherapy. Acta Oncol. 1996;35:159-63. [11] Takahashi T, Kumanomidou S, Takami S, Okada T, Adachi K, Jo Y, et al. A retrospective study of R-CHOP/CHOP therapy-induced nausea and vomiting in non-Hodgkin's lymphoma patients: a comparison of intravenous and oral 5-HT3 receptor antagonists. International journal of hematology. 2016. [12] Di Renzo N, Montanini A, Mannina D, Dondi A, Muci S, Mancuso S, et al. Single-dose palonosetron for prevention of chemotherapy-induced nausea and vomiting in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy containing steroids: results of a phase II study from the Gruppo Italiano per lo Studio dei Linfomi (GISL). Support Care Cancer. 2011;19:1505-10. [13] Miyata Y, Yakushijin K, Inui Y, Imamura Y, Goto H, Mizutani Y, et al. A prospective study of the antiemetic effect of palonosetron in malignant lymphoma patients treated with the CHOP regimen. International journal of hematology. 2016;104:682-91. [14] Lopez-Jimenez J, Martin-Ballesteros E, Sureda A, Uralburu C, Lorenzo I, del Campo R, et al. Chemotherapy-induced nausea and vomiting in acute leukemia and stem cell transplant patients: results of a multicenter, observational study. Haematologica. 2006;91:84-91. [15] Warr D. Prognostic factors for chemotherapy induced nausea and vomiting. European journal of pharmacology. 2014;722:192-6. [16] Lorusso V. Management of chemotherapy-induced nausea and vomiting by risk profile: role of netupitant/palonosetron. Ther Clin Risk Manag. 2016;12:917-25. [17] Arpornwirat W, Albert I, Hansen VL, Levin J, Bandekar RR, Grunberg SM. Phase 2 trial results with the novel neurokinin-1 receptor antagonist casopitant in combination with ondansetron and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting in cancer patients receiving moderately emetogenic chemotherapy. Cancer. 11
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FIGURE LEGEND Fig 1. Plasma concentrations of substance P before chemotherapy (control), at 24 h after starting chemotherapy, and at 72 h after starting chemotherapy in patients who had CINV or anorexia (solid line) after chemotherapy and those who did not (dotted line). Data from 1 patient without CINV at 72 h were not included. Table 1. Patient characteristics and chemotherapies
Patients
19
Gender male/female Median age (range), years
11/8 59 (28-70)
Lymphoma subtype follicular lymphoma (FL)
8
diffuse large B-cell lymphoma (DLBCL)
9
lymphoplasmacytic lymphoma (LPL)
1
small lymphocytic lymphoma (SLL)
1
Performance status 0
18
2
1
Chemotherapy CHOP*
17
THP-COP
2
*Two patients received a 75% dose of CHOP
13
Table 2. Risk of nausea, vomiting, or anorexia after CHOP chemotherapy
CINV or anorexia*1 +
-
female
6
2
male
1
10
yes
1
8
no
6
4
yes
2
1
no
5
11
yes
7
8
no
0
4
yes
4
1
no
2
1
p*2
Sex < 0.005
Habitual alcohol intake < 0.05
History of motion sickness 0.24
Anxiety for chemotherapy History of
0.086
pregnancy-associated emesis
0.67
*1 chemotherapy-induced nausea, vomiting or anorexia over grade 1 *2 chi-square test
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Table 3. Comparison of CINV patients with CHOP therapy with or without aprepitant
First CHOP (no aprepitant) Grade
nausea
vomiting
Second CHOP (with aprepitant)
anorexia
nausea*
vomiting
anorexia*
0
1
6
0
4
7
2
1
1
0
0
2
0
2
2
4
1
6
1
0
3
3
1
0
1
0
0
0
* grade was defined according to NCCN CTCAE v 4.0 * P < 0.05 with paired t test
15