December 2015, Vol. 4, No. 6

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Commentary: Treatment for Children Receiving Emetogenic Chemotherapy

Pediatric Oncology

Chemotherapy-induced nausea and vomiting is a frequent and potentially treatment-limiting complication of cancer therapy in both adults and children. However, pediatric oncologists have been keenly aware that while effective regimens have been developed for adults, effective regimens for children receiving emetogenic chemotherapy have been lacking.1-3

On September 2, 2015, the FDA approved an expanded indication for oral aprepitant, a substance P/neurokinin 1 (NK1) receptor antagonist.4 With this expanded indication, aprepitant capsules are now approved for use in combination with other antiemetic agents in patients 12 years of age and older and patients younger than 12 years who weigh at least 30 kg (approximately 66 pounds) for the prevention of acute and delayed nausea and vomiting associated with moderately or highly emetogenic chemotherapy.5

The FDA approval of this expanded indication for aprepitant was based in part on findings from a randomized, multicenter, double-blind, phase 3 study (NCT01362530), published by Kang and colleagues in the April 2015 issue of the Lancet Oncology, that assessed aprepitant in combination with a standard antiemetic regimen (ondansetron with or without dexamethasone) for the prevention of chemotherapy-induced nausea and vomiting in moderately or highly emetogenic chemotherapy regimens in patients 6 months to 17 years of age.6 The primary end point of the study was complete response (CR; ie, no vomiting and no use of rescue medication) in the delayed phase (25-20 hours following initiation of chemotherapy). The primary efficacy end point was chosen in consultation with the FDA because this was considered to be the phase in which treatment would have the most benefit. Secondary end points included CR in the acute phase (0-24 hours following initiation of chemotherapy), CR in the overall phase (up to 120 hours [5 days] following initiation of chemotherapy), and safety and tolerability. Results showed that a 3-day regimen of aprepitant combined with ondansetron was well tolerated and resulted in a higher proportion of patients achieving a CR across all 3 phases (acute, delayed, and overall). Results showed that, in the delayed phase, a 51% CR rate (77 of 152 patients) was observed with the aprepitant regimen compared with 26% (39 of 150 patients) with the control regimen (P <.0001); in the acute phase, a 66% CR rate (101 of 152 patients) was observed with the aprepitant regimen compared with 52% (78 of 150 patients) with the control regimen (P = .0135); and, in the overall phase, a 40% CR rate (61 of 152 patients) was observed with the aprepitant regimen compared with 20% (30 of 150 patients) with the control regimen (P = .0002). Thus, prevention of emesis was doubled at nearly all end points with the addition of oral aprepitant, providing a 20% to 30% absolute improvement in control of delayed emesis and in overall 5-day CRs. The proportion of patients who achieved a CR was lower for patients who received dexamethasone than for those who did not, particularly in the delayed and overall phases.

This phase 3 study represents the first large, randomized investigation of an NK1 receptor antagonist in the pediatric population. The results provide assurance to pediatric oncologists who previously have had to rely primarily on the results of a number of studies conducted in adults. For example, a randomized clinical study of an NK1 receptor antagonist in adults was published in 1999 in the New England Journal of Medicine, showing the safety, efficacy, and benefit of adding the agent in the prevention of delayed emesis after treatment with cisplatin.7 In 2003, 2 large trials of antiemetics in adults demonstrated the benefit of adding aprepitant in patients receiving cisplatin.8,9 In 2005, aprepitant was evaluated for the prevention of chemotherapy-induced nausea and vomiting in adult breast cancer patients receiving anthracyclines plus cyclophosphamide.10 That same year, a report was published that showed the efficacy of aprepitant in preventing chemotherapy-induced nausea and emesis in adults over multiple cycles of moderately emetogenic chemotherapy.11 In 2010, a report was published in which aprepitant was investigated in association with a broad range of moderately emetogenic chemotherapies and tumor types in adults.12 In 2012, aprepitant was studied in adult patients receiving cisplatin combination chemotherapy regimens over a 5-day period.13 In 2014, a study was published that showed the preservation of the benefit of aprepitant in adults over several chemotherapy cycles.14

The study by Kang and colleagues6 is the first to provide quality evidence for the use of this class of agent in children receiving many of these same types of treatment.

It is still unclear whether antiemetics are equally effective in adults and children. The proportions of patients achieving a CR in the Kang study were lower than those seen in studies of adults receiving moderately or highly emetogenic chemotherapy.5,8,9,15,16 The authors suggest that possible reasons for the lower CR rates in this study might be different emetogenicity, higher chemotherapy doses, and different combinations of chemotherapeutic agents between the pediatric and adult populations.17 The authors also pointed out that in many antiemetic studies conducted in adults, patients had been chemotherapy-naive or had not received many days of chemotherapy.8-10,16 In the Kang study, on the other hand, 85% to 90% of patients had previously received chemotherapy and were treated on multiple days.6

Kang and colleagues acknowledge that because the use of dexamethasone was left to the discretion of the investigator, it is possible that the corticosteroid was chosen disproportionately for those with poor previous control of emesis or those receiving the most difficult regimens. The elective use of dexamethasone may explain the fact that the proportion of patients who achieved a CR was lower for patients who received dexamethasone than for those who did not, particularly in the delayed and overall phases.

The results from this study are impressive and will undoubtedly impact daily practice for pediatric oncologists, and the addition of aprepitant will benefit the lives of chemotherapy patients and their families.

References

  1. Small BE, Holdsworth MT, Raisch DW, et al. Survey ranking of emetogenic control in children receiving chemotherapy. J Pediatr Hematol Oncol. 2000;22:125-132.
  2. Holdsworth MT, Raisch DW, Frost J. Acute and delayed nausea and emesis control in pediatric oncology patients. Cancer. 2006;106:931-940.
  3. Dupuis LL, Nathan PC. Optimizing emetic control in children receiving antineoplastic therapy: beyond the guidelines. Paediatr Drugs. 2010;12:51-61.
  4. Merck Newsroom. FDA approves pediatric indication for EMEND® (aprepitant) capsules in combination with other antiemetic agents. www.mercknewsroom.com/news-release/oncology-newsroom/fda-approves-pediatric-indication-emend-aprepitant-capsules-combinati. September 2, 2015.
  5. Emend [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc; 2015.
  6. Kang HJ, Loftus S, Taylor A, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16:385-394.
  7. Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. L-754,030 Antiemetic Trials Group. N Engl J Med. 1999;340:190-195.
  8. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer. 2003;97:3090-3098.
  9. Hesketh PJ, Grunberg SM, Gralla RJ, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin—the Aprepitant Protocol 052 Study Group. J Clin Oncol. 2003;21:4112-4119.
  10. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. J Clin Oncol. 2005;23:2822-2830.
  11. Herrstedt J, Muss HB, Warr DG, et al. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer. 2005;104:1548-1555.
  12. Rapoport BL, Jordan K, Boice JA, et al. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study. Support Care Cancer. 2010;18:423-431.
  13. Albany C, Brames MJ, Fausel C, et al. Randomized, double-blind, placebo-controlled, phase III cross-over study evaluating the oral neurokinin-1 antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in patients with germ cell tumors receiving 5-day cisplatin combination chemotherapy regimens: a Hoosier Oncology Group study. J Clin Oncol. 2012;30:3998-4003.
  14. Gralla RJ, Bosnjak SM, Hontsa A, et al. A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy. Ann Oncol. 2014;25:1333-1339.
  15. de Wit R, Danner SA, Bakker PJ, et al. Combined zidovudine and interferon-alpha treatment in patients with AIDS-associated Kaposi’s sarcoma. J Intern Med. 1991;229:35-40.
  16. Schmoll HJ, Aapro MS, Poli-Bigelli S, et al. Comparison of an aprepitant regimen with a multiple-day ondansetron regimen, both with dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol. 2006;17:1000-1006.
  17. Gore L, Chawla S, Petrilli A, et al. Aprepitant in adolescent patients for prevention of chemotherapy-induced nausea and vomiting: a randomized, double-blind, placebo-controlled study of efficacy and tolerability. Pediatr Blood Cancer. 2009;52:242-247.
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