- Email: [email protected]
Aprepitant for paediatric chemotherapy-induced nausea and vomiting – Authors' reply
Correspondence
chemotherapy-induced vomiting in paediatric patients receiving moderate and highly emetogenic chemotherapy. The Pediatric Oncology Group of Ontario guidelines recommend the same, with addition of an aprepitant for patients receiving highly emetogenic chemotherapy.2 However, dexamethasone was used in less than 30% of patients in both groups of this study, despite being mentioned as standard of care. Moreover, the study was powered on an assumption of 60% of patients in the control group achieving a complete response in the delayed phase, which is more likely to be based on the use of a combination of a 5-HT3 antagonist and dexamethasone, and not a 5-HT3 antagonist alone. In a randomised trial at our institute,3 patients receiving highly emetogenic chemotherapy were randomly assigned to receive aprepitant or placebo, both in addition to a 5-HT3 antagonist and dexamethasone. Complete responses were more common in the aprepitant group than in the control group in the acute phase, but not in the delayed or overall phase. Definitions of acute and delayed phases of chemotherapy-induced vomiting in Kang and colleagues’ study are different from those that are typically used. In a trial assessing the role of aprepitant in multipleday chemotherapy protocols,4 the acute phase was defined as until 24 h after the last day of chemotherapy. However, in Kang and colleagues’ investigation, acute phase was defined as 24 h after the initiation of chemotherapy. This definition would regard the days of subsequent chemotherapy as being in the delayed phase. Most of the patients in both groups received chemotherapy for more than 1 day, which makes the results difficult to analyse, because the delayed phase as defined in Kang and colleagues’ study would include what would normally be accepted as the acute phase, and would terminate earlier than the normally accepted delayed phase. www.thelancet.com/oncology Vol 16 June 2015
Around 60% of patients in both groups had previous chemotherapy before enrolment in this trial, and data on chemotherapy-induced vomiting in previous cycles have not been provided. Emesis during previous chemotherapy is one of the predictors of incidence and severity of vomiting in subsequent chemotherapy cycles.5 Therefore, an ideal population would have been chemotherapy-naive patients. It would be worth knowing the proportion of patients who achieved a complete response with aprepitant in a chemotherapy-naive population that received dexamethasone with 5-HT3 antagonist, using the more accepted definition of the delayed phase of chemotherapy-induced vomiting. Kang and colleagues’ results would then be more uniform and comparable with the existing data. We declare no competing interests.
Atul Batra, *Sameer Bakhshi [email protected] Department of Medical Oncology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India 1
2
3
4
5
Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol 2015; 16: 385–94. Dupuis LL, Boodhan S, Holdsworth M, Robinson PD, Hain R, Portwine C, et al. Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 2013; 60: 1073–82. Bakhshi S, Batra A, Biswas B, Dhawan D, Paul R, Sreenivas V. Aprepitant as an add-on therapy in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer 2015; published online April 8. DOI: 10.1007/s00520-015-2714-9. Albany C, Brames MJ, Fausel C, Johnson CS, Picus J, Einhorn LH. 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. Morrow GR, Roscoe JA, Hickok JT, Stern RM, Pierce HI, King DB, et al. Initial control of chemotherapy-induced nausea and vomiting in patient quality of life. Oncol Williston Park N 1998; 12: 32–37.
Authors’ reply We thank Atul Batra and Sameer Bakhasi, and Florian Slimano and colleagues, for their interest in our Article.1 As noted in the review2 by Aapro and Walko, cited by Slimano, “encephalopathy is a rare but wellknown adverse reaction to ifosfamide”, and concomitant ifosfamide and aprepitant might result in a “possible increased incidence of encephalopathy, not proven to be aprepitant related”. Notably, Slimano and colleagues do not provide any information to suggest that the incidence of encephalopathy has increased because of aprepitant use. Slimano and colleagues suggest preferential prophylaxis against chemotherapy-induced nausea and vomiting with a long-acting setron or a dopamine antagonist, but a recent study (NCT01442376) showed no difference between palonosetron and ondansetron for prevention of acute chemotherapy-induced nausea and vomiting in children, and controlled paediatric data for dopamine antagonists are scarce. By contrast, our study showed a substantial benefit of aprepitant when added to ondansetron for prevention of chemotherapy-induced nausea and vomiting in children. Although we agree with Slimano and colleagues that practitioners should consider the potential for adverse events when making treatment decisions, we believe that these decisions should be evidenced-based, and should take into account the potential risks and benefits. Batra and Bakhasi note several differences between their recent study of aprepitant in children, and our study. As emphasised in the accompanying Comment to our report,3 despite guideline recommendations, little information exists for the use of dexamethasone in children, and we saw that many physicians are reluctant to use dexamethasone for prophylaxis of chemotherapy-induced nausea and vomiting mainly out of concern that the potential benefits e260
Correspondence
could be outweighed by an increased risk of adverse events. Accordingly, we allowed, but did not require, the use of dexamethasone in our trial. We did stratify our enrolment and analyses by planned use of dexamethasone, and we reported that the aprepitant regimen was better than the control regimen, irrespective of dexamethasone use. We assumed that 60% of patients would achieve a complete response in the control group based on a previous study in adults.4 The definition of the endpoints used in our trial, including delayed chemotherapy-induced nausea and vomiting, were based on discussions with the US regulatory agency, and included the standard definitions that have been used in most chemotherapy-induced nausea and vomiting registration trials for
e261
many years. We noted that previous exposure to chemotherapy would tend towards worse outcomes, and would therefore be unlikely to overestimate the benefit attributable to aprepitant. Although we cannot conduct the analyses Batra and Bakhasi suggest (since efficacy data were not collected beyond day 5 in our study), we note that despite the differences in study design our results are entirely consistent with theirs, providing additional evidence to support the use of aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting in children. SG is an employee and stockholder of Merck. HJK and CMZ declare no competing interests.
*Stuart Green, Christian Michel Zwaan, Hyoung Jin Kang
Merck, Kenilworth, NJ, USA (SG); Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children’s Hospital, Seoul, South Korea (HJK); and Department of Pediatric Oncology/ Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, Netherlands (CMZ) 1
2
3
4
Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol 2015; 15: 385–94. Aapro MS, Walko CM. Aprepitant: drug–drug interactions in perspective. Ann Oncol 2010; 21: 2316–23. Gralla RJ. Anti-emetics in paediatric patients receiving chemotherapy. Lancet Oncol 2015; 16: 351–53. Beck TM, York M, Chang A, et al. Oral ondansetron 8 mg twice daily is as effective as 8 mg three times daily in the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. S3A-376 Study Group. Cancer Invest 1997; 15: 297–303.
[email protected]
www.thelancet.com/oncology Vol 16 June 2015
chemotherapy-induced vomiting in paediatric patients receiving moderate and highly emetogenic chemotherapy. The Pediatric Oncology Group of Ontario guidelines recommend the same, with addition of an aprepitant for patients receiving highly emetogenic chemotherapy.2 However, dexamethasone was used in less than 30% of patients in both groups of this study, despite being mentioned as standard of care. Moreover, the study was powered on an assumption of 60% of patients in the control group achieving a complete response in the delayed phase, which is more likely to be based on the use of a combination of a 5-HT3 antagonist and dexamethasone, and not a 5-HT3 antagonist alone. In a randomised trial at our institute,3 patients receiving highly emetogenic chemotherapy were randomly assigned to receive aprepitant or placebo, both in addition to a 5-HT3 antagonist and dexamethasone. Complete responses were more common in the aprepitant group than in the control group in the acute phase, but not in the delayed or overall phase. Definitions of acute and delayed phases of chemotherapy-induced vomiting in Kang and colleagues’ study are different from those that are typically used. In a trial assessing the role of aprepitant in multipleday chemotherapy protocols,4 the acute phase was defined as until 24 h after the last day of chemotherapy. However, in Kang and colleagues’ investigation, acute phase was defined as 24 h after the initiation of chemotherapy. This definition would regard the days of subsequent chemotherapy as being in the delayed phase. Most of the patients in both groups received chemotherapy for more than 1 day, which makes the results difficult to analyse, because the delayed phase as defined in Kang and colleagues’ study would include what would normally be accepted as the acute phase, and would terminate earlier than the normally accepted delayed phase. www.thelancet.com/oncology Vol 16 June 2015
Around 60% of patients in both groups had previous chemotherapy before enrolment in this trial, and data on chemotherapy-induced vomiting in previous cycles have not been provided. Emesis during previous chemotherapy is one of the predictors of incidence and severity of vomiting in subsequent chemotherapy cycles.5 Therefore, an ideal population would have been chemotherapy-naive patients. It would be worth knowing the proportion of patients who achieved a complete response with aprepitant in a chemotherapy-naive population that received dexamethasone with 5-HT3 antagonist, using the more accepted definition of the delayed phase of chemotherapy-induced vomiting. Kang and colleagues’ results would then be more uniform and comparable with the existing data. We declare no competing interests.
Atul Batra, *Sameer Bakhshi [email protected] Department of Medical Oncology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India 1
2
3
4
5
Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol 2015; 16: 385–94. Dupuis LL, Boodhan S, Holdsworth M, Robinson PD, Hain R, Portwine C, et al. Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients. Pediatr Blood Cancer 2013; 60: 1073–82. Bakhshi S, Batra A, Biswas B, Dhawan D, Paul R, Sreenivas V. Aprepitant as an add-on therapy in children receiving highly emetogenic chemotherapy: a randomized, double-blind, placebo-controlled trial. Support Care Cancer 2015; published online April 8. DOI: 10.1007/s00520-015-2714-9. Albany C, Brames MJ, Fausel C, Johnson CS, Picus J, Einhorn LH. 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. Morrow GR, Roscoe JA, Hickok JT, Stern RM, Pierce HI, King DB, et al. Initial control of chemotherapy-induced nausea and vomiting in patient quality of life. Oncol Williston Park N 1998; 12: 32–37.
Authors’ reply We thank Atul Batra and Sameer Bakhasi, and Florian Slimano and colleagues, for their interest in our Article.1 As noted in the review2 by Aapro and Walko, cited by Slimano, “encephalopathy is a rare but wellknown adverse reaction to ifosfamide”, and concomitant ifosfamide and aprepitant might result in a “possible increased incidence of encephalopathy, not proven to be aprepitant related”. Notably, Slimano and colleagues do not provide any information to suggest that the incidence of encephalopathy has increased because of aprepitant use. Slimano and colleagues suggest preferential prophylaxis against chemotherapy-induced nausea and vomiting with a long-acting setron or a dopamine antagonist, but a recent study (NCT01442376) showed no difference between palonosetron and ondansetron for prevention of acute chemotherapy-induced nausea and vomiting in children, and controlled paediatric data for dopamine antagonists are scarce. By contrast, our study showed a substantial benefit of aprepitant when added to ondansetron for prevention of chemotherapy-induced nausea and vomiting in children. Although we agree with Slimano and colleagues that practitioners should consider the potential for adverse events when making treatment decisions, we believe that these decisions should be evidenced-based, and should take into account the potential risks and benefits. Batra and Bakhasi note several differences between their recent study of aprepitant in children, and our study. As emphasised in the accompanying Comment to our report,3 despite guideline recommendations, little information exists for the use of dexamethasone in children, and we saw that many physicians are reluctant to use dexamethasone for prophylaxis of chemotherapy-induced nausea and vomiting mainly out of concern that the potential benefits e260
Correspondence
could be outweighed by an increased risk of adverse events. Accordingly, we allowed, but did not require, the use of dexamethasone in our trial. We did stratify our enrolment and analyses by planned use of dexamethasone, and we reported that the aprepitant regimen was better than the control regimen, irrespective of dexamethasone use. We assumed that 60% of patients would achieve a complete response in the control group based on a previous study in adults.4 The definition of the endpoints used in our trial, including delayed chemotherapy-induced nausea and vomiting, were based on discussions with the US regulatory agency, and included the standard definitions that have been used in most chemotherapy-induced nausea and vomiting registration trials for
e261
many years. We noted that previous exposure to chemotherapy would tend towards worse outcomes, and would therefore be unlikely to overestimate the benefit attributable to aprepitant. Although we cannot conduct the analyses Batra and Bakhasi suggest (since efficacy data were not collected beyond day 5 in our study), we note that despite the differences in study design our results are entirely consistent with theirs, providing additional evidence to support the use of aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting in children. SG is an employee and stockholder of Merck. HJK and CMZ declare no competing interests.
*Stuart Green, Christian Michel Zwaan, Hyoung Jin Kang
Merck, Kenilworth, NJ, USA (SG); Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children’s Hospital, Seoul, South Korea (HJK); and Department of Pediatric Oncology/ Hematology, Erasmus MC-Sophia Children’s Hospital, Rotterdam, Netherlands (CMZ) 1
2
3
4
Kang HJ, Loftus S, Taylor A, DiCristina C, Green S, Zwaan CM. Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial. Lancet Oncol 2015; 15: 385–94. Aapro MS, Walko CM. Aprepitant: drug–drug interactions in perspective. Ann Oncol 2010; 21: 2316–23. Gralla RJ. Anti-emetics in paediatric patients receiving chemotherapy. Lancet Oncol 2015; 16: 351–53. Beck TM, York M, Chang A, et al. Oral ondansetron 8 mg twice daily is as effective as 8 mg three times daily in the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy. S3A-376 Study Group. Cancer Invest 1997; 15: 297–303.
[email protected]
www.thelancet.com/oncology Vol 16 June 2015