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Registrative trials of antiemetic drugs: arrival or starting point?
Reflection and Reaction
Cisplatin was introduced into clinical practice in the 1970s. More than 30 years later, it remains the most used among drugs classified as highly emetogenic chemotherapy (HEC). In the decades since cisplatin was introduced, several randomised trials of antiemetic research have significantly improved the control of chemotherapy-induced nausea and vomiting (CINV).1 Although the heterogeneity of several factors (eg, type of patient, dose of cisplatin, dose and schedule of antiemetics, and definition of endpoints) make direct comparisons among trials particularly prone to bias, crucial progress was made in the prophylaxis of CINV associated with HEC. Between 1990 and 1991, randomised trials showing the superiority of the serotonin type 3 (5-HT₃)-receptor antagonist ondansetron over metoclopramide were published.2–4 In those trials, the proportion of patients obtaining complete or nearly complete control of emesis was consistently and significantly higher with ondansetron, although delayed emesis control was not as satisfactory as acute control. Several further trials followed in quick succession, and showed a significant benefit to emesis control with the addition of dexamethasone to ondansetron.5–7 Thus, dexamethasone plus a 5HT₃-receptor antagonist was the standard prophylaxis for CINV associated with cisplatin until the early 2000s. In 2003, further improvement was obtained by adding aprepitant, the first neurokinin-1 (NK1) receptor antagonist.8–10 Current international guidelines1,11,12 recommend a three-drug regimen for optimal prophylaxis of CINV in patients receiving HEC: the combination of dexamethasone, a 5HT₃-receptor antagonist, and aprepitant. Finally, a recently published trial showed that palonosetron, the youngest 5HT₃receptor antagonist, is more effective than granisetron in the control of delayed emesis.13 So what comes next? First of all, existing guidelines should be universally applied in clinical practice. Otherwise, there would be a dichotomy between the potential and achieved control of emesis, which is hard to accept from a human and a scientific perspective. In this issue of The Lancet Oncology, Grunberg and colleagues14 report that the addition of casopitant (as www.thelancet.com/oncology Vol 10 June 2009
a single day-one oral dose or in a mixed intravenous plus oral 3-day schedule) to dexamethasone and ondansetron improves CINV control. When the trial was done, guidelines already recommended threedrug combinations (dexamethasone, 5-HT₃-receptor antagonist, plus aprepitant) as standard.11 For ethical and methodological reasons, patients assigned to the control group of a randomised trial should always receive the best available treatment. Grunberg and colleagues state that the choice of a suboptimal control group was prompted by the consideration that aprepitant was not yet a community standard. This might reduce ethical concerns, because it is true that, if not enrolled in the Grunberg trial, patients would probably not have received aprepitant in clinical practice. However, it remains a shortcoming, because the results of this trial will probably lead to the approval of a second drug of the same class, without a direct comparison with aprepitant. No comparison was planned in Grunberg and colleagues’ study between the two experimental schedules of casopitant; apparently, no incremental benefit is seen with the 3-day schedule. Aprepitant has only been tested (and is approved) as a 3-day regimen.8–10 Unfortunately, the efficacy of day-2 and day-3 administrations is not verified, because none of the trials compared a single day-1 administration with the 3-day regimen.15 If similar efficacy were proven, single oral dose (of casopitant or aprepitant) might be preferable, in terms of patients’ convenience and side-effects as compared with 3-day regimens. In a reasonable world, costs should be lower as well. Grunberg and co-workers’ study is a further demonstration that NK1 receptor inhibition is a useful strategy in the prevention of CINV associated with HEC, but at least two relevant issues are unsolved. Namely, which is most effective between aprepitant and casopitant, and what is the optimum dosing schedule: a single day-1 dose or a 3-day regimen? Furthermore, with both aprepitant and casopitant, the control rate of delayed emesis is 10–15% lower than the rate of acute control.8–10 Although much progress has been made (delayed emesis would affect approximately
The printed journal includes an image merely for illustration
See Articles page 549 See From the Archives page 636
533
iStockphoto
Registrative trials of antiemetic drugs: arrival or starting point?
Reflection and Reaction
90% of patients treated with cisplatin in the absence of appropriate prophylaxis), to improve the control of delayed emesis should still be the goal of future trials. Unfortunately, antiemetic research is a field with very few trials compared with the volume of drug consumption, and the rate of non-profit studies is low. Consequently, there is a risk that the questions arising from registrative trials remain unsolved and treatment optimisation is delayed.
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Massimo Di Maio, Francesco Perrone* Clinical Trials Unit, National Cancer Institute, Via Mariano Semmola, 80131 Napoli, Italy [email protected] The authors declared no conflicts of interest. 1 2
3
4
5
Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008; 5: 32–43. Marty M, Pouillart P, Scholl S, et al. Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with highdose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990; 322: 816–21. De Mulder PH, Seynaeve C, Vermorken JB, et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind, crossover study. Ann Intern Med 1990; 113: 834–840. Hainsworth J, Harvey W, Pendergrass K, et al. A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy. J Clin Oncol 1991; 9: 721–28. Hesketh PJ, Harvey WH, Harker WG, et al. A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatininduced emesis. J Clin Oncol 1994; 12: 596–600.
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Roila F, Tonato M, Cognetti F, et al. Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 1991; 9: 675–78. Smyth JF, Coleman RE, Nicolson M, et al. Does dexamethasone enhance control of acute cisplatin induced emesis by ondansetron? BMJ 1991; 303: 1423–26. Hesketh PJ, Grunberg SM, Gralla RJ, et al. Aprepitant Protocol 052 Study Group. 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: 4112–19. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al; Aprepitant Protocol 054 Study Group. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapyinduced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 2003; 97: 3090–98. 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: 1000–06. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24: 2932–47. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Antiemesis. Version 3; 2009. http://www.nccn.org/ professionals/physician_gls/PDF/antiemesis.pdf (accessed April 29, 2009). Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol 2009; 10: 115–24. Grunberg SM, Rolski J, Strausz J, et al. Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, doubleblind, placebo-controlled trial. Lancet Oncol 2009; 10: 549–58. Roila F, Fatigoni S. New antiemetic drugs. Ann Oncol 2006; 17 (suppl 2): ii96–100.
Science Photo Library
Bevacizumab-associated gastrointestinal perforation
See Articles page 559
534
Bevacizumab, in combination with standard anticancer treatment, has been shown to improve survival or delay disease progression in several advanced solid tumours. However, a pivotal trial in advanced colorectal cancer1 brought bevacizumab-associated gastrointestinal perforation to the attention of the oncological community. Bevacizumab has changed the treatment paradigm for many solid tumours, and this uncommon complication has not altered the benefit–risk ratio. Through education and raising awareness both within clinical trials (as a targeted adverse event) and routine clinical practice, oncologists have learned to recognise and treat bevacizumab-associated gastrointestinal perforation early. Gastrointestinal perforation associated with bevacizumab has been defined as the finding of
intraperitoneal air with or without gastrointestinal or enterocutaneous fistula. Morbidity and especially mortality from gastrointestinal perforation is high, and therefore clinically important. Surgical management can be required, but is not always necessary, and although there might be an increased frequency of post-operative complications in patients receiving bevacizumab, this is outweighed by the benefits of surgical intervention where clinically indicated. In this issue of The Lancet Oncology, Hapani and colleagues2 report the results of a meta-analysis of reported randomised controlled trials to assess the risk of gastrointestinal perforation in patients with cancer treated with bevacizumab. They report an incidence of gastrointestinal perforation of 0·9%: a two-fold increased risk compared with control treatment alone, with mortality seen in over a fifth of www.thelancet.com/oncology Vol 10 June 2009
Cisplatin was introduced into clinical practice in the 1970s. More than 30 years later, it remains the most used among drugs classified as highly emetogenic chemotherapy (HEC). In the decades since cisplatin was introduced, several randomised trials of antiemetic research have significantly improved the control of chemotherapy-induced nausea and vomiting (CINV).1 Although the heterogeneity of several factors (eg, type of patient, dose of cisplatin, dose and schedule of antiemetics, and definition of endpoints) make direct comparisons among trials particularly prone to bias, crucial progress was made in the prophylaxis of CINV associated with HEC. Between 1990 and 1991, randomised trials showing the superiority of the serotonin type 3 (5-HT₃)-receptor antagonist ondansetron over metoclopramide were published.2–4 In those trials, the proportion of patients obtaining complete or nearly complete control of emesis was consistently and significantly higher with ondansetron, although delayed emesis control was not as satisfactory as acute control. Several further trials followed in quick succession, and showed a significant benefit to emesis control with the addition of dexamethasone to ondansetron.5–7 Thus, dexamethasone plus a 5HT₃-receptor antagonist was the standard prophylaxis for CINV associated with cisplatin until the early 2000s. In 2003, further improvement was obtained by adding aprepitant, the first neurokinin-1 (NK1) receptor antagonist.8–10 Current international guidelines1,11,12 recommend a three-drug regimen for optimal prophylaxis of CINV in patients receiving HEC: the combination of dexamethasone, a 5HT₃-receptor antagonist, and aprepitant. Finally, a recently published trial showed that palonosetron, the youngest 5HT₃receptor antagonist, is more effective than granisetron in the control of delayed emesis.13 So what comes next? First of all, existing guidelines should be universally applied in clinical practice. Otherwise, there would be a dichotomy between the potential and achieved control of emesis, which is hard to accept from a human and a scientific perspective. In this issue of The Lancet Oncology, Grunberg and colleagues14 report that the addition of casopitant (as www.thelancet.com/oncology Vol 10 June 2009
a single day-one oral dose or in a mixed intravenous plus oral 3-day schedule) to dexamethasone and ondansetron improves CINV control. When the trial was done, guidelines already recommended threedrug combinations (dexamethasone, 5-HT₃-receptor antagonist, plus aprepitant) as standard.11 For ethical and methodological reasons, patients assigned to the control group of a randomised trial should always receive the best available treatment. Grunberg and colleagues state that the choice of a suboptimal control group was prompted by the consideration that aprepitant was not yet a community standard. This might reduce ethical concerns, because it is true that, if not enrolled in the Grunberg trial, patients would probably not have received aprepitant in clinical practice. However, it remains a shortcoming, because the results of this trial will probably lead to the approval of a second drug of the same class, without a direct comparison with aprepitant. No comparison was planned in Grunberg and colleagues’ study between the two experimental schedules of casopitant; apparently, no incremental benefit is seen with the 3-day schedule. Aprepitant has only been tested (and is approved) as a 3-day regimen.8–10 Unfortunately, the efficacy of day-2 and day-3 administrations is not verified, because none of the trials compared a single day-1 administration with the 3-day regimen.15 If similar efficacy were proven, single oral dose (of casopitant or aprepitant) might be preferable, in terms of patients’ convenience and side-effects as compared with 3-day regimens. In a reasonable world, costs should be lower as well. Grunberg and co-workers’ study is a further demonstration that NK1 receptor inhibition is a useful strategy in the prevention of CINV associated with HEC, but at least two relevant issues are unsolved. Namely, which is most effective between aprepitant and casopitant, and what is the optimum dosing schedule: a single day-1 dose or a 3-day regimen? Furthermore, with both aprepitant and casopitant, the control rate of delayed emesis is 10–15% lower than the rate of acute control.8–10 Although much progress has been made (delayed emesis would affect approximately
The printed journal includes an image merely for illustration
See Articles page 549 See From the Archives page 636
533
iStockphoto
Registrative trials of antiemetic drugs: arrival or starting point?
Reflection and Reaction
90% of patients treated with cisplatin in the absence of appropriate prophylaxis), to improve the control of delayed emesis should still be the goal of future trials. Unfortunately, antiemetic research is a field with very few trials compared with the volume of drug consumption, and the rate of non-profit studies is low. Consequently, there is a risk that the questions arising from registrative trials remain unsolved and treatment optimisation is delayed.
6
7
8
9
Massimo Di Maio, Francesco Perrone* Clinical Trials Unit, National Cancer Institute, Via Mariano Semmola, 80131 Napoli, Italy [email protected] The authors declared no conflicts of interest. 1 2
3
4
5
Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol 2008; 5: 32–43. Marty M, Pouillart P, Scholl S, et al. Comparison of the 5-hydroxytryptamine3 (serotonin) antagonist ondansetron (GR 38032F) with highdose metoclopramide in the control of cisplatin-induced emesis. N Engl J Med 1990; 322: 816–21. De Mulder PH, Seynaeve C, Vermorken JB, et al. Ondansetron compared with high-dose metoclopramide in prophylaxis of acute and delayed cisplatin-induced nausea and vomiting. A multicenter, randomized, double-blind, crossover study. Ann Intern Med 1990; 113: 834–840. Hainsworth J, Harvey W, Pendergrass K, et al. A single-blind comparison of intravenous ondansetron, a selective serotonin antagonist, with intravenous metoclopramide in the prevention of nausea and vomiting associated with high-dose cisplatin chemotherapy. J Clin Oncol 1991; 9: 721–28. Hesketh PJ, Harvey WH, Harker WG, et al. A randomized, double-blind comparison of intravenous ondansetron alone and in combination with intravenous dexamethasone in the prevention of high-dose cisplatininduced emesis. J Clin Oncol 1994; 12: 596–600.
10
11
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Roila F, Tonato M, Cognetti F, et al. Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol 1991; 9: 675–78. Smyth JF, Coleman RE, Nicolson M, et al. Does dexamethasone enhance control of acute cisplatin induced emesis by ondansetron? BMJ 1991; 303: 1423–26. Hesketh PJ, Grunberg SM, Gralla RJ, et al. Aprepitant Protocol 052 Study Group. 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: 4112–19. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, et al; Aprepitant Protocol 054 Study Group. Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapyinduced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 2003; 97: 3090–98. 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: 1000–06. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 2006; 24: 2932–47. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Antiemesis. Version 3; 2009. http://www.nccn.org/ professionals/physician_gls/PDF/antiemesis.pdf (accessed April 29, 2009). Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet Oncol 2009; 10: 115–24. Grunberg SM, Rolski J, Strausz J, et al. Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy: a randomised, doubleblind, placebo-controlled trial. Lancet Oncol 2009; 10: 549–58. Roila F, Fatigoni S. New antiemetic drugs. Ann Oncol 2006; 17 (suppl 2): ii96–100.
Science Photo Library
Bevacizumab-associated gastrointestinal perforation
See Articles page 559
534
Bevacizumab, in combination with standard anticancer treatment, has been shown to improve survival or delay disease progression in several advanced solid tumours. However, a pivotal trial in advanced colorectal cancer1 brought bevacizumab-associated gastrointestinal perforation to the attention of the oncological community. Bevacizumab has changed the treatment paradigm for many solid tumours, and this uncommon complication has not altered the benefit–risk ratio. Through education and raising awareness both within clinical trials (as a targeted adverse event) and routine clinical practice, oncologists have learned to recognise and treat bevacizumab-associated gastrointestinal perforation early. Gastrointestinal perforation associated with bevacizumab has been defined as the finding of
intraperitoneal air with or without gastrointestinal or enterocutaneous fistula. Morbidity and especially mortality from gastrointestinal perforation is high, and therefore clinically important. Surgical management can be required, but is not always necessary, and although there might be an increased frequency of post-operative complications in patients receiving bevacizumab, this is outweighed by the benefits of surgical intervention where clinically indicated. In this issue of The Lancet Oncology, Hapani and colleagues2 report the results of a meta-analysis of reported randomised controlled trials to assess the risk of gastrointestinal perforation in patients with cancer treated with bevacizumab. They report an incidence of gastrointestinal perforation of 0·9%: a two-fold increased risk compared with control treatment alone, with mortality seen in over a fifth of www.thelancet.com/oncology Vol 10 June 2009