Comment
problematic metrics for establishment of efficacy. In an attempt to ameliorate such concerns, the investigators used a 2:1 randomisation design to minimise the number of patients randomly assigned to receive chemotherapy, which was expected to be worse than the experimental treatment group. In the future, investigators and regulatory authorities might consider exploring innovative alternatives to test the efficacy of new immunotherapy drugs without doing large, expensive, randomised phase 3 trials. For example, tumour assessment with immune-related response criteria rather than with conventional Response Evaluation Criteria in Solid Tumors might provide a more accurate assessment of objective response and progression-free survival in trials of immunotherapy drugs.7 The next frontier of immunotherapy will be combination strategies, including how and if to combine immunotherapies with chemotherapy, targeted treatments, and other immunotherapy drugs. For example, the preliminary reported clinical efficacy of concurrent nivolumab and ipilimumab seems to be distinct from monotherapy, with rapid and substantial tumour regression noted in a high proportion of patients.8 Future and continuing trials will further investigate such combinations, not only in melanoma, but also in other tumour types that seem promising.
Gerald Falchook Sarah Cannon Research Institute at HealthONE, Denver, CO 80218, USA [email protected] The author has received research funding from Millennium Pharmaceuticals, GlaxoSmithKline, EMD Serono, AstraZeneca, Vegenics, Celgene, Oncothyreon, Novartis, Kolltan Pharmaceuticals, ARMO Biosciences, Incyte, and the National Institutes of Health; travel reimbursement from GlaxoSmithKline, EMD Serono, and Millennium; and honoraria from EMD Serono. 1
2
3
4 5 6
7
8
Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; published online March 18. http://dx.doi. org/10.1016/S1470-2045(15)70076-8. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014; 384: 1109–17. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515: 563–67. Kurzrock R, Stewart DJ. Equipoise abandoned? Randomization and clinical trials. Ann Oncol 2013; 24: 2471–74. Miller FG, Joffe S. Equipoise and the dilemma of randomized clinical trials. N Engl J Med 2011; 364: 476–80. Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003; 327: 1459–61. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15: 7412–20. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: 122–33.
In The Lancet Oncology, Kang and colleagues1 describe safe and effective dosing of the neurokinin type-1 receptor antagonist aprepitant when added to a standard antiemetic regimen for children from age 6 months to 17 years. These findings provide much-needed data for a complication that affects daily paediatric oncology practice, and show the direction for quality clinical trials in the prevention of emesis in children receiving chemotherapy. The results are impressive: prevention of emesis was doubled at nearly all endpoints with the addition of oral aprepitant, providing a 20–30% absolute improvement in control of delayed emesis and in overall 5-day complete responses. This benefit comes without any suggestion of additional side-effects. This trial represents the largest investigation of a neurokinin type-1 receptor antagonist in children, and perhaps the largest well-designed anti-emetic study yet www.thelancet.com/oncology Vol 16 April 2015
done in paediatric oncology. The results provide assurance to paediatric oncologists who have previously had to rely primarily on trials in adults. The pharmacokinetic data suggest a slightly more rapid metabolism of aprepitant in children under the age of 6 years, but it is not clear if this has any clinically relevant effect. Randomised clinical studies with neurokinin type-1 receptor antagonists in adults began to appear in major publications more than 15 years ago, showing the safety, efficacy, and benefit of adding these agents.2 Aprepitant became commercially available in the USA in 2003. Although it is unfortunate that it has taken so long to produce quality evidence for the use of this class of agent in children, many large anti-emetic trials in adults have subsequently explored different challenges for neurokinin type-1 receptor antagonists that might affect paediatric practice. These trials showed the benefit
Simon Fraser/Royal Victoria Infirmary, Newcastle/SPL
Anti-emetics in paediatric patients receiving chemotherapy
Published Online March 12, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70099-9 See Articles page 385
351
Comment
of adding neurokinin type-1 receptor antagonists, and provided evidence supporting the use of neurokinin type-1 receptor antagonists in patients receiving cisplatin,2–4 anthracyclines plus cyclophosphamide,5 and in those receiving cisplatin over a number of days.6 Studies have shown the effect of aprepitant with other chemotherapy,7 and the preservation of benefit over several chemotherapy cycles8,9 with various neurokinin type-1 receptor antagonists. The study by Kang and colleagues1 is the first to provide guidance for children receiving many of these same types of treatment, in a large controlled setting. Several questions remain. One is whether antiemetics are equally effective in adults and children. Among the major risk factors for poor control of emesis in adults are younger age, female sex, low chronic intake of alcohol, previous chemotherapy, and multiple days of chemotherapy.6,10 Is control similar in both young adults and in adolescents, and are younger children at a different risk? These questions cannot be well addressed in the current study. As indicated by the authors, 85–90% of patients had previously received chemotherapy and were treated on multiple days. This situation contrasts with most trials in adults that are done largely in patients receiving their initial chemotherapy in a 1-day treatment; this places them at lower risk. The comparison between results from studies in adults and in children is made more difficult because a variety of chemotherapy agents were used in this study1 and most studies in adults concentrate on a single regimen.2–5 Of interest is the finding that the proportion of patients with complete control at 5 days in the adult trial of aprepitant in which patients received cisplatin on a number of days was similar to results in the this paediatric study (47% in the aprepitant group vs 15% in the control).6 Another question that is not answered in this study1 is the role of corticosteroids as anti-emetics in children. In this study it is problematic that the use of dexamethasone was elective (given to 43% of patients), as the authors acknowledge. It is possible that the corticosteroid was chosen disproportionately for those with poor previous control of emesis. This could predispose those receiving dexamethasone to a paradoxically poorer outcome. Another factor that might make answering this question more difficult in the present study is that patients receiving 352
aprepitant might have been given an under-dosage of the corticosteroid. It is well recognised that the mild 3A4 inhibition of aprepitant leads to increased corticosteroid exposure; however, this effect is much greater with orally administered corticosteroids than with those given intravenously (the latter route was used in this trial, and too large an attenuation of dexamethasone could have occurred).11 In addition to affecting daily practice, this trial provides strong evidence to advise guideline committees. To date, paediatric anti-emetic guidelines have been based on small trials and opinion.12 The results are also encouraging for planning future paediatric anti-emetic trials. Cooperative groups could easily initiate randomised trials to test the role of dexamethasone. A well-designed protocol could be stratified to address anti-emetic approaches among different chemotherapy regimens, and in those previously treated or not. It is notable that 97% of patients in the present study were adequately treated, and the patients and their families must have been encouraged by the marked benefit associated with the addition of aprepitant. Whether we read this study as a treating paediatric oncologist, or as a member of an anti-emetic guideline committee, or as a supportive care clinical trialist, we appreciate the contribution of Kang and colleagues.1 The results are impressive, but at the same time they show the need for improvement. We look forward to this study affecting high quality trials in the near future, by providing evidence that addresses common clinical issues. Richard J Gralla Albert Einstein College of Medicine, Jacobi Medical Center, 1400 Pelham Parkway South, Bronx, NY 10461, USA [email protected] RJG has served as a consultant to Helsinn, Merck, and Tesoro, and has received honoraria from Helsinn, Merck, and Eisai Pharmaceuticals. 1
2
3
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; published online March 12. http://dx.doi.org/10.1016/S14702045(15)70061-6. Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. N Engl J Med 1999; 340: 190–95. 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: 3090–98.
www.thelancet.com/oncology Vol 16 April 2015
Comment
4
5
6
7
8
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; 15: 4112–19. 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: 2822–30. Albany CI, 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; 32: 3998–4003. 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: 423–31. Herrstedt J, Muss HB, Warr DG, et al. Aprepitant Moderately Emetogenic Chemotherapy Study Group. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer 2005; 104: 1548–55.
9
10
11
12
Gralla RJ, Bosnjak SM, Honsta A, et al. A phase 3 study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting (CINV) over repeated cycles of chemotherapy. Ann Oncol 2014; 25: 1333–39. Grunberg SM, Masanori M, Gralla R. Management of nausea and vomiting. In: Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ, eds. Cancer management: a multidisciplinary approach, 12th edn. Norwalk, CT: CMP Medica, 2010: 893–904. McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 2003; 74: 17–24. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010; 21: 232–43.
Therapy for soft-tissue sarcoma typifies the refinement of treatment of solid tumours through molecular pathology. After registration of imatinib for gastrointestinal stromal tumour, the murine compound trabectedin was introduced as another targeted agent in sarcoma. The drug mainly showed activity in myxoid liposarcoma characterised by a FUS-CHOP or DDIT3-CHOP translocation.1 Its radiological response pattern resembles that of tyrosine kinase inhibitor treatment in gastrointestinal stromal tumour.2 The drug is registered in Europe—but not in the USA or Japan—for second-line therapy after chemotherapy with doxorubicin. The registration was based on a comparison of a 24 h infusional regimen with 1·5 mg/m2 vs a 3 h regimen of 1·2 mg/m2, but not on a randomised comparison against other drugs, placebo, or best supportive care. Trabectedin is frequently used in almost all sarcoma subtypes, but cumulative toxicity might be a problem if combined with other drugs.3 Clinical experience has proven that it works best in liposarcoma and leiomyosarcoma (socalled L-sarcomas). Its value in the neoadjuvant setting has been documented in a study on translocationassociated sarcomas, showing a pathological complete remission in three of 23 resection specimens.4 In The Lancet Oncology, Kawai and colleagues5 report a randomised, open-label, phase 2 study of trabectedin monotherapy after standard chemotherapy versus www.thelancet.com/oncology Vol 16 April 2015
best supportive care in Asian patients with advanced, translocation-related sarcoma. The study is the first to show the value of second-line therapy in a randomised fashion versus best supportive care. Median overall survival for metastatic sarcoma has been shown for multiple studies to be around 12 months.6 Thus, a nihilistic approach is sometimes taken after failure of first-line chemotherapy. Patients might be referred for complementary medicine to avoid being affected by more cytostatic drugs. Kawai and colleagues5 show that trabectedin therapy at a rather low toxicity converts into a survival advantage, and does not just improve the time to progression. Median progressionfree survival in the treatment group compared with best supportive care was extraordinary (5·6 months, 95% CI 4·1–7·5 vs 0·9 months, 0·7–1·0), with overall survival at 1 year of about 70%, plateauing until 18 months with the median not reached. Progressionfree survival in the best supportive care group was almost identical to the data from the placebo group in the pazopanib registration study.7 The median overall survival in the best supportive care cohort of 8 months after first-line therapy seems plausible and within the expected range because about 90% of pretreated patients had received anthracyclines, although no data on drug intensity are available. There are caveats. Different trials face different patient populations. The European Organisation
Centre Jean Perrin, ISM/Science Photo Library
Trabectedin: adding clarification rather than novelty
Published Online March 18, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70125-7 See Articles page 406
353
problematic metrics for establishment of efficacy. In an attempt to ameliorate such concerns, the investigators used a 2:1 randomisation design to minimise the number of patients randomly assigned to receive chemotherapy, which was expected to be worse than the experimental treatment group. In the future, investigators and regulatory authorities might consider exploring innovative alternatives to test the efficacy of new immunotherapy drugs without doing large, expensive, randomised phase 3 trials. For example, tumour assessment with immune-related response criteria rather than with conventional Response Evaluation Criteria in Solid Tumors might provide a more accurate assessment of objective response and progression-free survival in trials of immunotherapy drugs.7 The next frontier of immunotherapy will be combination strategies, including how and if to combine immunotherapies with chemotherapy, targeted treatments, and other immunotherapy drugs. For example, the preliminary reported clinical efficacy of concurrent nivolumab and ipilimumab seems to be distinct from monotherapy, with rapid and substantial tumour regression noted in a high proportion of patients.8 Future and continuing trials will further investigate such combinations, not only in melanoma, but also in other tumour types that seem promising.
Gerald Falchook Sarah Cannon Research Institute at HealthONE, Denver, CO 80218, USA [email protected] The author has received research funding from Millennium Pharmaceuticals, GlaxoSmithKline, EMD Serono, AstraZeneca, Vegenics, Celgene, Oncothyreon, Novartis, Kolltan Pharmaceuticals, ARMO Biosciences, Incyte, and the National Institutes of Health; travel reimbursement from GlaxoSmithKline, EMD Serono, and Millennium; and honoraria from EMD Serono. 1
2
3
4 5 6
7
8
Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 2015; published online March 18. http://dx.doi. org/10.1016/S1470-2045(15)70076-8. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014; 384: 1109–17. Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014; 515: 563–67. Kurzrock R, Stewart DJ. Equipoise abandoned? Randomization and clinical trials. Ann Oncol 2013; 24: 2471–74. Miller FG, Joffe S. Equipoise and the dilemma of randomized clinical trials. N Engl J Med 2011; 364: 476–80. Smith GC, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. BMJ 2003; 327: 1459–61. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15: 7412–20. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: 122–33.
In The Lancet Oncology, Kang and colleagues1 describe safe and effective dosing of the neurokinin type-1 receptor antagonist aprepitant when added to a standard antiemetic regimen for children from age 6 months to 17 years. These findings provide much-needed data for a complication that affects daily paediatric oncology practice, and show the direction for quality clinical trials in the prevention of emesis in children receiving chemotherapy. The results are impressive: prevention of emesis was doubled at nearly all endpoints with the addition of oral aprepitant, providing a 20–30% absolute improvement in control of delayed emesis and in overall 5-day complete responses. This benefit comes without any suggestion of additional side-effects. This trial represents the largest investigation of a neurokinin type-1 receptor antagonist in children, and perhaps the largest well-designed anti-emetic study yet www.thelancet.com/oncology Vol 16 April 2015
done in paediatric oncology. The results provide assurance to paediatric oncologists who have previously had to rely primarily on trials in adults. The pharmacokinetic data suggest a slightly more rapid metabolism of aprepitant in children under the age of 6 years, but it is not clear if this has any clinically relevant effect. Randomised clinical studies with neurokinin type-1 receptor antagonists in adults began to appear in major publications more than 15 years ago, showing the safety, efficacy, and benefit of adding these agents.2 Aprepitant became commercially available in the USA in 2003. Although it is unfortunate that it has taken so long to produce quality evidence for the use of this class of agent in children, many large anti-emetic trials in adults have subsequently explored different challenges for neurokinin type-1 receptor antagonists that might affect paediatric practice. These trials showed the benefit
Simon Fraser/Royal Victoria Infirmary, Newcastle/SPL
Anti-emetics in paediatric patients receiving chemotherapy
Published Online March 12, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70099-9 See Articles page 385
351
Comment
of adding neurokinin type-1 receptor antagonists, and provided evidence supporting the use of neurokinin type-1 receptor antagonists in patients receiving cisplatin,2–4 anthracyclines plus cyclophosphamide,5 and in those receiving cisplatin over a number of days.6 Studies have shown the effect of aprepitant with other chemotherapy,7 and the preservation of benefit over several chemotherapy cycles8,9 with various neurokinin type-1 receptor antagonists. The study by Kang and colleagues1 is the first to provide guidance for children receiving many of these same types of treatment, in a large controlled setting. Several questions remain. One is whether antiemetics are equally effective in adults and children. Among the major risk factors for poor control of emesis in adults are younger age, female sex, low chronic intake of alcohol, previous chemotherapy, and multiple days of chemotherapy.6,10 Is control similar in both young adults and in adolescents, and are younger children at a different risk? These questions cannot be well addressed in the current study. As indicated by the authors, 85–90% of patients had previously received chemotherapy and were treated on multiple days. This situation contrasts with most trials in adults that are done largely in patients receiving their initial chemotherapy in a 1-day treatment; this places them at lower risk. The comparison between results from studies in adults and in children is made more difficult because a variety of chemotherapy agents were used in this study1 and most studies in adults concentrate on a single regimen.2–5 Of interest is the finding that the proportion of patients with complete control at 5 days in the adult trial of aprepitant in which patients received cisplatin on a number of days was similar to results in the this paediatric study (47% in the aprepitant group vs 15% in the control).6 Another question that is not answered in this study1 is the role of corticosteroids as anti-emetics in children. In this study it is problematic that the use of dexamethasone was elective (given to 43% of patients), as the authors acknowledge. It is possible that the corticosteroid was chosen disproportionately for those with poor previous control of emesis. This could predispose those receiving dexamethasone to a paradoxically poorer outcome. Another factor that might make answering this question more difficult in the present study is that patients receiving 352
aprepitant might have been given an under-dosage of the corticosteroid. It is well recognised that the mild 3A4 inhibition of aprepitant leads to increased corticosteroid exposure; however, this effect is much greater with orally administered corticosteroids than with those given intravenously (the latter route was used in this trial, and too large an attenuation of dexamethasone could have occurred).11 In addition to affecting daily practice, this trial provides strong evidence to advise guideline committees. To date, paediatric anti-emetic guidelines have been based on small trials and opinion.12 The results are also encouraging for planning future paediatric anti-emetic trials. Cooperative groups could easily initiate randomised trials to test the role of dexamethasone. A well-designed protocol could be stratified to address anti-emetic approaches among different chemotherapy regimens, and in those previously treated or not. It is notable that 97% of patients in the present study were adequately treated, and the patients and their families must have been encouraged by the marked benefit associated with the addition of aprepitant. Whether we read this study as a treating paediatric oncologist, or as a member of an anti-emetic guideline committee, or as a supportive care clinical trialist, we appreciate the contribution of Kang and colleagues.1 The results are impressive, but at the same time they show the need for improvement. We look forward to this study affecting high quality trials in the near future, by providing evidence that addresses common clinical issues. Richard J Gralla Albert Einstein College of Medicine, Jacobi Medical Center, 1400 Pelham Parkway South, Bronx, NY 10461, USA [email protected] RJG has served as a consultant to Helsinn, Merck, and Tesoro, and has received honoraria from Helsinn, Merck, and Eisai Pharmaceuticals. 1
2
3
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; published online March 12. http://dx.doi.org/10.1016/S14702045(15)70061-6. Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. N Engl J Med 1999; 340: 190–95. 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: 3090–98.
www.thelancet.com/oncology Vol 16 April 2015
Comment
4
5
6
7
8
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; 15: 4112–19. 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: 2822–30. Albany CI, 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; 32: 3998–4003. 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: 423–31. Herrstedt J, Muss HB, Warr DG, et al. Aprepitant Moderately Emetogenic Chemotherapy Study Group. Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and emesis over multiple cycles of moderately emetogenic chemotherapy. Cancer 2005; 104: 1548–55.
9
10
11
12
Gralla RJ, Bosnjak SM, Honsta A, et al. A phase 3 study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting (CINV) over repeated cycles of chemotherapy. Ann Oncol 2014; 25: 1333–39. Grunberg SM, Masanori M, Gralla R. Management of nausea and vomiting. In: Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ, eds. Cancer management: a multidisciplinary approach, 12th edn. Norwalk, CT: CMP Medica, 2010: 893–904. McCrea JB, Majumdar AK, Goldberg MR, et al. Effects of the neurokinin1 receptor antagonist aprepitant on the pharmacokinetics of dexamethasone and methylprednisolone. Clin Pharmacol Ther 2003; 74: 17–24. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol 2010; 21: 232–43.
Therapy for soft-tissue sarcoma typifies the refinement of treatment of solid tumours through molecular pathology. After registration of imatinib for gastrointestinal stromal tumour, the murine compound trabectedin was introduced as another targeted agent in sarcoma. The drug mainly showed activity in myxoid liposarcoma characterised by a FUS-CHOP or DDIT3-CHOP translocation.1 Its radiological response pattern resembles that of tyrosine kinase inhibitor treatment in gastrointestinal stromal tumour.2 The drug is registered in Europe—but not in the USA or Japan—for second-line therapy after chemotherapy with doxorubicin. The registration was based on a comparison of a 24 h infusional regimen with 1·5 mg/m2 vs a 3 h regimen of 1·2 mg/m2, but not on a randomised comparison against other drugs, placebo, or best supportive care. Trabectedin is frequently used in almost all sarcoma subtypes, but cumulative toxicity might be a problem if combined with other drugs.3 Clinical experience has proven that it works best in liposarcoma and leiomyosarcoma (socalled L-sarcomas). Its value in the neoadjuvant setting has been documented in a study on translocationassociated sarcomas, showing a pathological complete remission in three of 23 resection specimens.4 In The Lancet Oncology, Kawai and colleagues5 report a randomised, open-label, phase 2 study of trabectedin monotherapy after standard chemotherapy versus www.thelancet.com/oncology Vol 16 April 2015
best supportive care in Asian patients with advanced, translocation-related sarcoma. The study is the first to show the value of second-line therapy in a randomised fashion versus best supportive care. Median overall survival for metastatic sarcoma has been shown for multiple studies to be around 12 months.6 Thus, a nihilistic approach is sometimes taken after failure of first-line chemotherapy. Patients might be referred for complementary medicine to avoid being affected by more cytostatic drugs. Kawai and colleagues5 show that trabectedin therapy at a rather low toxicity converts into a survival advantage, and does not just improve the time to progression. Median progressionfree survival in the treatment group compared with best supportive care was extraordinary (5·6 months, 95% CI 4·1–7·5 vs 0·9 months, 0·7–1·0), with overall survival at 1 year of about 70%, plateauing until 18 months with the median not reached. Progressionfree survival in the best supportive care group was almost identical to the data from the placebo group in the pazopanib registration study.7 The median overall survival in the best supportive care cohort of 8 months after first-line therapy seems plausible and within the expected range because about 90% of pretreated patients had received anthracyclines, although no data on drug intensity are available. There are caveats. Different trials face different patient populations. The European Organisation
Centre Jean Perrin, ISM/Science Photo Library
Trabectedin: adding clarification rather than novelty
Published Online March 18, 2015 http://dx.doi.org/10.1016/ S1470-2045(15)70125-7 See Articles page 406
353
