Comment
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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.
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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
Comment
for Research and Treatment of Cancer 62091 trial compared two trabectedin schedules to standard doxorubicin treatment in a randomised phase 2b study, intended to take the best schedule to phase 3. Unexpectedly, the proportion of patients achieving a response after treatment with doxorubicin was higher than that seen in more than a decade before, and both trabectedin schedules had to be stopped due to futility. In the study by Kawai and colleagues,5 the population is about a decade younger (median 39 years) than typically reported.6 In the best supportive care group, 61% of the patients had two or more lines of previous treatment but only 30% in the trabectedin group. The results also might have benefited from an imbalance between histologies. Myxoid liposarcoma is known to respond well to trabectedin and there were four more patients with this histology in the trabectedin group (14 vs 10). More aggressive subtypes such as synovial sarcoma (7 vs 11) or clear-cell sarcoma (1 vs 4) were disproportionally present in the best supportive care group. Tumour grading as the most important prognostic factor is not addressed in the analysis, and allowing a patient aged 40 years with a metastatic high-grade sarcoma to be assigned to best supportive care would probably not have happened had the trial been done in a European setting. There are no data on post-study chemotherapy, which would be interesting in those 70% of patients in the trabectedin group with a maximum of one line of previous treatment. In the phase 3 study of pazopanib versus placebo, overall survival was not improved despite significantly better progression-free survival.7 This fact was largely attributed to effective post-trial chemotherapy in the control group. There is real movement in drug treatment of soft-tissue sarcoma. Over decades, doxorubicin, ifosfamide, or their combination were the primary effective compounds. Trabectedin was added in 2007 and pazopanib in 2010. Expanded molecular characterisation will define further sarcoma subtypes beyond gastrointestinal stromal tumour, dermatofibrosarcoma protuberans,8 inflammatory myofibroblastic tumours,9 or perivascular epithelioid cell tumours10 to be treated with targeted therapy. An important trial underway is the CREATE study (NCT01524926) assessing crizotinib in different cancers with ALK translocation in subtypes of sarcoma, 354
kidney cancer, and anaplastic large-cell lymphoma. The results of another trabectedin phase 3 study in comparison with dacarbazin (SAR-3007 study; NCT01343277) in L-sarcomas are awaited. Most recently, in L-sarcoma, eribulin met the primary endpoint of improving overall survival in secondline therapy when compared with dacarbazin in a randomised phase 3 study (NCT01327885).11 Further progress should come soon. Peter Hohenberger Division of Surgical Oncology & Thoracic Surgery Mannheim, University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Theodor Kutzer Ufer 1, D-68165 Mannheim, Germany [email protected] PH reports grants and personal fees from PharmaMar, outside of the submitted work. 1
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Grosso F, Jones RL, Demetri GD, et al. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol 2007; 8: 595–602. Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007; 25: 1753–59. Kasper B, Reichardt P, Pink D, et al. Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG). Mar Drugs 2015; 13: 379–88. Gronchi A, Bui BN, Bonvalot S, et al. Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma. Ann Oncol 2012; 23: 771–76. Kawai A, Araki N, Sugiura H, et al. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol 2015; published online March 18. http://dx. doi.org/10.1016/S1470-2045(15)70098-7. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014; 15: 415–23. Van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379: 1879–86. Rutkowski P, Van Glabbeke M, Rankin CJ, et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol 2010; 28: 1772–79. Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALKrearranged inflammatory myofibroblastic tumor. N Engl J Med 2010; 363: 1727–33. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol 2010; 28: 835–40. Eisai Europe Limited. Phase III trial of anticancer agent Halaven® (eribulin) in soft tissue sarcoma shows overall survival benefit in primary endpoint. http://www.prnewswire.co.uk/news-releases/phase-iii-trialof-anticancer-agent-halaven-eribulin-in-soft-tissue-sarcoma-showsoverall-survival-benefit-in-primary-endpoint-293934521.html (accessed Feb 25, 2015).
www.thelancet.com/oncology Vol 16 April 2015
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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
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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
Comment
for Research and Treatment of Cancer 62091 trial compared two trabectedin schedules to standard doxorubicin treatment in a randomised phase 2b study, intended to take the best schedule to phase 3. Unexpectedly, the proportion of patients achieving a response after treatment with doxorubicin was higher than that seen in more than a decade before, and both trabectedin schedules had to be stopped due to futility. In the study by Kawai and colleagues,5 the population is about a decade younger (median 39 years) than typically reported.6 In the best supportive care group, 61% of the patients had two or more lines of previous treatment but only 30% in the trabectedin group. The results also might have benefited from an imbalance between histologies. Myxoid liposarcoma is known to respond well to trabectedin and there were four more patients with this histology in the trabectedin group (14 vs 10). More aggressive subtypes such as synovial sarcoma (7 vs 11) or clear-cell sarcoma (1 vs 4) were disproportionally present in the best supportive care group. Tumour grading as the most important prognostic factor is not addressed in the analysis, and allowing a patient aged 40 years with a metastatic high-grade sarcoma to be assigned to best supportive care would probably not have happened had the trial been done in a European setting. There are no data on post-study chemotherapy, which would be interesting in those 70% of patients in the trabectedin group with a maximum of one line of previous treatment. In the phase 3 study of pazopanib versus placebo, overall survival was not improved despite significantly better progression-free survival.7 This fact was largely attributed to effective post-trial chemotherapy in the control group. There is real movement in drug treatment of soft-tissue sarcoma. Over decades, doxorubicin, ifosfamide, or their combination were the primary effective compounds. Trabectedin was added in 2007 and pazopanib in 2010. Expanded molecular characterisation will define further sarcoma subtypes beyond gastrointestinal stromal tumour, dermatofibrosarcoma protuberans,8 inflammatory myofibroblastic tumours,9 or perivascular epithelioid cell tumours10 to be treated with targeted therapy. An important trial underway is the CREATE study (NCT01524926) assessing crizotinib in different cancers with ALK translocation in subtypes of sarcoma, 354
kidney cancer, and anaplastic large-cell lymphoma. The results of another trabectedin phase 3 study in comparison with dacarbazin (SAR-3007 study; NCT01343277) in L-sarcomas are awaited. Most recently, in L-sarcoma, eribulin met the primary endpoint of improving overall survival in secondline therapy when compared with dacarbazin in a randomised phase 3 study (NCT01327885).11 Further progress should come soon. Peter Hohenberger Division of Surgical Oncology & Thoracic Surgery Mannheim, University Medical Center, Medical Faculty Mannheim, University of Heidelberg, Theodor Kutzer Ufer 1, D-68165 Mannheim, Germany [email protected] PH reports grants and personal fees from PharmaMar, outside of the submitted work. 1
2
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5
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7
8
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Grosso F, Jones RL, Demetri GD, et al. Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. Lancet Oncol 2007; 8: 595–602. Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007; 25: 1753–59. Kasper B, Reichardt P, Pink D, et al. Combination of trabectedin and gemcitabine for advanced soft tissue sarcomas: results of a phase I dose escalating trial of the German Interdisciplinary Sarcoma Group (GISG). Mar Drugs 2015; 13: 379–88. Gronchi A, Bui BN, Bonvalot S, et al. Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma. Ann Oncol 2012; 23: 771–76. Kawai A, Araki N, Sugiura H, et al. Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study. Lancet Oncol 2015; published online March 18. http://dx. doi.org/10.1016/S1470-2045(15)70098-7. Judson I, Verweij J, Gelderblom H, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol 2014; 15: 415–23. Van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2012; 379: 1879–86. Rutkowski P, Van Glabbeke M, Rankin CJ, et al. Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol 2010; 28: 1772–79. Butrynski JE, D’Adamo DR, Hornick JL, et al. Crizotinib in ALKrearranged inflammatory myofibroblastic tumor. N Engl J Med 2010; 363: 1727–33. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol 2010; 28: 835–40. Eisai Europe Limited. Phase III trial of anticancer agent Halaven® (eribulin) in soft tissue sarcoma shows overall survival benefit in primary endpoint. http://www.prnewswire.co.uk/news-releases/phase-iii-trialof-anticancer-agent-halaven-eribulin-in-soft-tissue-sarcoma-showsoverall-survival-benefit-in-primary-endpoint-293934521.html (accessed Feb 25, 2015).
www.thelancet.com/oncology Vol 16 April 2015
