Opinion
VIEWPOINT
Carlo GambacortiPasserini, MD Department of Health Sciences, University of Milano-Bicocca, Monza, Italy; and Section of Hematology, San Gerardo Hospital, Monza, Italy. Rocco Piazza, MD, PhD Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
Corresponding Author: Carlo Gambacorti-Passerini, MD, Department of Health Sciences, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy (carlo.gambacorti @unimib.it). jamaoncology.com
Imatinib—A New Tyrosine Kinase Inhibitor for First-Line Treatment of Chronic Myeloid Leukemia in 2015 Imatinib mesylate changed the prognosis for chronic myeloid leukemia (CML) so dramatically that patients with newly diagnosed CML starting treatment with imatinib now have a normal life expectancy,1,2 compared with the historical median survival of 2 to 3 years. In addition to its outstanding therapeutic activity, imatinib possesses a remarkably safe profile. Second- and third-generation tyrosine kinase inhibitors(TKIs)weredevelopedprimarilyforsecond-andthirdline use: bosutinib monohydrate, dasatinib, nilotinib, and ponatinib hydrochloride constitute a set of formidable “sparewheels”forpatientswhoseimatinibtreatmentfails, giving a viable option to more than 50% of them. These drugs contributed to achieving the observed normal life expectancy in patients with CML who start first-line imatinib treatment. Dasatinib and nilotinib also obtained firstline indication and have been aggressively marketed as a replacement for the “aging” imatinib. The supposed superiority of second-generation TKIs is based on 2 registration studies, the DASISION and ENESTnd protocols, which showed a faster reduction of BCR/ABL 1 gene transcripts, a 10% to 15% increase in the rate of complete cytogenetic responses (CCRs) by 12 months, and a protection from progression to accelerated phase–blast crisis (APBC) of 2% to 3.5%. This last effect, however, is not established; although it was statistically significant in the ENESTnd study, it was reported as a statistically insignificant “trend” in the DASISION trial; in fact, a subsequent independent replica of the DASISION trial failed to show any difference in progression to APBC between patients treated with imatinib and dasatinib.3 Moreover, the way that data were initially collected in ENESTnd raises doubts that some patients could have discontinued participation in the study for reasons different from those reported.4 Because the difference in progression to APBC between the 2 groups of patients is small, even a few cases can make a substantial impact on the final results. In fact, a recent update of the ENESTnd study, presented at the 2014 American Society of Hematology meeting, showed that the difference in progression to APBC between the imatinib and the nilotinib 300 mg twice daily treatment groups lost its statistical significance.5 Finally, a recent replica of ENESTnd (ENESTChina) in 267 Chinese patients did not show any significant difference between patients with newly diagnosed CML receiving imatinib or nilotinib in overall survival, progression-free survival, progression to APBC (1.5% in each arm), and 6-month (66% vs 57%) and 12-month (77% vs 77%) CCR rates; the only significant difference observed was in the rate of major molecular response at 12 months.6
It has to be remembered that it has always been difficulttodiscernanindependentprognosticvalueformolecular responses outside of cytogenetic ones.7 If obtaining “faster and deeper” responses using second-generation TKIsdoesnotconvertintoabetterprognosis,thenthisphenomenon should not dictate a change in therapy by itself. Whereas the superiority of second-generation TKIs over imatinib in terms of first-line therapeutic activity seems questionable, the safety profiles of these drugs are also a matter of debate. Dasatinib’s safety profile includes pleural and pericardial effusion in a sizeable proportion of patients, especially after long-term use. Nilotinib is even more dangerous: the drug causes a sort of “metabolic syndrome” characterized by increased glucose, cholesterol, and triglyceride levels, which lead to clinical diabetes mellitus in up to 18% of patients and to accelerated atherosclerosis and arterial thrombosis including peripheral arterial occlusive disease in a yetunspecified proportion of patients, which can be gauged to be between 5% and 25% after 5 years of treatment.8 Imatinib, in contrast, shows a remarkably safe toxicity profile, even in long-term studies9; however, its adverse effects are felt by patients and can diminish their quality of life, decrease adherence, and cause treatment failures and must therefore be tackled by treating physicians. In this respect, the logistical organization of care plays a fundamental role in the final outcome, as witnessed by wide variations in response rates in different logistical settings. The rates of CCR after 12 months of imatinib therapy can span from values close to 90%1 down to 40% and even 18%.8 A recent analysis performed in the US community setting of the types of logistical and geographical CML management, and effects on patients’ survival,10 supports this conclusion. A final point concerns the costs of the different therapies: even when other factors are not considered, the cost forusingimatinibisgoingtodecreasesubstantiallyin2015, at least in the United States, because of patent expiration. Therefore, the cost of 1 quality-adjusted life-year saved using the different TKIs is going to diverge dramatically in favor of imatinib. This fact will need proper consideration when budget-conscious decisions are made in the future. Generic imatinib has been available since 2013 in Canada and South Korea, at prices between 10% and 25% of the branded version. The availability of generic imatinib will facilitate access to this costly drug in countries such as the UnitedStatesandwillcontributetoeliminatingtherelated financial hurdles that were documented in previous multinational studies.9 In such a scenario, if generic imatinib will cost between 10% and 30% as much as the branded productandtheorganizationofcareforpatientswithCML (Reprinted) JAMA Oncology May 2015 Volume 1, Number 2
Copyright 2015 American Medical Association. All rights reserved.
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143
Opinion Viewpoint
is optimized,8,9 an amelioration of CML long-term prognosis in the United States can be expected and will be testified by the shrinkage of the differences in CML mortality between Surveillance, Epidemiology, and End Results and other registries such as the Swedish Cancer Registry, which are presently approximately 20%.
with imatinib: a long-term single institution analysis. Am J Hematol. 2014;89(10):E184-E187.
ARTICLE INFORMATION Published Online: March 12, 2015. doi:10.1001/jamaoncol.2015.50. Conflict of Interest Disclosures: Dr GambacortiPasserini has received research grants from Pfizer and serves on the advisory boards of Pfizer and Bristol-Myers Squibb. No other disclosures are reported. Funding/Support: This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC 2013 IG-14249 to Dr Gambacorti-Passerini). Role of the Funder/Sponsor: The funder had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Correction: This article was corrected online April 10, 2015, for an incorrect drug name in the last sentence of the third paragraph. REFERENCES 1. Viganò I, Di Giacomo N, Bozzani S, Antolini L, Piazza R, Gambacorti Passerini C. First-line treatment of 102 chronic myeloid leukemia patients
VIEWPOINT
Reshma Jagsi, MD, DPhil Department of Radiation Oncology, University of Michigan, Ann Arbor; and Center for Bioethics and Social Science in Medicine, University of Michigan, Ann Arbor.
Corresponding Author: Reshma Jagsi, MD, DPhil, Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Dr, UHB2C490, SPC 5010, Ann Arbor, MI 48109-5010 (rjagsi @med.umich.edu). 144
Thus, what is “aging” here is only the lifespan of the imatinib patent; imatinib is well, and its generic form represents the true “new” TKI for 2015. Rigorous quality control on the activity and safety of generic imatinib and a sufficiently high number of producers (>5) will be vital to ensure confidence in its use.
2. Hehlmann R, Müller MC, Lauseker M, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol. 2014;32(5):415-423. 3. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120(19): 3898-3905. 4. Simonsson B, Porkka K, Richter J. Second-generation BCR-ABL kinase inhibitors in CML. N Engl J Med. 2010;363(17):1673. 5. Larson RA, Kim D-W, Issaragrilsil S, et al. Efficacy and safety of nilotinib (NIL) vs imatinib (IM) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): long-term follow-up (f/u) of ENESTnd. Blood. 2014;124(21):abstr 4541;ASH annual meeting.
chronic myeloid leukemia in chronic phase (CML-CP): ENESTchina 12-month primary analysis. Blood. 2013;122(21):abstr 1497; ASH annual meeting. 7. Marin D. Patient with chronic myeloid leukemia in complete cytogenetic response: what does it mean, and what does one do next? J Clin Oncol. 2014;32(5):379-384. 8. Gambacorti-Passerini C, Piazza R. How I treat newly diagnosed chronic myeloid leukemia in 2015. Am J Hematol. 2015;90(2):156-161. 9. Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103 (7):553-561. 10. Chen CJ, Chen L, Dhanda R, et al. Treatment response monitoring in chronic phase CML (CP-CML) patients receiving tyrosine kinase inhibitor (TKI) therapy in US Oncology Network. J Clin Oncol. 2013;31(suppl):abstr 7096; ASCO annual meeting.
6. Huang X, Wang J, Baccarani M, et al. Frontline nilotinib results in superior rates of molecular response versus imatinib in Chinese patients with
Hypofractionated Whole Breast Radiotherapy Adapting to the Evidence Increased consciousness about the costs of cancer care, which substantially impact both society and the finances of individual patients, motivates interest in opportunities to improve efficiency. In the field of radiation oncology, hypofractionation—reducingthenumberofdailyradiation treatments by giving higher doses per fraction—is one of the most promising opportunities of this sort. Hypofractionation can improve convenience and lower costs, and growing evidence attests to its safety and efficacy in selected clinical settings. Therefore, it is unsurprising that hypofractionation is the subject of 2 of the first “top 5” opportunities in the Choosing Wisely campaign of the American Society of Radiation Oncology (ASTRO). Given the sheer number of women who receive radiation therapy as part of breast-conserving therapy for breast cancer each year, hypofractionation has the potential for particularly dramatic impact in this setting. Numerous trials have demonstrated substantial improvements in locoregional control from the administration of radiotherapy after breast-conserving surgery, and metaanalyses have established a modest survival gain in patients with invasive disease.1 In light of the fractionation schedules administered in most of these trials,
physicians have traditionally counseled patients to expect 5 or more weeks of daily radiation treatments after breast-conserving surgery if they wish to avoid mastectomy. Unfortunately, this could diminish access to breast conservation in populations that face geographic, financial, or other barriers to the receipt of protracted courses of radiotherapy. Overthepastdecade,high-qualityrandomizedtrials2,3 havegeneratedevidencesupportingtheefficacyandsafety ofhypofractionatedwhole-breastradiationtherapyinvolving approximately 3 weeks of daily treatments in selected patients compared with traditional schedules spanning 5 weeks or longer. A large Canadian trial randomized womenwithinvasive,node-negativebreastcancerafterlumpectomytoahypofractionatedcourseof42.5Gyin16fractions vs a standard course of 50 Gy in 25 fractions. Early results emergedoveradecadeago,andamorerecentreportdemonstratedcontinuedequivalenceinbothefficacyandsafety at 10 years.2 Similar results emerged from several British trials, including the UK Standardisation of Breast Radiotherapy (START) B trial,3 which randomized women to 40 Gy in 15 fractions vs 50 Gy in 25 fractions, finding that late adverseeffectsmightactuallybelowerafterhypofraction-
JAMA Oncology May 2015 Volume 1, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://oncology.jamanetwork.com/ by a University of Hong Kong Libraries User on 08/17/2015
jamaoncology.com
VIEWPOINT
Carlo GambacortiPasserini, MD Department of Health Sciences, University of Milano-Bicocca, Monza, Italy; and Section of Hematology, San Gerardo Hospital, Monza, Italy. Rocco Piazza, MD, PhD Department of Health Sciences, University of Milano-Bicocca, Monza, Italy.
Corresponding Author: Carlo Gambacorti-Passerini, MD, Department of Health Sciences, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy (carlo.gambacorti @unimib.it). jamaoncology.com
Imatinib—A New Tyrosine Kinase Inhibitor for First-Line Treatment of Chronic Myeloid Leukemia in 2015 Imatinib mesylate changed the prognosis for chronic myeloid leukemia (CML) so dramatically that patients with newly diagnosed CML starting treatment with imatinib now have a normal life expectancy,1,2 compared with the historical median survival of 2 to 3 years. In addition to its outstanding therapeutic activity, imatinib possesses a remarkably safe profile. Second- and third-generation tyrosine kinase inhibitors(TKIs)weredevelopedprimarilyforsecond-andthirdline use: bosutinib monohydrate, dasatinib, nilotinib, and ponatinib hydrochloride constitute a set of formidable “sparewheels”forpatientswhoseimatinibtreatmentfails, giving a viable option to more than 50% of them. These drugs contributed to achieving the observed normal life expectancy in patients with CML who start first-line imatinib treatment. Dasatinib and nilotinib also obtained firstline indication and have been aggressively marketed as a replacement for the “aging” imatinib. The supposed superiority of second-generation TKIs is based on 2 registration studies, the DASISION and ENESTnd protocols, which showed a faster reduction of BCR/ABL 1 gene transcripts, a 10% to 15% increase in the rate of complete cytogenetic responses (CCRs) by 12 months, and a protection from progression to accelerated phase–blast crisis (APBC) of 2% to 3.5%. This last effect, however, is not established; although it was statistically significant in the ENESTnd study, it was reported as a statistically insignificant “trend” in the DASISION trial; in fact, a subsequent independent replica of the DASISION trial failed to show any difference in progression to APBC between patients treated with imatinib and dasatinib.3 Moreover, the way that data were initially collected in ENESTnd raises doubts that some patients could have discontinued participation in the study for reasons different from those reported.4 Because the difference in progression to APBC between the 2 groups of patients is small, even a few cases can make a substantial impact on the final results. In fact, a recent update of the ENESTnd study, presented at the 2014 American Society of Hematology meeting, showed that the difference in progression to APBC between the imatinib and the nilotinib 300 mg twice daily treatment groups lost its statistical significance.5 Finally, a recent replica of ENESTnd (ENESTChina) in 267 Chinese patients did not show any significant difference between patients with newly diagnosed CML receiving imatinib or nilotinib in overall survival, progression-free survival, progression to APBC (1.5% in each arm), and 6-month (66% vs 57%) and 12-month (77% vs 77%) CCR rates; the only significant difference observed was in the rate of major molecular response at 12 months.6
It has to be remembered that it has always been difficulttodiscernanindependentprognosticvalueformolecular responses outside of cytogenetic ones.7 If obtaining “faster and deeper” responses using second-generation TKIsdoesnotconvertintoabetterprognosis,thenthisphenomenon should not dictate a change in therapy by itself. Whereas the superiority of second-generation TKIs over imatinib in terms of first-line therapeutic activity seems questionable, the safety profiles of these drugs are also a matter of debate. Dasatinib’s safety profile includes pleural and pericardial effusion in a sizeable proportion of patients, especially after long-term use. Nilotinib is even more dangerous: the drug causes a sort of “metabolic syndrome” characterized by increased glucose, cholesterol, and triglyceride levels, which lead to clinical diabetes mellitus in up to 18% of patients and to accelerated atherosclerosis and arterial thrombosis including peripheral arterial occlusive disease in a yetunspecified proportion of patients, which can be gauged to be between 5% and 25% after 5 years of treatment.8 Imatinib, in contrast, shows a remarkably safe toxicity profile, even in long-term studies9; however, its adverse effects are felt by patients and can diminish their quality of life, decrease adherence, and cause treatment failures and must therefore be tackled by treating physicians. In this respect, the logistical organization of care plays a fundamental role in the final outcome, as witnessed by wide variations in response rates in different logistical settings. The rates of CCR after 12 months of imatinib therapy can span from values close to 90%1 down to 40% and even 18%.8 A recent analysis performed in the US community setting of the types of logistical and geographical CML management, and effects on patients’ survival,10 supports this conclusion. A final point concerns the costs of the different therapies: even when other factors are not considered, the cost forusingimatinibisgoingtodecreasesubstantiallyin2015, at least in the United States, because of patent expiration. Therefore, the cost of 1 quality-adjusted life-year saved using the different TKIs is going to diverge dramatically in favor of imatinib. This fact will need proper consideration when budget-conscious decisions are made in the future. Generic imatinib has been available since 2013 in Canada and South Korea, at prices between 10% and 25% of the branded version. The availability of generic imatinib will facilitate access to this costly drug in countries such as the UnitedStatesandwillcontributetoeliminatingtherelated financial hurdles that were documented in previous multinational studies.9 In such a scenario, if generic imatinib will cost between 10% and 30% as much as the branded productandtheorganizationofcareforpatientswithCML (Reprinted) JAMA Oncology May 2015 Volume 1, Number 2
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://oncology.jamanetwork.com/ by a University of Hong Kong Libraries User on 08/17/2015
143
Opinion Viewpoint
is optimized,8,9 an amelioration of CML long-term prognosis in the United States can be expected and will be testified by the shrinkage of the differences in CML mortality between Surveillance, Epidemiology, and End Results and other registries such as the Swedish Cancer Registry, which are presently approximately 20%.
with imatinib: a long-term single institution analysis. Am J Hematol. 2014;89(10):E184-E187.
ARTICLE INFORMATION Published Online: March 12, 2015. doi:10.1001/jamaoncol.2015.50. Conflict of Interest Disclosures: Dr GambacortiPasserini has received research grants from Pfizer and serves on the advisory boards of Pfizer and Bristol-Myers Squibb. No other disclosures are reported. Funding/Support: This study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC 2013 IG-14249 to Dr Gambacorti-Passerini). Role of the Funder/Sponsor: The funder had no role in the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Correction: This article was corrected online April 10, 2015, for an incorrect drug name in the last sentence of the third paragraph. REFERENCES 1. Viganò I, Di Giacomo N, Bozzani S, Antolini L, Piazza R, Gambacorti Passerini C. First-line treatment of 102 chronic myeloid leukemia patients
VIEWPOINT
Reshma Jagsi, MD, DPhil Department of Radiation Oncology, University of Michigan, Ann Arbor; and Center for Bioethics and Social Science in Medicine, University of Michigan, Ann Arbor.
Corresponding Author: Reshma Jagsi, MD, DPhil, Department of Radiation Oncology, University of Michigan, 1500 E Medical Center Dr, UHB2C490, SPC 5010, Ann Arbor, MI 48109-5010 (rjagsi @med.umich.edu). 144
Thus, what is “aging” here is only the lifespan of the imatinib patent; imatinib is well, and its generic form represents the true “new” TKI for 2015. Rigorous quality control on the activity and safety of generic imatinib and a sufficiently high number of producers (>5) will be vital to ensure confidence in its use.
2. Hehlmann R, Müller MC, Lauseker M, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol. 2014;32(5):415-423. 3. Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood. 2012;120(19): 3898-3905. 4. Simonsson B, Porkka K, Richter J. Second-generation BCR-ABL kinase inhibitors in CML. N Engl J Med. 2010;363(17):1673. 5. Larson RA, Kim D-W, Issaragrilsil S, et al. Efficacy and safety of nilotinib (NIL) vs imatinib (IM) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): long-term follow-up (f/u) of ENESTnd. Blood. 2014;124(21):abstr 4541;ASH annual meeting.
chronic myeloid leukemia in chronic phase (CML-CP): ENESTchina 12-month primary analysis. Blood. 2013;122(21):abstr 1497; ASH annual meeting. 7. Marin D. Patient with chronic myeloid leukemia in complete cytogenetic response: what does it mean, and what does one do next? J Clin Oncol. 2014;32(5):379-384. 8. Gambacorti-Passerini C, Piazza R. How I treat newly diagnosed chronic myeloid leukemia in 2015. Am J Hematol. 2015;90(2):156-161. 9. Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103 (7):553-561. 10. Chen CJ, Chen L, Dhanda R, et al. Treatment response monitoring in chronic phase CML (CP-CML) patients receiving tyrosine kinase inhibitor (TKI) therapy in US Oncology Network. J Clin Oncol. 2013;31(suppl):abstr 7096; ASCO annual meeting.
6. Huang X, Wang J, Baccarani M, et al. Frontline nilotinib results in superior rates of molecular response versus imatinib in Chinese patients with
Hypofractionated Whole Breast Radiotherapy Adapting to the Evidence Increased consciousness about the costs of cancer care, which substantially impact both society and the finances of individual patients, motivates interest in opportunities to improve efficiency. In the field of radiation oncology, hypofractionation—reducingthenumberofdailyradiation treatments by giving higher doses per fraction—is one of the most promising opportunities of this sort. Hypofractionation can improve convenience and lower costs, and growing evidence attests to its safety and efficacy in selected clinical settings. Therefore, it is unsurprising that hypofractionation is the subject of 2 of the first “top 5” opportunities in the Choosing Wisely campaign of the American Society of Radiation Oncology (ASTRO). Given the sheer number of women who receive radiation therapy as part of breast-conserving therapy for breast cancer each year, hypofractionation has the potential for particularly dramatic impact in this setting. Numerous trials have demonstrated substantial improvements in locoregional control from the administration of radiotherapy after breast-conserving surgery, and metaanalyses have established a modest survival gain in patients with invasive disease.1 In light of the fractionation schedules administered in most of these trials,
physicians have traditionally counseled patients to expect 5 or more weeks of daily radiation treatments after breast-conserving surgery if they wish to avoid mastectomy. Unfortunately, this could diminish access to breast conservation in populations that face geographic, financial, or other barriers to the receipt of protracted courses of radiotherapy. Overthepastdecade,high-qualityrandomizedtrials2,3 havegeneratedevidencesupportingtheefficacyandsafety ofhypofractionatedwhole-breastradiationtherapyinvolving approximately 3 weeks of daily treatments in selected patients compared with traditional schedules spanning 5 weeks or longer. A large Canadian trial randomized womenwithinvasive,node-negativebreastcancerafterlumpectomytoahypofractionatedcourseof42.5Gyin16fractions vs a standard course of 50 Gy in 25 fractions. Early results emergedoveradecadeago,andamorerecentreportdemonstratedcontinuedequivalenceinbothefficacyandsafety at 10 years.2 Similar results emerged from several British trials, including the UK Standardisation of Breast Radiotherapy (START) B trial,3 which randomized women to 40 Gy in 15 fractions vs 50 Gy in 25 fractions, finding that late adverseeffectsmightactuallybelowerafterhypofraction-
JAMA Oncology May 2015 Volume 1, Number 2 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://oncology.jamanetwork.com/ by a University of Hong Kong Libraries User on 08/17/2015
jamaoncology.com
