The
n e w e ng l a n d j o u r na l
4. Fernandes N, Bryant D, Griffith L, et al. Outcomes for pa-
tients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis. CMAJ 2014;186:E596-E609. DOI: 10.1056/NEJMc1415933
To the Editor: I believe the OHRP is correct in its reasoning. If there is a broadly constructed set of opinions about the standard of care, it is possible, indeed probable, that two accepted treatments could have major differences in risk. To do a study comparing those treatments could well increase the risk to the patient on the basis of hidden bias. This situation could also happen if the center conducting the study has participating physicians who have enough difference in experience or skill such that there is a hidden alteration of risk to the patients enrolled in one group of the study. This is a real concern. My group has been approached in the past year to participate in two studies in which these types of differences and risks could be discerned. We declined to participate. Jeffrey L. Kaufman, M.D. Baystate Vascular Services Springfield, MA [email protected] No potential conflict of interest relevant to this letter was reported. DOI: 10.1056/NEJMc1415933
of
m e dic i n e
ies are proposed in which patients might be randomly assigned to such treatments, he and his group are in a better position than are his patients to decide whether those studies are acceptable. By declining to participate, he is denying his patients a choice about treatments that many of his colleagues offer. Even the OHRP, in its draft guidelines, does not go this far. Instead, the OHRP would mandate that patients be told that doctors generally know what is best for their patients. It would also mandate that patients be told that studies are always riskier than simply following their doctors’ recommendations. But the OHRP would at least allow patients to choose. In a different approach, Fernandes et al. gathered evidence and analyzed it. The evidence is pretty clear. Patients who enroll in clinical trials do not have worse outcomes than patients who choose not to enroll in such studies. Doctors do not always know what is best. Patients who are asked to participate in trials need to know the facts about the riskiness of treatments and the riskiness of research. The OHRP draft guidelines assume that research is riskier than treatment outside a research protocol. The data do not support that assumption. Patients have a right to that data in order to help them make an informed decision. John D. Lantos, M.D. Children’s Mercy Hospital Kansas City, MO [email protected]
The Authors Reply: These two letters highlight different ways of thinking about the ethical is- John A. Spertus, M.D., M.P.H. Luke’s Mid-America Heart Institute sues that are associated with risk, research, and St. Kansas City, MO patient–doctor communication. Kaufman correctSince publication of their article, the authors report no furly points out that commonly used treatments can ther potential conflict of interest. have different risks. He suggests that when stud- DOI: 10.1056/NEJMc1415933
Outpatient Oral Treatment for Acute Promyelocytic Leukemia To the Editor: Zhu and Huang (Dec. 4 issue)1 report excellent, though preliminary, outcome results in 20 patients with non–high-risk acute promyelocytic leukemia (APL) treated with oral arsenic and all-trans retinoic acid (ATRA) in a “largely home-based treatment protocol.” Once
884
regarded as a rapidly fatal disease, APL is now curable in most cases with the use of targeted treatment alone and without chemotherapy.2 However, population-based studies of APL have shown rates of early death of up to 29% in developed countries such as Sweden and the United
n engl j med 372;9 nejm.org february 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at The University Of Illinois on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
States. These data emphasize early death as a major obstacle to the final cure and temper enthusiasm about clinical trial results.3 Rapid diagnosis and administration of ATRA or arsenic (or both), aggressive transfusion support, and strict medical surveillance are of utmost importance in order to identify severe complications of APL promptly because, even for the most accomplished of experts, such complications are frequently unpredictable.4 The study by Zhu and Huang included mostly low-risk cases, allowing for less stringent policies concerning the monitoring of patients and transfusion support. We would recommend that, regardless of presenting features and initial risk assessment, all patients with APL be hospitalized and stringently monitored during the first 2 to 3 weeks of therapy. Francesco Lo-Coco, M.D. Laura Cicconi, M.D. University Tor Vergata Rome, Italy [email protected] Dr. Lo-Coco reports receiving consulting and lecture fees from Teva Pharmaceutical Industries and Lundbeck. No other potential conflict of interest relevant to this letter was reported. 1. Zhu HH, Huang XJ. Oral arsenic and retinoic acid for non–
high-risk acute promyelocytic leukemia. N Engl J Med 2014;371: 2239-41. 2. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-21. 3. Lo-Coco F. ED in APL: tip of the iceberg? Blood 2011;118: 1188-9. 4. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113: 1875-91.
The Authors Reply: Lo-Coco and Cicconi raise concerns about the risk of outpatient treatment for APL especially in the early days of treatment. We initially wanted to explore the feasibility of using solely outpatient treatment of low-risk patients (especially those with normal platelet and fibrinogen levels) under stringent outpatient monitoring (Table S1 in the Supplementary Appendix, available with the full text of the article). If the patient’s condition deteriorated, he or she was hospitalized in time to avoid early complications. Our study showed that outpatient treatment of some low-risk patients with APL could be successfully accomplished with the use of careful monitoring. We agree with Lo-Coco and Cicconi that all patients with APL should be hospitalized and carefully monitored during the first 2 to 3 weeks of therapy to reduce the risk of early death. Once the platelet counts and coagulation function recover and no signs of the differentiation syndrome have appeared, the patients may be monitored during outpatient treatment under close follow-up. This approach has been adopted in our ongoing prospective, multicenter, randomized trial in China (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054). Hong-Hu Zhu, M.D. Xiao-Jun Huang, M.D. Peking University People’s Hospital Beijing, China [email protected] Since publication of their letter, the authors report no further potential conflict of interest. DOI: 10.1056/NEJMc1500125
DOI: 10.1056/NEJMc1500125
Mitochondrial Donation — How Many Women Could Benefit? To the Editor: Inherited mutations in mitochondrial DNA (mtDNA) are an important cause of genetic diseases for which there is no effective treatment. New techniques that are based on in vitro fertilization (IVF), including pronuclear and metaphase II spindle transfer,1,2 have the potential to prevent the transmission of serious mtDNA diseases. However, before these techniques are permitted in the United Kingdom, Parliament must agree to new regulations regarding enforce-
ment of the Human Fertilisation and Embryology Act (1990). Central to the debate about the use of these IVF techniques is estimating how many women could potentially benefit from these procedures. This calculation depends on the prevalence of clinically relevant pathogenic mtDNA mutations in the population and the fertility of women with pathogenic mtDNA mutations. Using fertility data regarding live births per 1000 person-years among women 15 years of
n engl j med 372;9 nejm.org february 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at The University Of Illinois on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
885
n e w e ng l a n d j o u r na l
4. Fernandes N, Bryant D, Griffith L, et al. Outcomes for pa-
tients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis. CMAJ 2014;186:E596-E609. DOI: 10.1056/NEJMc1415933
To the Editor: I believe the OHRP is correct in its reasoning. If there is a broadly constructed set of opinions about the standard of care, it is possible, indeed probable, that two accepted treatments could have major differences in risk. To do a study comparing those treatments could well increase the risk to the patient on the basis of hidden bias. This situation could also happen if the center conducting the study has participating physicians who have enough difference in experience or skill such that there is a hidden alteration of risk to the patients enrolled in one group of the study. This is a real concern. My group has been approached in the past year to participate in two studies in which these types of differences and risks could be discerned. We declined to participate. Jeffrey L. Kaufman, M.D. Baystate Vascular Services Springfield, MA [email protected] No potential conflict of interest relevant to this letter was reported. DOI: 10.1056/NEJMc1415933
of
m e dic i n e
ies are proposed in which patients might be randomly assigned to such treatments, he and his group are in a better position than are his patients to decide whether those studies are acceptable. By declining to participate, he is denying his patients a choice about treatments that many of his colleagues offer. Even the OHRP, in its draft guidelines, does not go this far. Instead, the OHRP would mandate that patients be told that doctors generally know what is best for their patients. It would also mandate that patients be told that studies are always riskier than simply following their doctors’ recommendations. But the OHRP would at least allow patients to choose. In a different approach, Fernandes et al. gathered evidence and analyzed it. The evidence is pretty clear. Patients who enroll in clinical trials do not have worse outcomes than patients who choose not to enroll in such studies. Doctors do not always know what is best. Patients who are asked to participate in trials need to know the facts about the riskiness of treatments and the riskiness of research. The OHRP draft guidelines assume that research is riskier than treatment outside a research protocol. The data do not support that assumption. Patients have a right to that data in order to help them make an informed decision. John D. Lantos, M.D. Children’s Mercy Hospital Kansas City, MO [email protected]
The Authors Reply: These two letters highlight different ways of thinking about the ethical is- John A. Spertus, M.D., M.P.H. Luke’s Mid-America Heart Institute sues that are associated with risk, research, and St. Kansas City, MO patient–doctor communication. Kaufman correctSince publication of their article, the authors report no furly points out that commonly used treatments can ther potential conflict of interest. have different risks. He suggests that when stud- DOI: 10.1056/NEJMc1415933
Outpatient Oral Treatment for Acute Promyelocytic Leukemia To the Editor: Zhu and Huang (Dec. 4 issue)1 report excellent, though preliminary, outcome results in 20 patients with non–high-risk acute promyelocytic leukemia (APL) treated with oral arsenic and all-trans retinoic acid (ATRA) in a “largely home-based treatment protocol.” Once
884
regarded as a rapidly fatal disease, APL is now curable in most cases with the use of targeted treatment alone and without chemotherapy.2 However, population-based studies of APL have shown rates of early death of up to 29% in developed countries such as Sweden and the United
n engl j med 372;9 nejm.org february 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at The University Of Illinois on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
correspondence
States. These data emphasize early death as a major obstacle to the final cure and temper enthusiasm about clinical trial results.3 Rapid diagnosis and administration of ATRA or arsenic (or both), aggressive transfusion support, and strict medical surveillance are of utmost importance in order to identify severe complications of APL promptly because, even for the most accomplished of experts, such complications are frequently unpredictable.4 The study by Zhu and Huang included mostly low-risk cases, allowing for less stringent policies concerning the monitoring of patients and transfusion support. We would recommend that, regardless of presenting features and initial risk assessment, all patients with APL be hospitalized and stringently monitored during the first 2 to 3 weeks of therapy. Francesco Lo-Coco, M.D. Laura Cicconi, M.D. University Tor Vergata Rome, Italy [email protected] Dr. Lo-Coco reports receiving consulting and lecture fees from Teva Pharmaceutical Industries and Lundbeck. No other potential conflict of interest relevant to this letter was reported. 1. Zhu HH, Huang XJ. Oral arsenic and retinoic acid for non–
high-risk acute promyelocytic leukemia. N Engl J Med 2014;371: 2239-41. 2. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-21. 3. Lo-Coco F. ED in APL: tip of the iceberg? Blood 2011;118: 1188-9. 4. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113: 1875-91.
The Authors Reply: Lo-Coco and Cicconi raise concerns about the risk of outpatient treatment for APL especially in the early days of treatment. We initially wanted to explore the feasibility of using solely outpatient treatment of low-risk patients (especially those with normal platelet and fibrinogen levels) under stringent outpatient monitoring (Table S1 in the Supplementary Appendix, available with the full text of the article). If the patient’s condition deteriorated, he or she was hospitalized in time to avoid early complications. Our study showed that outpatient treatment of some low-risk patients with APL could be successfully accomplished with the use of careful monitoring. We agree with Lo-Coco and Cicconi that all patients with APL should be hospitalized and carefully monitored during the first 2 to 3 weeks of therapy to reduce the risk of early death. Once the platelet counts and coagulation function recover and no signs of the differentiation syndrome have appeared, the patients may be monitored during outpatient treatment under close follow-up. This approach has been adopted in our ongoing prospective, multicenter, randomized trial in China (Chinese Clinical Trial Registry number, ChiCTR-TRC-13004054). Hong-Hu Zhu, M.D. Xiao-Jun Huang, M.D. Peking University People’s Hospital Beijing, China [email protected] Since publication of their letter, the authors report no further potential conflict of interest. DOI: 10.1056/NEJMc1500125
DOI: 10.1056/NEJMc1500125
Mitochondrial Donation — How Many Women Could Benefit? To the Editor: Inherited mutations in mitochondrial DNA (mtDNA) are an important cause of genetic diseases for which there is no effective treatment. New techniques that are based on in vitro fertilization (IVF), including pronuclear and metaphase II spindle transfer,1,2 have the potential to prevent the transmission of serious mtDNA diseases. However, before these techniques are permitted in the United Kingdom, Parliament must agree to new regulations regarding enforce-
ment of the Human Fertilisation and Embryology Act (1990). Central to the debate about the use of these IVF techniques is estimating how many women could potentially benefit from these procedures. This calculation depends on the prevalence of clinically relevant pathogenic mtDNA mutations in the population and the fertility of women with pathogenic mtDNA mutations. Using fertility data regarding live births per 1000 person-years among women 15 years of
n engl j med 372;9 nejm.org february 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at The University Of Illinois on March 13, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
885
