The
n e w e ng l a n d j o u r na l
Since publication of their article, the authors report no further potential conflict of interest. 1. Neugebauer H, Creutzfeldt CJ, Hemphill JC III, Heusch
of
m e dic i n e
mann PU, Jüttler E. DESTINY-S: attitudes of physicians toward disability and treatment in malignant MCA infarction. Neurocrit Care 2014 February 19 (Epub ahead of print). DOI: 10.1056/NEJMc1404585
Chemoimmunotherapy for Chronic Lymphocytic Leukemia To the Editor: Goede et al. (March 20 issue)1 report improved outcomes in patients with chronic lymphocytic leukemia (CLL) and coexisting conditions who received obinutuzumab in combination with chlorambucil. This conclusion is flawed because of underdosing of chlorambucil. In Germany, chlorambucil is licensed for treatment of CLL starting at 0.4 mg per kilogram of body weight every other week, with gradual increases in increments of 0.1 mg per kilogram until there is a clinical response or toxicity. The study, however, used a fixed dose of 0.5 mg per kilogram every other week without escalation. The dose escalation of chlorambucil is based on earlier data by Knospe et al.,2 who described a remission rate of 61% among untreated patients with CLL; this rate is higher than the 31.4% rate reported by Goede et al. Knospe and colleagues reported a median maximum dose of 0.90 mg per kilogram (range, 0.40 to 1.83). So far, no other chlorambucil dosing schedule has been shown to be superior. Goede and colleagues cite a study that compared chlorambucil with fludarabine.3 In that study, the planned dose escalation of chlorambucil, starting at 0.4 mg per kilogram, was not performed in most of the patients; thus the median dose was only 0.5 mg per kilogram every other week. The similar progression-free survival among patients in the chlorambucil and fludarabine groups in that study cannot justify the lowering of an established and approved dose regimen. We believe that treating control patients below the therapeutic standard jeopardizes the validity of study results and, moreover, violates rules in the Declaration of Helsinki that a new intervention must be tested against “the best proven intervention.” 4 Jürgen Spehn, M.D. Klinikum Links der Weser Bremen, Germany [email protected]
Bernd Mühlbauer, M.D. Institute for Clinical Pharmacology Bremen, Germany No potential conflict of interest relevant to this letter was reported.
2348
1. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlor-
ambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370:1101-10. 2. Knospe WH, Loeb V Jr, Huguley CM Jr. Bi-weekly chlorambucil treatment of chronic lymphocytic leukemia. Cancer 1974; 33:555-62. 3. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382-91. 4. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. 59th WMA general assembly, Seoul. 2008 (http://www.wma.net/en/ 30publications/10policies/b3/17c.pdf). DOI: 10.1056/NEJMc1404855
The Authors Reply: In reply to Spehn and Mühl bauer: we urge caution when comparing results of historical studies with those of recent trials like ours. Knospe et al. reported the feasibility of dose escalation of chlorambucil in a relatively small number of patients who on average were 10 to 15 years younger than the patients in our trial. Such a dosing regimen is more difficult to implement in an elderly patient population.1 More importantly, the method of assessing the response to treatment differed considerably between the trials. Guidelines for assessment of the response,2 confirmatory imaging technology, and independent review panels were not available in earlier eras; the reported response rates thus cannot be reliably compared. We do not believe that our results were flawed by the chlorambucil treatment schedule, nor do we believe that patients in our trial were unethically undertreated with chlorambucil. In other trials, the administration of similar or even higher cumulative doses of chlorambucil yielded response rates and progression-free survival times that compared well with those observed in our trial.3-5 In addition, our study underwent thorough review by ethics committees and health authorities. Valentin Goede, M.D. Kirsten Fischer, M.D. Michael Hallek, M.D. Center of Integrated Oncology Cologne–Bonn Cologne, Germany [email protected] Since publication of their article, the authors report no further potential conflict of interest.
n engl j med 370;24 nejm.org june 12, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF GEORGIA on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence 1. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line thera-
py with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382-91. 2. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood 2008;111:5446-56. [Erratum, Blood 2008;112:5259.] 3. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine com-
pared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750-7. 4. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009;27:4378-84. 5. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the Phase III Study Complement 1 (OMB110911). Blood 2013;122:528. abstract. DOI: 10.1056/NEJMc1404855
Surgical Safety Checklists in Ontario, Canada To the Editor: As described by Urbach et al. (March 13 issue),1 the surgical safety checklist is a tool designed to ensure that the incidence of errors related to communication in the operating theater is minimized.2 As Leape3 emphasizes in the editorial accompanying the article, the diligence with which the checklist is developed and applied is critical to its effectiveness. As a cardiac anesthesiologist, I have witnessed discussions that have averted potential errors during and after surgery. Accreditation Canada has adopted the Safe Surgical Checklist as a Required Organizational Practice. As an accreditor, I have evaluated approximately 10 operating rooms since the mandatory introduction of the checklist in Ontario. During these visits, I have observed practices ranging from a thorough evaluation to a perfunctory lip-service discussion, as Leape suggests is possible. In order to unlock the full value of the checklist, it will be necessary to educate surgical teams on the concept of near misses. Near misses are poorly understood by health care professionals. When near misses are reported and analyzed, it often uncovers system deficiencies that when corrected lead to safer patient care. James A. Robblee, M.D. University of Ottawa Heart Institute Ottawa, ON, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Urbach DR, Govindarajan A, Saskin R, Wilton AS, Baxter
NN. Introduction of surgical safety checklists in Ontario, Canada. N Engl J Med 2014;370:1029-38. 2. Haynes AB, Weiser TG, Berry WR, et al. A surgical safety checklist to reduce morbidity and mortality in a global population. N Engl J Med 2009;360:491-9. 3. Leape LL. The checklist conundrum. N Engl J Med 2014;370: 1063-4. DOI: 10.1056/NEJMc1404583
To the Editor: Using administrative data from 101 hospitals, Urbach and colleagues report no statistically significant reduction in rates of death or complications after self-reported implementation of a surgical safety checklist mandated by the Ontario Ministry of Health and Long-Term Care. The findings, while disappointing, are not surprising, given the study’s methodology. The authors neither evaluated the validity of reported claims of checklist use nor collected process measures to assess trends in compliance with known standards of care, even though the difference between reported compliance and actual adherence can frequently be vastly divergent.1 Implementation of and adherence to checklists were important features of checklist studies conducted by the World Health Organization (WHO)2 and the Surgical Patient Safety System (SURPASS) Collaborative Group.3 Finally, the overall rates of death and complications presented by Urbach et al. are exceedingly low. This is probably because of the high number of low-risk procedures, thus limiting the capacity of improved compliance to actually improve outcomes. Checklists are useful for improving team communication and function but are insufficient for creating value without strong implementation programs and clinical leadership.4 Thomas G. Weiser, M.D., M.P.H. Thomas M. Krummel, M.D. Stanford University Stanford, CA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Levy SM, Senter CE, Hawkins RB, et al. Implementing a sur-
gical checklist: more than checking a box. Surgery 2012;152: 331-6. 2. Haynes AB, Weiser TG, Berry WR, et al. A surgical safety checklist to reduce morbidity and mortality in a global population. N Engl J Med 2009;360:491-9. 3. de Vries EN, Prins HA, Crolla RM, et al. Effect of a compre-
n engl j med 370;24 nejm.org june 12, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF GEORGIA on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2349
n e w e ng l a n d j o u r na l
Since publication of their article, the authors report no further potential conflict of interest. 1. Neugebauer H, Creutzfeldt CJ, Hemphill JC III, Heusch
of
m e dic i n e
mann PU, Jüttler E. DESTINY-S: attitudes of physicians toward disability and treatment in malignant MCA infarction. Neurocrit Care 2014 February 19 (Epub ahead of print). DOI: 10.1056/NEJMc1404585
Chemoimmunotherapy for Chronic Lymphocytic Leukemia To the Editor: Goede et al. (March 20 issue)1 report improved outcomes in patients with chronic lymphocytic leukemia (CLL) and coexisting conditions who received obinutuzumab in combination with chlorambucil. This conclusion is flawed because of underdosing of chlorambucil. In Germany, chlorambucil is licensed for treatment of CLL starting at 0.4 mg per kilogram of body weight every other week, with gradual increases in increments of 0.1 mg per kilogram until there is a clinical response or toxicity. The study, however, used a fixed dose of 0.5 mg per kilogram every other week without escalation. The dose escalation of chlorambucil is based on earlier data by Knospe et al.,2 who described a remission rate of 61% among untreated patients with CLL; this rate is higher than the 31.4% rate reported by Goede et al. Knospe and colleagues reported a median maximum dose of 0.90 mg per kilogram (range, 0.40 to 1.83). So far, no other chlorambucil dosing schedule has been shown to be superior. Goede and colleagues cite a study that compared chlorambucil with fludarabine.3 In that study, the planned dose escalation of chlorambucil, starting at 0.4 mg per kilogram, was not performed in most of the patients; thus the median dose was only 0.5 mg per kilogram every other week. The similar progression-free survival among patients in the chlorambucil and fludarabine groups in that study cannot justify the lowering of an established and approved dose regimen. We believe that treating control patients below the therapeutic standard jeopardizes the validity of study results and, moreover, violates rules in the Declaration of Helsinki that a new intervention must be tested against “the best proven intervention.” 4 Jürgen Spehn, M.D. Klinikum Links der Weser Bremen, Germany [email protected]
Bernd Mühlbauer, M.D. Institute for Clinical Pharmacology Bremen, Germany No potential conflict of interest relevant to this letter was reported.
2348
1. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlor-
ambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370:1101-10. 2. Knospe WH, Loeb V Jr, Huguley CM Jr. Bi-weekly chlorambucil treatment of chronic lymphocytic leukemia. Cancer 1974; 33:555-62. 3. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382-91. 4. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. 59th WMA general assembly, Seoul. 2008 (http://www.wma.net/en/ 30publications/10policies/b3/17c.pdf). DOI: 10.1056/NEJMc1404855
The Authors Reply: In reply to Spehn and Mühl bauer: we urge caution when comparing results of historical studies with those of recent trials like ours. Knospe et al. reported the feasibility of dose escalation of chlorambucil in a relatively small number of patients who on average were 10 to 15 years younger than the patients in our trial. Such a dosing regimen is more difficult to implement in an elderly patient population.1 More importantly, the method of assessing the response to treatment differed considerably between the trials. Guidelines for assessment of the response,2 confirmatory imaging technology, and independent review panels were not available in earlier eras; the reported response rates thus cannot be reliably compared. We do not believe that our results were flawed by the chlorambucil treatment schedule, nor do we believe that patients in our trial were unethically undertreated with chlorambucil. In other trials, the administration of similar or even higher cumulative doses of chlorambucil yielded response rates and progression-free survival times that compared well with those observed in our trial.3-5 In addition, our study underwent thorough review by ethics committees and health authorities. Valentin Goede, M.D. Kirsten Fischer, M.D. Michael Hallek, M.D. Center of Integrated Oncology Cologne–Bonn Cologne, Germany [email protected] Since publication of their article, the authors report no further potential conflict of interest.
n engl j med 370;24 nejm.org june 12, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF GEORGIA on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
correspondence 1. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line thera-
py with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382-91. 2. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood 2008;111:5446-56. [Erratum, Blood 2008;112:5259.] 3. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine com-
pared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750-7. 4. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009;27:4378-84. 5. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the Phase III Study Complement 1 (OMB110911). Blood 2013;122:528. abstract. DOI: 10.1056/NEJMc1404855
Surgical Safety Checklists in Ontario, Canada To the Editor: As described by Urbach et al. (March 13 issue),1 the surgical safety checklist is a tool designed to ensure that the incidence of errors related to communication in the operating theater is minimized.2 As Leape3 emphasizes in the editorial accompanying the article, the diligence with which the checklist is developed and applied is critical to its effectiveness. As a cardiac anesthesiologist, I have witnessed discussions that have averted potential errors during and after surgery. Accreditation Canada has adopted the Safe Surgical Checklist as a Required Organizational Practice. As an accreditor, I have evaluated approximately 10 operating rooms since the mandatory introduction of the checklist in Ontario. During these visits, I have observed practices ranging from a thorough evaluation to a perfunctory lip-service discussion, as Leape suggests is possible. In order to unlock the full value of the checklist, it will be necessary to educate surgical teams on the concept of near misses. Near misses are poorly understood by health care professionals. When near misses are reported and analyzed, it often uncovers system deficiencies that when corrected lead to safer patient care. James A. Robblee, M.D. University of Ottawa Heart Institute Ottawa, ON, Canada [email protected] No potential conflict of interest relevant to this letter was reported. 1. Urbach DR, Govindarajan A, Saskin R, Wilton AS, Baxter
NN. Introduction of surgical safety checklists in Ontario, Canada. N Engl J Med 2014;370:1029-38. 2. Haynes AB, Weiser TG, Berry WR, et al. A surgical safety checklist to reduce morbidity and mortality in a global population. N Engl J Med 2009;360:491-9. 3. Leape LL. The checklist conundrum. N Engl J Med 2014;370: 1063-4. DOI: 10.1056/NEJMc1404583
To the Editor: Using administrative data from 101 hospitals, Urbach and colleagues report no statistically significant reduction in rates of death or complications after self-reported implementation of a surgical safety checklist mandated by the Ontario Ministry of Health and Long-Term Care. The findings, while disappointing, are not surprising, given the study’s methodology. The authors neither evaluated the validity of reported claims of checklist use nor collected process measures to assess trends in compliance with known standards of care, even though the difference between reported compliance and actual adherence can frequently be vastly divergent.1 Implementation of and adherence to checklists were important features of checklist studies conducted by the World Health Organization (WHO)2 and the Surgical Patient Safety System (SURPASS) Collaborative Group.3 Finally, the overall rates of death and complications presented by Urbach et al. are exceedingly low. This is probably because of the high number of low-risk procedures, thus limiting the capacity of improved compliance to actually improve outcomes. Checklists are useful for improving team communication and function but are insufficient for creating value without strong implementation programs and clinical leadership.4 Thomas G. Weiser, M.D., M.P.H. Thomas M. Krummel, M.D. Stanford University Stanford, CA [email protected] No potential conflict of interest relevant to this letter was reported. 1. Levy SM, Senter CE, Hawkins RB, et al. Implementing a sur-
gical checklist: more than checking a box. Surgery 2012;152: 331-6. 2. Haynes AB, Weiser TG, Berry WR, et al. A surgical safety checklist to reduce morbidity and mortality in a global population. N Engl J Med 2009;360:491-9. 3. de Vries EN, Prins HA, Crolla RM, et al. Effect of a compre-
n engl j med 370;24 nejm.org june 12, 2014
The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF GEORGIA on August 11, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
2349
