Abiraterone in Metastatic Prostate Cancer

correspondence

The Authors Reply: We agree with Iorio et al. that our study findings should be interpreted with caution, but we want to emphasize that the increased risk of inhibitor development associated with the second-generation, full-length factor VIII product cannot be explained by any other plausible factor. We adjusted for all known confounders and included the 58 patients who had not yet reached the study end point; we believe that the reasons for the exclusion of the remaining 74 patients (11.4%) — including the absence of informed consent, unavailable data, and the fact that these patients had not yet been treated — render their exclusion highly unlikely to have caused selection bias. Temporal trend analysis, as suggested, is complicated by the later introduction of the third-generation product. Moreover, we adjusted for factors that could have changed over time, including the start of prophylaxis and dosage. We feel that no meaningful new information can be obtained by adding this analysis to the overall study. With respect to cell

lines, only one company produced recombinant factor VIII products that were derived from BHK cells,1,2 which means that cell-line–based analysis would not have yielded different results. H. Marijke van den Berg, M.D., Ph.D. University Hospital Utrecht Utrecht, the Netherlands [email protected]

Samantha C. Gouw, M.D., Ph.D. Academic Medical Center Amsterdam, the Netherlands

Johanna G. van der Bom, M.D., Ph.D. Leiden University Medical Center Leiden, the Netherlands Since publication of their article, the authors report no further potential conflict of interest. 1. Jiang R, Monroe T, McRogers R, Larson PJ. Manufacturing

challenges in the commercial production of recombinant coagulation factor VIII. Haemophilia 2002;8:Suppl 2:1-5. 2. Pipe SW. The promise and challenges of bioengineered recombinant clotting factors. J Thromb Haemost 2005;3:1692701. DOI: 10.1056/NEJMc1301995

Abiraterone in Metastatic Prostate Cancer To the Editor: In their article on the COU-AA-302 study, Ryan et al. (Jan. 10 issue)1 report improved progression-free survival with abiraterone–prednisone as compared with prednisone alone among patients with metastatic castration-resistant prostate cancer who had not received chemotherapy. It would be useful to know the views of the authors on clinical measurements (e.g., the Gleason score and pretrial prostate-specific antigen [PSA] doubling time) that could guide therapy and predict the response to abiraterone over prednisone alone or chemotherapy. The prednisone-alone group in this study had a prolonged survival as compared with the survival reported in previous trials. Could such minimally symptomatic patients begin to receive prednisone alone initially, with the addition of abiraterone on disease progression? Moreover, the median duration of prednisone use was more than 2 years in the abiraterone group. Chemotherapy with a taxane, usually administered with prednisone, was subsequently administered to the majority of patients. Hypogonadism from antiandrogen therapy and long-term glucocorticoid therapy increase the risk of osteoporosis and fractures among men.2,3

The authors should discuss the frequency of osteoporosis, avascular necrosis of the femoral head, and skeleton-related events such as pathologic fractures. Finally, initiation of bisphosphonates after randomization was precluded. Did the trial patients receive inhibitors of receptor activator of nuclear factor κB ligand or bisphosphonates when osteoporosis developed? Ganessan Kichenadasse, F.R.A.C.P. Christos Karapetis, F.R.A.C.P. Flinders University Adelaide, SA, Australia [email protected] No potential conflict of interest relevant to this letter was reported. 1. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in meta-

static prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138-48. [Erratum, N Engl J Med 2013;368:584.] 2. Bilezikian JP. Osteoporosis in men. J Clin Endocrinol Metab 1999;84:3431-4. 3. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 2005;352:154-64. DOI: 10.1056/NEJMc1301594

To the Editor: Abiraterone extends life in patients with metastatic castration-resistant prostate cancer. We have treated a 63-year-old man whose

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metastatic prostate cancer (Gleason score, 9) progressed despite orchiectomy and docetaxel. He declined further docetaxel and received oral abiraterone. He had a brief psychiatric illness at 25 years of age and surgery for colon cancer at 61 years of age in 2010. Three days after the initiation of treatment with abiraterone plus prednisone, his behavior was violent and bizarre. In the clinic, he sat on the doctor’s lap and described hearing voices. Blood tests and imaging of the brain were not diagnostic. He was disoriented and confused. When his condition improved to his baseline condition, he was discharged to his daughter’s home. Treatment with abiraterone was initiated again, but he was found by police disoriented in a vacant lot. He said that “medicine makes me crazy.” On psychiatric examination, he was found to be psychotic and needed inpatient care. He required restraints until his condition was stabilized with the administration of quetiapine and a benzodiazepine, and he was hospitalized for 4 weeks. His illness may reflect underlying bipolar affective disorder unmasked by abiraterone, rather than primary abirateroneinduced delirium. Data are lacking on such adverse effects.1,2 Lawrence W. Raymond, M.D. Jewell P. Carr, M.D. Cecilie Only, M.D. Carolinas HealthCare System Charlotte, NC [email protected] No potential conflict of interest relevant to this letter was reported. 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and

increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995-2005. 2. Attard G, Reid AH, A’Hern R, et al. Selective inhibition of CYP 17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009; 27:3742-8. DOI: 10.1056/NEJMc1301594

The Authors Reply: Kichenadasse and Karapetis raise an important question regarding whether baseline clinical measurements could guide therapy and predict response to abiraterone. Studies are ongoing to develop a prognostic model for predicting overall survival in response to abira terone among patients with metastatic castration-resistant prostate cancer who have received docetaxel1 and among patients such as those described in our article who have not received previous chemotherapy. 1458

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The use of prednisone as an active comparison drug has been previously described in the literature.2-4 In our study, prednisone also served as an active comparison drug; 24% of patients in the prednisone-alone group had a 50% or more decrease in the level of PSA and 16% had a defined objective response according to modified Response Evaluation Criteria in Solid Tumors. However, there is clearly a significantly higher degree of benefit (both clinically and statistically) from the combination of prednisone plus abiraterone than from prednisone alone when all the end points (e.g., radiographic progressionfree survival, overall survival, time to initiation of cytotoxic chemotherapy, time to opiate use for cancer-related pain, time to PSA progression, and time to decline in the Eastern Cooperative Oncology Group performance score by ≥1 point) are considered. The initiation of treatment with prednisone alone may mask the full potential clinical benefit of abiraterone, since the effects of abiraterone after patients have received prednisone have not been prospectively studied. Kichenadasse and Karapetis also raise concerns about long-term glucocorticoid use in our study; however, as we stated in our article, the safety profile was not different from that observed in previous studies1 despite a longer duration of treatment with abiraterone–prednisone. This finding is supported by a query of the COU-AA-302 database with the use of terms for osteoporosis and osteopenia according to the standardized Medical Dictionary for Regulatory Activities, excluding pathologic fractures: 39 patients (7.2%) in the abiraterone–prednisone group and 36 patients (6.7%) in the prednisone-alone group had these conditions. It is important to clarify that patients in our study were allowed to receive bisphosphonates after randomization if they were receiving the medication before study initiation. At baseline, 36% of patients in the abiraterone–prednisone group and 33% in the prednisone-alone group were receiving bisphosphonates. Concomitantly, 38% of patients in the abiraterone–prednisone group and 36% in the prednisone-alone group were receiving bisphosphonates. Raymond et al. describe a patient with abnormal behavior after the administration of abir aterone. We observed only one such case in patients in our study, and it was in the prednisone-alone group.



correspondence 2. Berry W, Dakhil S, Modiano M, Gregurich M, Asmar L.

Charles J. Ryan, M.D. University of California, San Francisco San Francisco, CA [email protected]

Arturo Molina, M.D. Thomas Griffin, M.D. Janssen Research and Development Los Angeles, CA Since publication of their article, the authors report no further potential conflict of interest. 1. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and

increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995-2005.

Phase III study of mitoxantrone plus low dose prednisone versus low dose prednisone alone in patients with asymptomatic hormone refractory prostate cancer. J Urol 2002;168:2439-43. 3. Fossá SD, Slee PH, Brausi M, et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a phase III study of the European Organization for Research and Treatment of Cancer genitourinary group. J Clin Oncol 2001;19:62-71. 4. Sternberg CN, Petrylak DP, Sartor O, et al. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial. J Clin Oncol 2009;27:5431-8. DOI: 10.1056/NEJMc1301594

A Simulation-Based Trial of Surgical-Crisis Checklists To the Editor: Arriaga and colleagues (Jan. 17 issue)1 report a 75% reduction in omission errors with implementation of a surgical-crisis checklist during simulated operative events. They do not mention what education and training on use of the checklist the participants received before the simulated events. Clinicians who are not accustomed to using a checklist or other cognitive aids are unlikely to use such an aid during a critical event, simulated or otherwise, unless instruction and training in the use of the tools are provided. Although the reduction in missed steps is remarkable, the goal in critical events should be completion of 100% of key steps 100% of the time. Do Arriaga and colleagues have any insight as to why more key steps were not performed in the scenarios in which a checklist was used? Regardless of design or implementation, no checklist can compensate for diagnostic or fixation errors. Did the researchers find any difference between scenarios in which checklists were available and those in which they were not available with respect to diagnostic accuracy or the incidence of fixation errors? Scott C. Watkins, M.D.

that this intervention significantly improved the management of simulated operating-room crises. Notably, only 3% of the participants were attending surgeons, and none of the investigated critical events were specific to the operating room. Within these limitations, however, may lie opportunities. The physician-predominant involvement, multidisciplinary nature, and portfolio of investigated critical events (including anaphylaxis, asystolic cardiac arrest, hemorrhage, hypotension and hypoxemia, and unstable tachycardia) all bear considerable resemblance to situations frequently faced in the emergency department. With widening acceptance of and evidence and growing support for the use of checklists in the surgical setting, the time is right to examine their potential usefulness outside the operating room.1-3 It would be important, however, to establish their role within or interaction with formal life-support algorithms; this would require close collaboration with relevant steering committees.

Vanderbilt University Medical Center Nashville, TN [email protected] No potential conflict of interest relevant to this letter was reported.

Joseph Shalhoub, M.R.C.S.

1. Arriaga AF, Bader AM, Wong JM, et al. Simulation-based

trial of surgical-crisis checklists. N Engl J Med 2013;368:246-53.

DOI: 10.1056/NEJMc1301994

To the Editor: Arriaga et al. support the implementation of surgical-crisis checklists. They found

Mahiben Maruthappu, F.R.S.A. Harvard University Cambridge, MA

Imperial College London London, United Kingdom No potential conflict of interest relevant to this letter was reported. 1. 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. 2. de Vries EN, Prins HA, Crolla RMPH, et al. Effect of a comprehensive surgical safety system on patient outcomes. N Engl J Med 2010;363:1928-37.



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