Bortezomib in Multiple Myeloma
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Richardson et al. (June 16 issue)1 showed that, in relapsed multiple myeloma, bortezomib improved survival in comparison with high-dose dexamethasone. According to Trippoli et al.2 and Sonneveld et al.,3 life expectancy for patients with myeloma who are alive at 1 year after treatment is about 1.5 additional years (range, 0.253 to 2.472). Bortezomib costs 49,077 ($59,991 in the United States at the current exchange rates) per patient on the basis of the schedule outlined in the article and current Italian prices.4 Considering that some treatment cycles are discontinued early because of side effects or death, the incremental cost of bortezomib as compared with dexamethasone is about 40,000 ($48,942) per patient. Improving survival by 14 percent at 1 year gives a lifetime gain of at least 21 years (14 x 1.5) for every 100 patients. On the basis of these data, the cost per life-year gained for bortezomib as compared with dexamethasone is 190,476 ($232,924). This analysis suggests that the benefit of bortezomib has a cost that exceeds current international benchmarks.5
Michele Cecchi, Pharm.D.
Erminia Caccese, Pharm.D.
Andrea Messori, Pharm.D.
Azienda Careggi
50134 Florence, Italy
mk4126@mclink.it
References
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487-2498.
Trippoli S, Messori A, Becagli P, Alterini R, Tendi E. Treatments for newly diagnosed multiple myeloma: analysis of survival data and cost-effectiveness evaluation. Oncol Rep 1998;5:1475-1482.
Sonneveld P, Suciu S, Weijermans P, et al. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol 2001;115:895-902.
Decreto Ministeriale 26-1-2005. Gazzetta Ufficiale della Repubblica Italiana. February 4, 2005.
Messori A, Trippoli S, Vaiani M. Efficacy, safety, and cost of new anticancer drugs: price needs to be evaluated against effectiveness. BMJ 2002;325:1302-1302.
To the Editor: In her editorial, Dispenzieri1 states that the survival analysis in the bortezomib trial reported by Richardson et al. involved a 22 percent loss to follow-up. According to the online Supplementary Appendix accompanying the full text of Richardson and colleagues' report, 150 patients were lost to follow-up. By back-calculation, we determined that the number of deaths was about 135. Thus, the benefit of bortezomib could easily be wiped out if only 10 to 20 patients in the dexamethasone group died while lost to follow-up. In addition, there was an insufficient length of follow-up and a severe censoring of the disease-progression end point.1
Jan P. Vandenbroucke, M.D.
Judith R. Kroep, M.D.
Leiden University Medical Center
2300RC Leiden, the Netherlands
j.p.vandenbroucke@lumc.nl
References
Dispenzieri A. Bortezomib for myeloma -- much ado about something. N Engl J Med 2005;352:2546-2548.
The authors reply: We greatly appreciate the questions from Drs. Vandenbrouke and Kroep regarding some of the statistical methods. The reasons for censoring, including the number of patients lost to follow-up in the analyses of survival and the time to progression, were inaccurate as provided in the Supplementary Appendix, and we sincerely regret the error. A revised version of the Supplementary Appendix is available with the full text of the article at www.nejm.org. In the survival analyses, the correct numbers of patients lost to follow-up were 11 (3 percent) and 6 (2 percent) in the bortezomib and dexamethasone groups, respectively. Therefore, only 2.5 percent of the patients were lost to follow-up in terms of survival, and it is highly unlikely that the loss of 2.5 percent of the patients would significantly affect the results. Drs. Vandenbroucke and Kroep are correct in suggesting that the length of follow-up is limited, because only 20 percent of the patients had died at the cutoff time for data collection. However, this limitation was a result of the decision on the part of the independent data monitoring committee to recommend discontinuing treatment in the high-dose dexamethasone group and offer crossover to bortezomib after the prespecified interim analysis. It is possible that subsequent analyses may be confounded by early crossover from high-dose dexamethasone to bortezomib, but the collection of survival data for both treatment groups is continuing, and we will present these updated results as soon as they are available.
We also appreciate the letter from Dr. Cecchi and colleagues regarding the cost benefit of bortezomib. Their estimate of the cost-effectiveness of bortezomib in this letter is not correct. The mean number of treatment cycles in the study was 6 rather than 11. The mean body-surface area of patients was 1.89 m2 rather than 2 m2. Furthermore, it is premature to use survival data to model cost-effectiveness on the basis of data from the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial, since fewer than one third of the events had occurred at the cutoff point for data collection. In a comprehensive, published analysis that was performed on the basis of data from patients with relapsed and refractory myeloma and that accounted for the costs of therapy, disease complications, and management of adverse events, bortezomib, as compared with best supportive care, had an incremental cost-effectiveness ratio of $45,356 per life-year gained.1 In another analysis, bortezomib had an incremental cost-effectiveness ratio as low as 25,271 ($30,910) per life-year gained,2 suggesting that the ratio fell below the international benchmark.3,4 These findings suggest that bortezomib is a cost-effective option for patients with relapsed multiple myeloma.
Paul G. Richardson, M.D.
Dana–Farber Cancer Institute
Boston, MA 02115
paul_richardson@dfci.harvard.edu
Anthony L. Boral, M.D., Ph.D.
Millennium Pharmaceuticals
Cambridge, MA 02139
Kenneth C. Anderson, M.D.
Dana–Farber Cancer Institute
Boston, MA 02115
References
Mehta J, Duff SB, Gupta S. Cost effectiveness of bortezomib in the treatment of advanced multiple myeloma. Manag Care Interface 2004;17:52-61.
Michele Cecchi, Pharm.D.
Erminia Caccese, Pharm.D.
Andrea Messori, Pharm.D.
Azienda Careggi
50134 Florence, Italy
mk4126@mclink.it
References
Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487-2498.
Trippoli S, Messori A, Becagli P, Alterini R, Tendi E. Treatments for newly diagnosed multiple myeloma: analysis of survival data and cost-effectiveness evaluation. Oncol Rep 1998;5:1475-1482.
Sonneveld P, Suciu S, Weijermans P, et al. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol 2001;115:895-902.
Decreto Ministeriale 26-1-2005. Gazzetta Ufficiale della Repubblica Italiana. February 4, 2005.
Messori A, Trippoli S, Vaiani M. Efficacy, safety, and cost of new anticancer drugs: price needs to be evaluated against effectiveness. BMJ 2002;325:1302-1302.
To the Editor: In her editorial, Dispenzieri1 states that the survival analysis in the bortezomib trial reported by Richardson et al. involved a 22 percent loss to follow-up. According to the online Supplementary Appendix accompanying the full text of Richardson and colleagues' report, 150 patients were lost to follow-up. By back-calculation, we determined that the number of deaths was about 135. Thus, the benefit of bortezomib could easily be wiped out if only 10 to 20 patients in the dexamethasone group died while lost to follow-up. In addition, there was an insufficient length of follow-up and a severe censoring of the disease-progression end point.1
Jan P. Vandenbroucke, M.D.
Judith R. Kroep, M.D.
Leiden University Medical Center
2300RC Leiden, the Netherlands
j.p.vandenbroucke@lumc.nl
References
Dispenzieri A. Bortezomib for myeloma -- much ado about something. N Engl J Med 2005;352:2546-2548.
The authors reply: We greatly appreciate the questions from Drs. Vandenbrouke and Kroep regarding some of the statistical methods. The reasons for censoring, including the number of patients lost to follow-up in the analyses of survival and the time to progression, were inaccurate as provided in the Supplementary Appendix, and we sincerely regret the error. A revised version of the Supplementary Appendix is available with the full text of the article at www.nejm.org. In the survival analyses, the correct numbers of patients lost to follow-up were 11 (3 percent) and 6 (2 percent) in the bortezomib and dexamethasone groups, respectively. Therefore, only 2.5 percent of the patients were lost to follow-up in terms of survival, and it is highly unlikely that the loss of 2.5 percent of the patients would significantly affect the results. Drs. Vandenbroucke and Kroep are correct in suggesting that the length of follow-up is limited, because only 20 percent of the patients had died at the cutoff time for data collection. However, this limitation was a result of the decision on the part of the independent data monitoring committee to recommend discontinuing treatment in the high-dose dexamethasone group and offer crossover to bortezomib after the prespecified interim analysis. It is possible that subsequent analyses may be confounded by early crossover from high-dose dexamethasone to bortezomib, but the collection of survival data for both treatment groups is continuing, and we will present these updated results as soon as they are available.
We also appreciate the letter from Dr. Cecchi and colleagues regarding the cost benefit of bortezomib. Their estimate of the cost-effectiveness of bortezomib in this letter is not correct. The mean number of treatment cycles in the study was 6 rather than 11. The mean body-surface area of patients was 1.89 m2 rather than 2 m2. Furthermore, it is premature to use survival data to model cost-effectiveness on the basis of data from the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial, since fewer than one third of the events had occurred at the cutoff point for data collection. In a comprehensive, published analysis that was performed on the basis of data from patients with relapsed and refractory myeloma and that accounted for the costs of therapy, disease complications, and management of adverse events, bortezomib, as compared with best supportive care, had an incremental cost-effectiveness ratio of $45,356 per life-year gained.1 In another analysis, bortezomib had an incremental cost-effectiveness ratio as low as 25,271 ($30,910) per life-year gained,2 suggesting that the ratio fell below the international benchmark.3,4 These findings suggest that bortezomib is a cost-effective option for patients with relapsed multiple myeloma.
Paul G. Richardson, M.D.
Dana–Farber Cancer Institute
Boston, MA 02115
paul_richardson@dfci.harvard.edu
Anthony L. Boral, M.D., Ph.D.
Millennium Pharmaceuticals
Cambridge, MA 02139
Kenneth C. Anderson, M.D.
Dana–Farber Cancer Institute
Boston, MA 02115
References
Mehta J, Duff SB, Gupta S. Cost effectiveness of bortezomib in the treatment of advanced multiple myeloma. Manag Care Interface 2004;17:52-61.