Journal of the National Cancer Institute Advance Access originally published online on February 26, 2008
JNCI Journal of the National Cancer Institute 2008 100(5):373; doi:10.1093/jnci/djn012
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2008. Published by Oxford University Press.
CORRESPONDENCE |
Re: When You Look Matters: The Effect of Assessment Schedule on Progression-Free Survival
Affiliations of authors: Dana-Farber Cancer Institute, Boston, MA (PGR, KCA); Weill Medical College of Cornell University, New York Presbyterian Hospital, New York (RN); Hospital Clinic of Barcelona, Barcelona, Spain (JB)
Correspondence to: Paul G. Richardson, MD, Dana-Farber Cancer Institute, 44 Binney Street, Dana 1B02, Boston, MA 02115 (e-mail: paul_richardson{at}dfci.harvard.edu).
Panageas et al. (1) recently showed that progression-free survival (PFS) is dependent on the assessment schedule; the same is true of time to progression (TTP). Other factors that may affect TTP include: 1) whether it is measured from diagnosis, randomization, or first dose; 2) whether progression is defined by investigator assessment or a consistently applied algorithm; and 3) different qualities of response. Paradoxically, in clinical trials of treatment for multiple myeloma (MM), a high complete response (CR) rate may result in a shorter-than-expected median TTP, an observation that is inconsistent with the greater clinical benefit typically associated with CR.
In multiple myeloma, changes in the level of serum and urine M-protein are the basis for assessing response to therapy and monitoring disease evolution. The European Group for Blood and Marrow Transplantation (2) defines a CR, in part, as an immunofixation-negative, 100% decrease in M-protein in both serum and urine, and it defines relapse from CR as reappearance of M-protein on immunofixation. This strict definition of relapse could lead to a paradoxically shorter remission duration in patients achieving CR than in those achieving a partial response (PR; 
50% to <100% decrease in M-protein), with progression from PR requiring a greater than 25% increase in M-protein, which must also be at least 5 g/L (2). Relapse from CR and progression are defined events in Kaplan–Meier analyses of TTP/PFS. However, as noted in the International Uniform Response Criteria for Multiple Myeloma (3), such "events," particularly relapse from CR, may not correspond with true symptomatic relapse; therefore, reporting of time to next treatment is suggested (3), which reflects the clinical benefit of a prolonged TTP requiring intervention associated with CR.
As an illustration of the limitations of TTP as an endpoint in multiple myeloma, we examined data from a subset analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions trial in relapsed multiple myeloma patients (4) that were recently presented at the International Myeloma Workshop (5). In this updated analysis of the 331 bortezomib-treated patients, TTP was similar in patients achieving CR and in those achieving PR. In contrast, time to next therapy (first dose of bortezomib to first dose of next anti-MM therapy) and treatment-free interval (last dose of bortezomib to first dose of next anti-MM therapy), which reflect clinical benefit, were substantially longer in patients achieving CR than in those attaining only PR (27.1 vs 14.0 months and 24.1 vs 6.4 months, respectively) (5).
These data add to the considerations raised by Panageas et al. (1) when interpreting PFS/TTP in cancer trials and support the notion that, in multiple myeloma trials, TTP "per se" may not truly reflect the overall clinical benefit of therapy. Clinicians should be aware that shorter-than-expected TTP may in fact be associated with longer time to next therapy or treatment-free interval; therefore, caution should be exercised when interpreting TTP and comparing these results across trials. What may in fact be more important to patients is time off therapy, which is better reflected by measuring time to next therapy or treatment-free interval. This is particularly important with novel agents such as bortezomib, which is known for achieving high rates of CR, in turn a critical parameter of clinical benefit associated with improved overall survival (6).
REFERENCES
1. Panageas KS, Ben-Porat L, Dickler MN, Chapman PB, Schrag D. When you look matters: the effect of assessment schedule on progression-free survival. J Natl Cancer Inst (2007) 99(6):428–432.
2. Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol (1998) 102(5):1115–1123.[CrossRef][Web of Science][Medline]
3. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 20(9):1467–1473.[CrossRef][Web of Science][Medline]
4. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med (2005) 352(24):2487–2498.
5. Niesvizky R, Richardson PG, Rajkumar SV, et al. Quality of response with bortezomib in APEX [abstract]. Haematologica (2007) 92(Suppl 2):161–162.
6. Wang M, Delasalle K, Thomas S, Giralt S, Alexanian R. Complete remission represents the major surrogate marker of long survival in multiple myeloma [abstract]. Blood (2006) 108(11):123a–124a.[CrossRef]
Article about this Correspondence
Related Article in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2007 99: 428-432.
J Natl Cancer Inst 2007 99: 428-432.
This article has been cited by other articles:
|
|
 |
|
  J. F. San Miguel, R. Schlag, N. K. Khuageva, M. A. Dimopoulos, O. Shpilberg, M. Kropff, I. Spicka, M. T. Petrucci, A. Palumbo, O. S. Samoilova, et al. Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma N. Engl. J. Med., August 28, 2008; 359(9): 906 - 917. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||