TheAssociation BetweenMeasures of Progression and Survival in Castrate-Metastatic Prostate Cancer

Purpose:To explore the association between progression-free survival and overall survival time in patients with castration-resistant prostate cancer treated with microtubule-targeted therapies. Experimental Design:We retrospectively studied patients treated in three trials evaluating a taxane or an epothilone for progressive castration-resistant prostate cancer. Study subjects were 98 patients with bone metastases; 63 of them also had soft tissue lesions. All scans were reviewed independently. Associations of radiographic progression-free survival and prostatespecific antigen (PSA) progression-free survival with survival time were measuredusingKendall’s s, adjusted for right censoring. A smoothing procedure was applied to estimate Kendall’s s within each neighborhood of the follow-up process. Results: The overall associations between progression-free survival time and overall survival time were moderate: 0.4 for radiographic progression-free survival and 0.33 for PSA progression-free survival. The association between radiographic progression-free survival and overall survival was weakest early in the follow-up process, whereas the PSA association was weakest when the progression-free survival ^ related event (PSA progression, death, or censoring) occurred after 6 months from the start of treatment. Conclusions: Current measures of progression-free survival time for men with castrationresistant prostate cancer are not strongly concordant with survival time. Factors that attenuate the association include interval censoring and the discontinuation of therapy early in the followup due to imaging changes that may not reflect true failure of the treatment. For radiographic progression-free survival, the association may be increased by requiring confirmation of progression with a second scan, as is routinely done when assessing response. Criteria to assess outcomes in therapeutic trials aim to provide objective and reproducible measures which reflect clinical benefit to patients. The difficulties in assessing the response to treatments in prostate cancer are well recognized across the spectrum of the disease. This is because changes in radionuclide bone scan are difficult to quantify objectively and reproducibly (1), and changes in prostate-specific antigen (PSA) may be dissociated from clinical outcomes such that a post-therapy decline may not mean that the drug has ‘‘worked’’, and an increasing value that it has not. The situation is complicated further by the fact that the most widely used criteria, Response Evaluation Criteria in Solid Tumors (2), adapt poorly to the most common clinical manifestations of prostate cancer (3). Although dramatic responses associated with effective therapies can be identified with Response Evaluation Criteria in Solid Tumors, targeted approaches that stabilize or slow tumor growth and which are not cytotoxic, may not. Given these difficulties, we proposed that the outcome measures for prostate cancer clinical trials shift to what is done routinely in clinical practice, focusing less on whether a drug has induced a response to a determination of when it has failed (3). From the point of view of a clinical trial or clinical practice, the measure that considers when a drug has not worked at all or is no longer effective is represented best by progression-free survival, the time from the start of therapy to progression of disease, death, or last follow-up. Because it is closer to survival time in the follow-up process, one would postulate that progression-free survival would be a more informative (predictive) intermediate end point with a stronger association with survival. In fact, there are few studies that have explored this association in prostate cancer, or for any cancer type. This is in part because the methodology required is nonstandard, as both progression-free survival and overall survival are time to event end points. As a result, any measure of association must account for censoring in progression-free survival and overall survival. Variability is increased because survival times are assessed daily, whereas progression-free survival is assessed at Cancer Therapy: Clinical Authors’Affiliations: Genitourinary Oncology Service, Department of Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, and Department of Medicine,Weill Medical College of Cornell University, NewYork, NewYork Received 7/31/06; revised10/24/06; accepted12/8/06. Grant support:Memorial Sloan-Kettering Cancer Center Specialized Programs of Research Excellence in Prostate Cancer, CA-05826, and the Prostate Cancer Foundation. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18U.S. C.Section1734 solely to indicate this fact. Requests for reprints:Howard I. Scher, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, NewYork, NY 10021. Phone: 646-422-4323; Fax: 212-9880851; E-mail: scherh@mskcc.org. F2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-06-1885 www.aacrjournals. org Clin Cancer Res 2007;13(5) March1, 2007 1488 Research. on May 24, 2017. © 2007 American Association for Cancer clincancerres.aacrjournals. org Downloaded from intervals. If the intervals between assessments are too long, a measure of progression-free survival can become meaningless. In this report, we explore the association between progression-free survival and overall survival for patients with progressive castrate-metastatic prostate cancer (4) enrolled in three sequential trials of microtubule-targeted cytotoxic agents. Our goal was to assess whether the common intermediate end points for metastatic prostate cancer, radiographic progressionfree survival and PSA progression-free survival, were in concordance with survival time. A close association between progression-free survival time and overall survival would support the use of progression-free survival as an intermediate end point for prostate cancer clinical trials, with the potential to accelerate drug development in this patient population. Materials andMethods The relationship between progression-free survival and overall survival was determined from an analysis of outcomes from the subset of men treated at Memorial Sloan-Kettering Cancer Center who were enrolled on three sequential multicenter Institutional Review Board– approved protocols evaluating microtubule-targeted chemotherapy (5–7). Enrollment required histologically confirmed adenocarcinoma of the prostate, a Karnofsky performance status of z70%, a testosterone level of <50 ng/mL, and documented disease progression following a trial of antiandrogen withdrawal as appropriate. PSA progression was defined as a minimum of three increasing PSA levels obtained 2 or more weeks apart, in which the range of values was at least 25% (8). The event was recorded on the date of the first PSA increase. If a PSA event did not occur, censoring was defined at the date of the last PSA recorded measure. Radiographic progression was defined as new or progressive (25% bidimensional increase) soft tissue masses on computerized tomography or magnetic resonance imaging, or new lesions on radionuclide bone scan. All imaging studies were reviewed in a blinded fashion by a radiologist. The probability of progressing by time t in the presence of competing causes of death was estimated by the cumulative incidence function. Association analyses with two time to event variables. In this analysis, the progression-free survival time (S) and overall survival time (T) were subject to censoring. The measure of association was Kendall’s s adjusted for censoring, defined as s 1⁄4 4PrðTi > Tj; Si > SjÞ 1; where (Si,Ti) represent the progression-free and overall survival times for the ith subject. The measure varies between 1 and 1, with 1 representing perfect concordance between the time to event variables and 1 representing perfect discordance between the variables; a measure of zero represents no relationship between the two variables. Kendall’s s is estimated through the ranks S and T ; it measures the level of concordance and discordance in the ranks of S and T between each pair of subjects. For any pair of subjects i and j , concordance implies that if the progression-free survival of subject i is greater (less) than the progression-free survival of subject j , then the survival time of subject i is greater (less) than the survival time of subject j . Discordance means that if the progression-free survival of subject i is greater (less) than the progression-free survival of subject j , then the survival time of subject i is less (greater) than the survival time of subject j . Kendall’s s provides a measure of the difference between the concordance and discordance outcomes for all pairs of subjects. The SE of this estimate can be derived from U-statistic theory (9). As a result of censoring, the ranks of the progression-free survival times (S) and the survival times (T) are less certain. For example, suppose subject 1 has a progression-free survival and overall survival time pair, measured in months, equal to (S1,T1) = (7, 12), and subject 2 has the failure time pair (S2,T2) = (8, 15). Since (T2 > T1) and (S2 > S1), these two subjects have concordant failure times; subject 2 has the higher survival and progression-free survival times. Suppose, however, that the 12-month survival time for subject 1 represents a censored time, or the last follow-up time. Then the concordance between these two subjects is unknown. It is unclear whether the ultimate survival time for subject 1 would be greater or less than subject 2. All that is known is that the progression-free survival time for subject 2 is greater than the progression-free survival time for subject 1. The association between time to progression and death as a fu