Prepared by the PCRI Helpstaff with oversight by Stephen B. Strum, MD
Reprinted from PCRI Insights October 2000 vol. 3, no. 3
Concordance is a concept that is pertinent when the cell population of the tumor is not homogeneous but rather is heterogeneous. If the tumor cell population is heterogeneous, it may be more or less responsive to a particular therapy. In the clinical evaluation of a patient’s response to anti-cancer treatment, this may express itself grossly as a mixed tumor response with some lesions decreasing in volume while others remain the same or show increased growth. At a cellular level, heterogeneity of a tumor population may express itself with the elevation of multiple biomarkers, each of which may represent different cell populations or clones.
A mixed response to treatment at this level may be reflected by one biomarker showing a significant drop while another is increasing in value. To achieve a meaningful remission that equates with prolonging survival, our goal is the concordant drop of any abnormal biomarkers. For example, in testicular cancer, complete remission and prolonged survival is only found when there is a concordant drop in all abnormal biomarkers. The need for a concordant drop in the biomarkers seen in all malignancies, including breast and prostate cancer, is also a requisite for prolonged response equating with increased survival. In essence, concordance of biomarker and/or any kind of clinical response is tantamount to a more complete response leading to a longer duration of response.
The single study in the field of prostate cancer that clearly demonstrates this is that of Steineck et al.1 In that study, they evaluated 107 patients with androgen-independent prostate cancer (AIPC) who had been treated on seven different protocols at the Memorial Sloan-Kettering Cancer Center. For PAP and PSA, a minimum 50% or 80% decrease from baseline documented on three separate occasions a minimum of six weeks apart was required to categorize a patient as having a decline. Nineteen patients (18%) had either a 50% decline in PAP or PSA, while 13 (68%) of them had a decline of both markers. Six (32%) patients showed discordance between the two parameters. The median survival of patients showing declines in both markers exceeded that of patients showing declines in PSA alone by one year. The authors concluded that post-therapy declines in PSA and PAP represent reproducible endpoints for clinical trials in AIPC. The requirement of a repeated and parallel decline in both markersmay improve the results observed by monitoring declines in PSA alone. The results of this study are shown in Figure 1.
Concordance as a desirable endpoint can also be important in evaluating staging. In the August 2000 issue of Insights (vol. 3, no. 2, p 4), the discussion of endorectal MRI with spectroscopy indicated that specificity for intra-glandular prostate cancer involvement increased to 91% from 55% when both the endorectal MRI AND the spectroscopy indicated such findings. A 91% specificity would signify that when intraglandular PC was seen, this impression was only wrong 9% of the time due to false positive findings. Therefore, what you see is most likely what you really have.
Lastly, concordance in clinical results is an important concept regarding confirmation of therapeutic response. Suppose a patient on intermit intermittent androgen deprivation has been off therapy with Lupron and Flutamide for 20 months but has been maintained during this time on Proscar. His PSA has risen during this off time to only 2.2 but the DRE (digital rectal examination) reveals a palpable nodule consistent with T2a PC (see Insights, vol.3, no.1, pp 8-9).Without the input of the DRE, the PSA findings would not alarm us, but the discordant nature of the biologic expression of the PSA and the DRE should lead the astute clinician to suspect that the patient has sufficient regrowth of PC to warrant further evaluation (perhaps with an endorectal MRI with spectroscopy) before restarting ADT. In this example, we are looking for concordant clinical evidence of quiescent disease, and the occurrence of discordant findings is a signal mandating further evaluation.
1. Steineck G, Kelly WK, Mazumdar M, et al: Acid phosphatase:
defining a role in androgen-independent prostate cancer.
Urology 47:719-26, 1996.