Evaluation of Biomarkers of Survival Response in Hormone-refractory Prostate Cancer Patients Treated with

Hormone-refractory prostate cancer (HRPC) patients often have nonmeasurable disease. In such patients, predictive biomarkers other than tumor response may be required to compare therapeutic effects. We examined the predictive value for survival of various clinical and laboratory parameters, including prostate-specific antigen (PSA), in HRPC patients treated with suramin. Data from 103 HRPC patients were analyzed using various survival analyses, the likelihood ratio approach, and logistic regression analyses. When pretreatment factors, percentage decrease in PSA at 4 weeks from start of treatment (A PSA), and updated survival data were fit by a multivariate Cox proportional hazards model, acid phosphatase, lactate dehydrogenase, and PSA were significant, with risk ratios close to 1. There was a decrease in likelihood ratio with increasing PSA. A logistic regression model was developed to predict the probability of < 1 year of survival from the start of treatment. Hemoglobin and A PSA were found to be significant variables. However, in view of the complexities involving the relationship between PSA expression and prostate cancer growth and possible selective effect of treatment on PSA, further prospective testing is necessary. Therefore, I .PSA cannot necessarily be used as a biomarker for survival response in individual patients during the evaluation of the therapeutic response of HRPC to new antineoplastic drugs. Introduction Tumor response, measured by bidimensional reduction in tumor size, has been traditionally used to evaluate therapeutic effects of systemic cancer treatments. This response criterion. however, cannot always be evaluated because it is dependent on the ability to quantify tumor lesions objectively. Patients with HRPC5 often have bone-only (i.e. , nonmeasurable) disease. It is, therefore, important to investigate other predictive biomarkers that might be used to evaluate and compare therapeutic effects in patients with HRPC. Serum PSA has been used widely as a tumor marker. In view of the lack of other quantitative measurements in the majority of patients with HRPC. PSA is also used in the assessment of therapeutic efficacy. In two Phase I trials at the University of Maryland Cancer Center, 103 HRPC patients were treated with suramin. These studies have been reported elsewhere (1-3). In an earlier report (4), we examined PSA as a predictive biomarker for survival in these patients. Here. we have reanalyzed these data using updated survival data. We have also examined many additional factors as possible predictors of survival. We did not evaluate the relationship between changes in PSA measurements and tumor response because tumor response was not measurable in most of these patients. Furthermore, we have applied new methodology, specifically, the LR approach (5), to analyzing these data. Finally, we have developed a multivariate model for the probability of < I year of survival from the start of the treatment (6). We hoped to identify potential predictive biomarker(s) of survival that could be used as end point(s) for response in individual patients typically entered in Phase II efficacy clinical trials of HRPC. Although it might be assumed that an agent causing a reduction in PSA would do so by reducing tumor burden, it is important to realize that drugs may produce PSA changes through mechanisms other than cell death. Theoretically, the plasma PSA concentration reflects the rate of PSA synthesis per unit volume of tumor tissue. the rate of tumor growth. and the rate at which PSA is cleared from the blood. A reduction in either of the first two processes or an increase in the third would result in a decrease in PSA. If an agent did not affect prostate tumor growth but did reduce PSA synthesis or enhance PSA clearance, plasma PSA concentrations would decrease. Such effects, therefore, may confound the value of PSA as predictive of a reduction in tumor size. Materials and Methods Data. Data on the following pretreatment factors: age; performance status; weight; Hb: alkaline phosphatase: ACP: LDH: PSA concentration; platelet, WBC, and lymphocyte counts: S The abbreviations used are: HRPC, hormone-refractory prostate cancer; PSA. prostate-specific antigen; LR, likelihood ratio; Hb. hemoglobin; ACP. acid phosphatase; LDH. lactate dehydrogenase; CI. confidence interval; RR. risk ratio. on October 20, 2017. © 1998 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from 632 Short Communication: Survival Biomarkers in Prostate Cancer Table I Patient characteristics Characteristic value Total no. of patients 103 Target plasma suramin concentration (no. of patients) Cohort I (175-300 sg/ml) 22 Cohort 2 ( 150-250 gsg/ml) 23 Cohort 3 ( 100-200 sg/ml) 22 Cohort 4 (fixed regimen) 36 Age, yr lmedian (range)l 66 (44-85) Performance status (no. of patients)