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Prostate-specific antigen velocity and survival for patients with hormone-refractory metastatic prostate carcinoma
Version of Record online: 6 DEC 2005
Copyright © 2005 American Cancer Society
Volume 106, Issue 1, pages 63–67, 1 January 2006
How to Cite
Rozhansky, F., Chen, M.-H., Cox, M. C., Dahut, W., Figg, W. D. and D'Amico, A. V. (2006), Prostate-specific antigen velocity and survival for patients with hormone-refractory metastatic prostate carcinoma. Cancer, 106: 63–67. doi: 10.1002/cncr.21576
- Issue online: 23 DEC 2005
- Version of Record online: 6 DEC 2005
- Manuscript Accepted: 28 JUL 2005
- Manuscript Revised: 30 JUN 2005
- Manuscript Received: 7 MAR 2005
- cytostatic therapy;
- prostate carcinoma;
- prostate-specific antigen
The authors investigated whether prostate-specific antigen (PSA) velocity was associated significantly with the time to death after randomization among patients with hormone-refractory metastatic prostate carcinoma (HRMPC) who were treated with cytotoxic, cytotatic, or combination therapy.
The study cohort included 213 men with HRMPC who were treated on 3 prospective, randomized Phase II studies between February 1996 and October 2001. Cox regression analysis was used to evaluate whether there was a significant association between PSA velocity and the time to death after randomization, controlling for treatment and known prognostic factors.
Increasing PSA velocity was associated significantly with shorter survival after randomization (P = 0.005) controlling for treatment and known prognostic factors. The adjusted hazard ratio for death was 1.8 (95% confidence interval [95% CI], 1.3–2.5; P = 0.0004) for men who had a PSA velocity > 0.0 ng/mL per month compared with men who had a PSA velocity ≤ 0.0 ng/mL per month. Estimates of survival 2 years after randomization for these men were 16% (95% CI, 7–25%) and 44% (95% CI, 35–53%), respectively.
PSA velocity was associated significantly with the length of survival among men with HRMPC who received cytotoxic, cytostatic, or combination therapy. Cancer 2006. © 2005 American Cancer Society.
Prostate-specific antigen (PSA) failure after radical prostatectomy (RP) or external beam radiation therapy (RT) occurs in up to 30% of patients with clinically localized prostate carcinoma within 10 years of treatment.1–5 Although not all patients with PSA failure after RP or RT will develop distant metastases, the majority of men with metastatic prostate carcinoma will develop androgen independence and will die from their disease. Several authors have reported on the association between survival and several factors, including lactate dehydrogenase (LDH), PSA, alkaline phosphatase (Alk Phos), Gleason score, Eastern Cooperative Oncology Group (ECOG) performance status, and hemoglobin (Hgb), in men with hormone-refractory metastatic prostate carcinoma (HRMPC).6–10 Although the factors that predict survival are known, until recently, no therapeutic regimen has been shown to prolong survival in this setting.11
In 2001, it was shown that bone-targeted consolidation therapy, consisting of 1 dose of Sr-89 plus doxorubicin once per week for 6 weeks given to patients with stable or responding advanced androgen-independent carcinoma of the prostate after induction chemotherapy, improved overall survival.12 Then, in 2004, 2 Phase III prospective randomized controlled trials demonstrated a significant prolongation of overall survival in patients who were treated with docetaxel in combination with prednisone or estramustine compared with the prior standard of mitoxantrone with prednisone, which improved quality of life but not overall survival.13, 14 Moreover, Crawford et al.15 noted that there was a significant association between PSA velocity and time to death after randomization and raised the possibility that this time-dependent PSA construct may forecast survival accurately in men with HRMPC who undergo cytotoxic chemotherapy.
Although the extension in survival due to the cytotoxic effect of docetaxel in patients with HRMPC is an important advance, it took 4 years to prove. Furthermore, early markers of death are needed for different classes of drugs to expedite drug discovery for men with advanced prostate carcinoma. Therefore, the objective of the current study was to evaluate whether the PSA velocity was associated significantly with the length of survival after randomization for patients with HRMPC who were treated with cytotoxic, cytostatic, or combination therapy when controlling for known prognostic factors and treatment received.
MATERIALS AND METHODS
Patient Selection, Staging, and Treatment
Baseline, treatment, and follow-up information from 3 randomized, prospective Phase II multiinstitutional studies that enrolled 213 men who were treated for HRMPC formed the data base for this study.16–18 In the first randomized, prospective Phase II study,16 74 men were enrolled who were treated initially either with docetaxel (n = 25 patients) or with a combination of thalidomide with docetaxel (n = 49 patients) between December 1999 and October 2001. In the second randomized, prospective Phase II study,17 72 men were enrolled, and 36 patients on each treatment arm were treated initially with ketoconazole with or without alendronate. For the third study,18 67 patients were enrolled, including 54 patients who were receiving low-dose thalidomide and 13 patients receiving high-dose thalidomide.
An approved and signed Internal Review Board informed consent form was obtained for each patient prior to study entry. In all patients, the evaluation of disease extent at diagnosis included a bone scan; serum Hgb, Alk Phos, LDH, and PSA levels; and ECOG performance status assessment. The median age of patients at the time of study entry was 72 years (range, 43–94 yrs). The baseline pretreatment clinical characteristics of the 213 eligible study patients stratified by treatment received are shown in Table 1.
|Clinical characteristics at randomization||Study cohort (%)a|
|< 50 yrs||4 (2)|
|50–59 yrs||42 (20)|
|60–69 yrs||75 (35)|
|70–74 yrs||44 (21)|
|75–80 yrs||39 (18)|
|≥ 80 yrs||9 (4)|
|≤ 4 ng/mL||5 (2)|
|> 4–10 ng/mL||9 (4)|
|> 10–20 ng/mL||20 (9)|
|> 20 ng/mL||179 (84)|
|≤ 6||24 (11)|
|Median LDH (range) (IU/L)||197.3 (99–2077)|
|Median Hgb (range) (g/dL)||12.8 (7.2–15.4)|
|Median Alk Phos (range) (IU/L)||138 (50–4630)|
The median follow-up for the entire study cohort of 213 patients was 1.25 years (range, 0.07–5.32 yrs), and follow-up started on the day of randomization. Overall, at the time of the current analysis, 168 of 213 men (79%) had died.
Calculation of the PSA velocity
To calculate the PSA velocity, Day 0 was defined as the day of randomization. The PSA values that we used to calculate the PSA velocity included the baseline PSA value and all PSA measurements after Day 14 and before Day 183 (i.e., 6 mos) to allow adequate time to permit and assess for a PSA response. A minimum of 2 PSA values with a median of 3 (range, 2–6 PSA values) was used to calculate PSA velocity. The PSA velocity was calculated by using linear regression analysis.19
Cox regression analyses
The primary endpoint of the current study was overall survival. A Cox proportional hazards regression model20 was used to evaluate whether PSA velocity, ECOG performance status, age, and serum levels of PSA, Hgb, LDH, and Alk Phos were associated significantly with the time to death after randomization. For all Cox regression analyses,20 Time 0 was taken as the day of randomization, and the assumptions of the Cox model were tested and met. Because of the wide variation in the PSA, LDH, and Alk Phos levels, as shown in Table 1, a logarithmic transformation was used for these variables. PSA velocity, log PSA, Hgb, log LDH, and log Alk Phos serum levels were evaluated as continuous variables. The ECOG performance status was evaluated as a categoric variable, with a performance status of 0 used as the baseline. In addition, the PSA velocity also was evaluated as a categorical variable dichotomized about the value of 0.0 ng/mL per month. The adjusted hazard ratio (AHR) for death and the associated 95% confidence intervals (95% CI) were calculated using the proportional hazards model.20 For illustrative purposes, Kaplan–Meier estimates21 of survival dichotomized about the value of 0.0 ng/mL per month for the PSA velocity were compared using a log-rank test. All statistical tests were 2-sided, and P values < 0.05 were considered statistically significant.
The first, median, and third quartiles of PSA velocity were − 10.8 ng/mL per month, − 1.6 ng/mL per month, and 17.8 ng/mL per month, respectively. Table 2 shows that an increasing PSA velocity was associated significantly with shorter survival after randomization (AHR of 1.002; 95% CI, 1.001–1.004 [P = 0.005]), controlling for treatment and known prognostic factors. The AHR for death was 1.8 (95% CI, 1.3–2.5; P = 0.0004) for men who had a PSA velocity > 0.0 ng/mL per month compared with men who had a PSA velocity ≤ 0.0 ng/mL per month. Figure 1 shows that the estimates of survival 2 years after randomization were 44% (95% CI, 35–53%) versus 16% (95% CI, 7–25%) for men in the study cohort who had a PSA velocity ≤ 0.0 ng/mL per month compared with a PSA velocity > 0.0 ng/mL per month, respectively.
|Covariate||No. of patients||No. of events||Unadjusted||Adjusteda||Adjustedb|
|HR (95% CI)||P value||HR (95%CI)||P value||HR (95%CI)||P value|
|LDH (IU/L)||213||168||3.92 (2.37–6.49)||< 0.0001||2.77 (1.57–4.88)||0.0004||2.96 (1.69,5.19)||0.0001|
|Hgb (g/dL)||213||168||0.66 (0.59–0.73)||< 0.0001||0.66 (0.57–0.76)||< 0.0001||0.67 (0.59–0.77)||< 0.0001|
|Age||213||168||0.99 (0.97–1.01)||0.329||1.00 (0.98–1.02)||0.838||1.00 (0.98–1.02)||0.747|
|ECOG PS 0||50||31||1.0c||—||1.0c||—||1.0c||—|
|ECOG PS 1 or 2||163||137||1.88 (1.26–2.80)||0.002||1.82 (1.18–2.81)||0.007||1.64 (1.07–2.51)||0.022|
|Alk Phos (IU/L)||213||168||1.61 (1.30–2.0)||< 0.0001||1.30 (0.96–1.77)||0.086||1.30 (0.96–1.75)||0.088|
|Trial 1 Rx||54||49||0.97 (0.52–1.81)||0.931||1.07 (0.70–1.62)||0.738||1.05 (0.70–1.59)||0.812|
|Trial 2 Rx||36||27||0.95 (0.55–1.66)||0.860||0.77 (0.48–1.25)||0.297||0.86 (0.53–1.39)||0.532|
|Trial 3 Rx||49||33||0.66 (0.37–1.14)||0.137||0.96 (0.62–1.50)||0.868||1.08 (0.69–1.71)||0.725|
|PSA velocity ≤ 0.0 ng/mL/month||132||99||1.0c||—||—||—||1.0c||—|
|PSA velocity > 0.0 ng/mL/month||81||69||1.81 (1.32–2.47)||0.0002||—||—||1.84 (1.31–2.58)||0.0004|
|PSA velocitya||213||168||1.002 (1.000–1.003)||0.0132||1.002 (1.001–1.004)||0.005||—||—|
|PSA (ng/mL)||213||168||1.17 (1.05–1.30)||0.005||0.87 (0.76–1.00)||0.052||0.88 (0.77–1.01)||0.075|
Although the values for LDH, Hgb, Alk Phos, PSA, and ECOG performance status were associated significantly with the time to death in the univariate analysis, only LDH (AHR of 2.77; 95% CI, 1.57–4.88 [P = 0.0004]), Hgb (AHR of 0.66; 95% CI, 0.57–0.76 [P < 0.0001]), and ECOG performance status (AHR of 1.82; 95% CI, 1.18–2.81 [P = 0.007]) maintained a significant association with the time to death in the multivariate analysis.
In 1989, Ferro et al.22 reported that post-treatment PSA changes were clinically relevant indicators of response in patients with HRMPC. Since then, the majority of phase II trials have used the changes in PSA levels as markers of response.23–25 In 1999, Scher et al. showed that a posttherapy decline > 50% in the serum PSA level was associated with prolonged survival in patients with HRMPC.26 Refining this concept further, it was noted that patients with HRMPC who had PSA declines ≤ 50% also may experience a prolongation in survival if the rate of PSA fall after treatment is rapid compared with the rate of incline.27 Moreover, Crawford et al.15 noted that there was a significant association between the PSA velocity measured during the first 3 months of chemotherapy and the time to death in a randomized trial that compared 2 cytotoxic chemotherapy regimens in patients with HRMPC who were enrolled in Southwest Oncology Group Study S9916. That observation was tested further by using the Prentice28 criteria and raised the possibility that PSA velocity, which is a time-dependent PSA construct, may serve as a surrogate marker for death in men with HRMPC who undergo cytotoxic chemotherapy.
In the current study, in which the agents that have been defined as the most effective (i.e., thalidomide, docetaxel, ketoconazole, and alendronate) were used, the association between PSA velocity and time to death, as reported by Crawford et al., was validated for men with HRMPC, but only in the setting of cytotoxic, cytostatic, or combined cytotoxic and cytostatic therapies. Specifically, controlling for treatment and known prognostic factors, an increasing PSA velocity was associated with a significantly shorter survival after randomization (P = 0.005).
It is interesting to note that PSA velocity was analyzed as a continuous variable (i.e., it could take on negative or positive values) and, as a continuous covariate, was associated significantly with length of survival after therapy after adjusting for confounders that had a P value = 0.005, as shown in Table 2. Therefore, the current study has provided evidence to show that PSA velocity in responders and nonresponders is associated significantly with the length of survival.
The clinical significance of this finding is that time-dependent PSA measures, such as PSA velocity, may be considered as an intermediate endpoint for death when measuring the clinical efficacy of novel agents for patients with HRMPC. Such early endpoints may help to provide the basis for future studies to expedite drug discovery for men with hormone-refractory prostate carcinoma, who often have a median survival of < 2 years.
Similar to other investigators,6–10 we found that LDH, ECOG performance status, and Hgb were significant prognostic factors of overall survival in men with HRMPC. These results are consistent with reports that have shown an association between performance status and outcome29, 30 and the adverse effect of anemia on survival.31, 32 Anemia may reflect advanced disease (i.e., myelophthisis), the effect of prior interventions (hormones, chemotherapy, and RT), or the nutritional status of a patient. It has been observed in many studies that markers of tumor burden, such as increased LDH32, 33 and Alk Phos,33 are predictive.34 It is interesting to note that we could not demonstrate any impact of Alk Phos on survival in the current study, possibly reflecting the fact that some elevations in Alk Phos are the result of bone healing and not progressive disease.
A potential limitation of this study should be considered. The Cox analyses performed were based on a meta-analysis of 3 randomized Phase II studies and not on a single, large Phase III study. Although attempts were made to control for the known prognostic factors and treatments using the proportional hazards model, validation of these findings from a large, prospective, randomized study is needed to be certain that unknown prognostic factors that were not controlled for did not impact the study findings. However, despite this potential limitation, the results of the current study suggest that the PSA velocity is associated significantly with the length of survival for men with HRMPC who receive cytotoxic, cytostatic, or combination therapy.
- 15Three-month change in PSA as a surrogate endpoint for mortality in advanced hormone-refractory prostate cancer (HRPC): data from Southwest Oncology Group Study S9916 [abstract 4505]. Proc Am Soc Clin Oncol. 2004; 23: 382., , , et al.
- 18A randomized Phase II trial of thalidomide, an angiogenesis inhibitor, in patients with androgen-independent prostate cancer. Clin Cancer Res. 2001; 8: 1888–1893., , , et al.
- 19Survival analysis: techniques for censored and truncated data. In: KleinJP, MoeschbergerML, editors. Techniques for censored and truncated data in survival analysis. New York: Springer-Verlag, 1997: 229–281., .
- 20NeterJ, WassermanW, KutnerM, editors. Simultaneous inferences and other topic in regression analysis-1. In: NeterJ, WassermanW, KutnerM, editors. Applied linear regression models, 1st ed. Homewood, Il: Richard D. Irwin Inc., 1983: 150–153.
- 27A reduction in the rate of PSA rise following chemotherapy in patients with metastatic hormone refractory prostate cancer (HRPC) predicts survival: results of a pooled analysis of CALGB HRPC trials. J Clin Oncol. 2004; 22(14S): 537–556., , , .