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Clinical Cancer Research Vol. 11, 8669-8673, December 15, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Time to Detectable Metastatic Disease in Patients with Rising Prostate-Specific Antigen Values following Surgery or Radiation Therapy

Susan F. Slovin1, Andrew S. Wilton2, Glenn Heller2 and Howard I. Scher1

Authors' Affiliations: Departments of 1 Medicine and 2 Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York

Requests for reprints: Susan F. Slovin, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 646-422-4470; Fax: 212-988-0701; E-mail: slovins{at}mskcc.org.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: To determine factors associated with the development of radiographic metastatic progression for patients with recurrent prostate cancer following surgery and/or radiation therapy with prostate-specific antigen (PSA) doubling times of <12 months.

Experimental Design: One hundred and forty-eight patients with rising PSA values after primary therapy and a PSA doubling time of <12 months enrolled on clinical protocols were followed and monitored at protocol-specified intervals with examinations, PSA determinations, and imaging studies that included a computed tomography or magnetic resonance imaging and bone scan until metastases were detected. Metastasis-free survival was estimated using the Kaplan-Meier method and factors predictive of progression-free survival were estimated using the proportional hazards model. A nomogram based on the Cox model was constructed.

Results: Metastatic events were documented in 74% (110 of 148) of patients during the follow-up period. The median progression-free survival was 19 months, with 3- and 5-year metastatic progression–free survival of 32% and 16%, respectively. T stage (P = 0.07) and Gleason grade (P = 0.006) at the time of diagnosis, PSA values at the time of protocol entry (P < 0.001), and PSA doubling time (P < 0.001) were associated with progression in univariate analysis. These were combined into a nomogram to assess risk for an individual patient.

Conclusions: Tumor characteristics at the time of diagnosis, PSA doubling time following relapse, and the PSA value at the time of the protocol are predictive of metastatic progression. Because the PSA value at the time of monitoring was predictive, early treatment to prevent metastatic progression is favored.

Prostate-specific antigen (PSA) doubling times, reflecting the rate of increase in PSA values, have been associated with outcomes for men with prostate cancer across the spectrum of the illness from prediagnosis to post–hormone-treated failure (1–7). Prognostic information is most needed for men with rising PSA values after surgery or radiation therapy where the change in the biochemical marker is the only manifestation of the disease (8). Patients in this group, in a state of rising PSA (9), now represent the second largest group of men with prostate cancer. Management is focused on first determining whether the increase in PSA values is due exclusively to recurrent or persistent disease in the prostate or prostate bed, disease outside of this area, or both. The significance is that disease that is exclusively local may still be curable, whereas systemic occurrences generally are not. The caveat is that even when the PSA value is determined to represent systemic disease and is left untreated, clinically detectable metastases, and ultimately prostate cancer–specific mortality, may not be manifest for months or even years.

To define outcomes more precisely, several groups have recently explored associations between PSA kinetics and outcomes in this patient group. Most have focused on two clinical end points: detectable metastases on an imaging study, the point in the illness where the risk of a prostate cancer–specific death exceeds that of other causes (10), and prostate cancer–specific survival. These estimations are important for patient counseling and factor heavily in the decision of whether systemic treatment is needed and what it should be, and for clinical trial design. The implication is that treatment can be safely deferred for those with low-risk disease, and started early for those with a high risk of metastatic progression or prostate cancer–specific mortality. Exactly what level of risk would influence a patient to accept treatment, or a physician to offer it, varies by individual.

Of the factors included in the prognostic analyses reported to date, PSA doubling time (PSADT), the rate of rise in PSA values over time, is dominant (7, 10–15). A significant limitation of all of these analyses is that they are retrospective, the imaging modalities used to detect disease were not done at fixed intervals, and that the number of events on which the models are based is often quite small. Consequently, the uncertainty in predicting these clinical outcomes was great. The current report evaluated men, with a PSADT of 12 months or less after surgery and or radiation therapy, who were enrolled prospectively on Institutional Review Board–approved clinical protocols testing alternatives to androgen deprivation. The patients were followed with examinations and imaging studies at fixed intervals until metastatic disease was detected. We show that the prognosis was highly variable, but could be defined more accurately by including tumor factors assessed at the time of diagnosis, and the level of PSA where observation was begun.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
 References
 
The patient cohort under analysis consisted of 148 patients prospectively enrolled in sequential Institutional Review Board–approved vaccine protocols after informed consent had been obtained (13–18). All had evidence of recurrent disease manifested as a rising PSA after surgery or radiation therapy for clinically localized disease, a PSADT of 12 months or less, with no detectable metastases on bone scan and computed tomography or magnetic resonance imaging. Patients who had lymph nodes measuring up to 1 cm on baseline computer-assisted tomography scans were considered eligible. Factors analyzed were T stage, Gleason score, and PSA values at the time of diagnosis, as well as the type of local therapy (surgery or radiation). The pathologic stage was used for those who underwent radical prostatectomy. Also considered were the alkaline phosphatase, hemoglobin, lactate dehydrogenase, and PSA values at the time of protocol treatment. The prevaccination PSADT was also calculated. Patients were monitored at a minimum of 3-month intervals with physician visits, laboratory studies including a complete blood count with differential, blood urea nitrogen, creatinine, total bilirubin, alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvate transaminase, calcium, albumin, phosphorus, PSA and acid phosphatase, and imaging studies which included a bone scan and computer-assisted tomography scans of the abdomen and pelvis. Patients were considered to have "progressed" if they developed new lesions on radionuclide bone scan, or if lymph node size exceeded 2 cm.

The primary outcome measure was metastasis-free survival defined as being alive with no detectable disease on an imaging study; this was estimated using the method of Kaplan and Meier. Comparisons between groups were made with the log-rank test, and the proportional hazards model was used to determine factors predictive for metastasis-free survival. A nomogram based on this Cox model was then constructed.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Patient characteristics are listed in Table 1A and B. For discrete covariates, the frequency of each category is provided, and for continuously valued covariates, the median and the first and third quartiles are given. Overall, 53% of the patients had organ-confined disease, and 9% of the patients had evidence of nodal spread. Approximately 70% had a Gleason score of 7 or lower, whereas the median PSA values at the time of diagnosis was 10.6 mg/mL (range, 1.8-200). Previous therapy was divided evenly between radiation therapy and surgery. The median and interquartile ranges for PSA, alkaline phosphatase, hemoglobin, lactate dehydrogenase, and PSADT are also shown. Note that the median PSA values at the time of protocol enrollment was 8.2 ng/mL and median PSADT was 4.7 months. The median follow-up considered as the time to metastases, death, or to last follow-up visit, was 19.0 months, with a range of 1 to 75.3 months. Overall, 110 of the 148 (74%) patients showed evidence of metastatic progression to date, at a median of 19 months (Fig. 1), with estimated 3- and 5-year metastasis-free survival rates of 32% (95% confidence interval, 24-40) and 16% (95% confidence interval, 9-25), respectively. At present, 15 (10%) patients have died of prostate cancer, and 133 remain alive.


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  		Table 1. Patient demographics

 


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  		Fig. 1. Kaplan-Meier curve of overall clinical metastasis-free survival.

 
In univariate analysis, patients with a higher T stage (log rank test, P = 0.07) and Gleason score of 7 or greater at the time of diagnosis were more likely to develop metastatic disease (log rank test; P = 0.006). The type of primary therapy, surgery or radiation therapy, and the presence of nodal disease were not predictive, although the number of patients with nodal involvement was small. The alkaline phosphatase (P = 0.81), hemoglobin (P = 0.16), and lactate dehydrogenase (P = 0.29) levels at the time of protocol enrollment were not predictive (Table 2A).


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  		Table 2. Results of the Cox proportional hazards model

 
The results of the Cox proportional hazards model are given in Table 2B. Using backwards selection, T stage (P = 0.02), and Gleason score (P = 0.02) at the time of diagnosis, preprotocol PSADT (P = 0.001) and PSA level at the time of protocol therapy (P < 0.001) were independent predictors for metastatic progression. Patient-specific predictions of the median time to metastatic progression and the probabilities for remaining metastasis-free at 1 and 2 years are shown by the nomogram in Fig. 2. Each covariate scale position has a corresponding points scale (top scale). For example, a baseline PSA of 1.0 contributes ~15 points to the total points scale. A point value for each predictor is determined and summed to compute the total points for a patient. This value is located on the total points scale (fourth from the bottom). The predicted 1- and 2-year progression-free survival, and the median progression-free survival is then determined by drawing a vertical line down from the total points scale to the respective predicted outcome scale.



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  		Fig. 2. Nomogram used to predict patient-specific probabilities of metastasis-free survival at 1 and 2 years, and the median progression-free survival time.

 
The predictive accuracy of the nomogram was assessed using the concordance index. Similar to the area under the receiver operating characteristic curve, the concordance index provides the probability that in a randomly selected pair of patients, the patient with the longer progression-free survival had the better predicted outcome from the nomogram. The concordance index ranges between 0.5 and 1.0, with 1.0 representing a model with perfect discrimination, and 0.5 indicating that a coin flip would provide as accurate information as the model. We used bootstrapping with 200 replicates to obtain a relatively unbiased estimate. Specifically, this was done by first computing the apparent accuracy of the model using the entire data set. Second, we computed the accuracy on a sample of the same size but drawn with replacement. Third, we calculated the accuracy of this second model, using the original data set. Optimism is defined as the difference between the second and third accuracies in this process. After repeating this process 200 times, the mean optimism was subtracted from the first model accuracy to arrive at a nearly unbiased estimate. The bootstrap corrected concordance index was 0.69, indicating adequate discriminatory power for this model.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Our study identifies variables collected in the context of routine patient management that can be used to estimate the risk of developing detectable metastasis on an imaging study. As outlined in the clinical states model (9), the transition to a state of clinical metastasis is the point in the illness where the risk of prostate cancer–specific mortality exceeds that of other causes (10). Predictive factors included characteristics of the disease at the time of diagnosis, PSA kinetics after relapse, and a measure reflecting the current burden of disease. The study is unique in that men were enrolled prospectively on a clinical protocol and followed at predefined intervals with physical examinations and imaging studies until metastatic disease was documented. As the primary therapeutic intervention did not affect PSA kinetics,3 the outcomes effectively represent the untreated natural history of the disease. The effect of these prognostic features makes a case for earlier intervention.

Other models designed to predict metastatic progression have been reported for patients in the rising PSA state. All include a PSADT variable. In a notable series from Johns Hopkins in which patients did not receive androgen deprivation until metastatic disease was documented, high-grade disease in the prostatectomy specimen, short time intervals to biochemical relapse (≤2 versus >2 years), and rapid PSADTs (<10 versus ≥10 months) predicted for a metastatic event (10). In the first update of this cohort, time to PSA failure was no longer predictive when PSADT was considered (11). In another series, a PSADT of ≤6 months was associated with a 5-year metastasis-free survival of 64% versus 93% for patients who had a longer PSADT (12), whereas a second reported detectable metastases at 5 and 10 years in 10% and 29%, respectively, for those with a PSADT of 12 months or less versus 0% and 17% for those with a longer PSADT. The estimation in the latter trial, however, was based on a total of 23 metastatic events representing 10% (23 of 211) of the patient population reported (15). A third trial used a PSADT cutoff of 8 months or less (16). A more recent report included 1,650 patients treated with external beam radiation therapy, of whom 381 (23%) developed a biochemical recurrence, and 98 (26%) developed distant metastases at an incidence of 10%, 21%, and 29% at 1, 3, and 5 years, respectively. For this cohort, clinical T stage (P ≤ 0.001) and Gleason score (P = 0.007) at diagnosis, and PSADT (P < .001), were the only independent variables that predicted for distant metastases. Dividing patients on the basis of a PSADT of 0 to 3, 3 to 6, 6 to 12, and 12 months or more, the frequency of metastatic disease was 49%, 41%, 20%, and 7% at 3 years, respectively (P < 0.001) representing a 7.0-, 6.6-, and 2.8-fold increased risk relative to those with the slowest (>12 months) doubling times. The median follow-up time was 92 months from the completion of radiotherapy (7). A limitation of all of these studies was their retrospective nature, that the imaging studies to detect disease were not done at prespecified intervals, and none accounted for the PSA level at the time therapy was being considered.

An additional consideration when evaluating these reports is how to estimate PSADT. Questions remain as to the optimal number of PSA values that should be used, whether the values need to be consecutive, and whether these values should be separated by a minimum period of time. For this report, a total of four values obtained sequentially prior to protocol entry were used. In others, as few as two values are used (10). This alone explains some of the inconsistencies observed. Complicating the issue further is that values can fluctuate independent of treatment (17) and the kinetics of PSA elevations in more than one-third of the patients follow higher order kinetics (18).

In addition to counseling the individual patient, assessing the risk of metastatic progression is important in clinical trial design. Enrolling patients with similar risk profiles helps to insure the homogeneity of the population, and is particularly important when a rising biochemical marker is the sole manifestation of the illness (8). In this regard, many now consider treatment for patients with PSADT of 6 months or less, which represents ~15% to 20% of the populations reported (5, 19).

In this article, we have developed a model to predict the probability of metastatic progression for patients with rising PSA levels. The model was constructed from prospective data, using imaging modalities to detect disease, employed at predetermined time intervals. The factors found to be predictive of the time to metastatic progression were: baseline PSA, PSADT, T stage, and Gleason score. These factors when taken together, however, do not form a surrogate for the time to metastatic progression. The discriminatory power of this model, as measured by the concordance index, was 0.69. Thus, there remain factors, either unknown or unmeasured, which could contribute substantially to our understanding of how and when a patient transitions to the metastatic state. Corroborating this result, when calibration or the strength of association is considered, PSA metrics typically account for only 20% of the explained outcome (20). More than 80% of the association is not explained. Based on these results, it would seem that PSA-based information remains only one of many variables that need to be considered when formulating treatment decisions, and that future research needs to explore biological processes outside the PSA domain to enable more accurate prediction of the metastatic transition.


   Acknowledgments
 
We thank Dr. Stephen Freedland for his helpful comments.


   Footnotes
 
Grant support: The Prostate Cancer Foundation, The Sharon Hels and Brad Reed Fund, The Sara Chait Foundation, and The Carol Ann Mazzella Fund.

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 with 18 U.S.C. Section 1734 solely to indicate this fact.

3 Slovin, et al., submitted. Back

Received 8/ 1/05; revised 9/ 6/05; accepted 9/15/05.


   References
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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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