The kinetics and relationships between testosterone (T) and prostate-specific antigen (PSA) during the first off-treatment interval in men with nonmetastatic prostate cancer treated prospectively on a clinical trial of intermittent androgen deprivation were analyzed. Time to PSA rise and time to PSA rise after first T > 50 ng/dL were prognostic for progression to castration resistance.
Intermittent androgen deprivation (IAD) represents an alternative to continuous AD with quality-of-life benefit and no evidence of inferior overall survival for nonmetastatic prostate cancer. Early markers of prognosis for men treated with IAD have not been described.
Patients and Methods
Men with nonmetastatic prostate cancer were treated with 9 months of leuprolide and flutamide followed by a variable off-treatment interval; AD was resumed when prostate specific antigen (PSA) reached a prespecified value (1 ng/mL, radical prostatectomy; 4 ng/mL, intact prostate). Cycles were repeated until castration resistance (marking the advent of castration-resistant prostate cancer [CRPC]), defined as 2 PSA rises with testosterone (T) ≤ 50 ng/dL. Kinetics and relationships of PSA and T levels were evaluated, with a focus on times to rise in each level, during the first off-treatment interval. Associations with CRPC and prostate cancer mortality were estimated using Cox proportional hazards models controlling for age and Gleason score.
Each 30-day increase in time to PSA rise was associated with a 21% reduction in the risk of developing CRPC (95% CI, 3%-36%;P = .02). Longer time (≥ 60 days) to PSA rise after rise to T > 50 ng/dL was associated with a 71% reduction in the risk of developing CRPC (95% CI, 92% reduction to 2% inflation;P = .05). Time to first T > 50 ng/dL and PSA doubling time were not prognostic for progression to CRPC. No time interval was prognostic for prostate cancer mortality.
During the first off-treatment interval of IAD, longer times to PSA rise overall and after T > 50 ng/dL were associated with reduced risk of developing CRPC.
Owing to issues surrounding the morbidity and cost of continuous androgen deprivation (CAD), multiple randomized studies of intermittent androgen deprivation (IAD) versus CAD have been performed.1 and 2Overall survival and time to castration resistance have been similar, but there is evidence of less toxicity for those treated with IAD. Recently, a large trial of IAD versus CAD for men who underwent radiation for prostate cancer found no difference in overall survival, with more prostate cancer–related deaths for those receiving IAD yet more non–prostate cancer–associated deaths for those receiving CAD. 1 These findings suggest that IAD should be a standard of care for men treated with androgen deprivation (AD) in this setting.
There are few markers prognostic for progression to castration-resistant prostate cancer (CRPC) or prostate cancer mortality (PCM). This is particularly true for men undergoing IAD. The present authors have previously found that, when a predetermined prostate-specific antigen (PSA) threshold is used in a prospective trial of IAD, the duration from the end of AD to reaching that threshold (defining the first off-treatment interval) is prognostic for time to CRPC and death. 3 However, this prognostic time interval requires follow-up for long periods until the PSA threshold is met and AD is resumed for a second treatment cycle. An earlier biologic and prognostic marker would be useful both in the clinic and to stratify risk for future clinical trials. For this reason, this study evaluated times to testosterone (T) and PSA rises, times between these events, and PSA doubling time (PSAdt) during the first off-treatment interval of IAD as potential prognostic time intervals for time to CRPC and PCM in men with nonmetastatic castration-sensitive prostate cancer in this prospective trial of IAD.
A prospective trial of IAD for men with nonmetastatic prostate cancer with either locally advanced prostate cancer or biochemical relapse of the disease after failure of primary therapy was initiated to study the time to CRPC as well as numerous physiologic, emotional, and cognitive effects of AD.3 and 4Key eligibility requirements included a histologic diagnosis of prostate cancer, at least 2 consecutive rises in PSA at least 2 weeks apart, original American Urological Association stage A2-D1, no detectable metastasis by bone and computed tomography scans, Eastern Cooperative Oncology Group performance status 0 or 1, and pretreatment T > 100 ng/dL. Late enrollment was permitted as long as the duration of therapy was < 10 months. Patients could have received prior AD for neoadjuvant, adjuvant, or salvage settings as long as the duration of AD was ≤ 3 months and it was completed ≥ 1 year before study entry. Each patient signed a written informed consent form approved by the University of Washington institutional review board.
Initial treatment consisted of 9 months of combined AD with flutamide at 250 mg 3 times daily and a luteinizing hormone–releasing hormone agonist ( Figure 1 ). Patients with toxicity from flutamide were switched to bicalutamide, 50 mg daily. At the end of the 9 months of treatment induction, AD was stopped provided that the PSA value was ≤ 1 ng/mL and not rising. PSA levels were measured monthly throughout IAD therapy, whereas T was measured quarterly during the 9-month on-treatment intervals and monthly during off-treatment intervals. When the PSA reached an arbitrary, prespecified threshold of 1 ng/mL for those after radical prostatectomy and 4 ng/mL for those with an intact prostate (radiation or primary AD), a new cycle was initiated with another 9 months of combined AD. All patients continued cycling on and off therapy until the development of CRPC, defined as 2 serial rises in PSA while on AD with T < 50 ng/dL.
Four time intervals of interest during the first off-treatment interval were analyzed in this exploratory analysis: time from completion of AD to first T > 50 ng/dL, time from first T > 50 to PSA rise of ≥ 0.1 ng/mL, time from completion of AD to PSA rise of ≥ 0.1 ng/mL, and PSA doubling time (PSAdt) ( Figure 1 ). PSAdt was calculated by using the first 3 PSA measurements starting from PSA rise in the Memorial Sloan Kettering online nomogram. 5 To be eligible for this analysis, patients must have had a sufficient number of measurements for determining at least 1 of these 4 time intervals of interest and a T recovery to > 100 ng/dL during the first off-treatment interval to eliminate the possibility of chronic castration without therapy.
Cox proportional hazards models were used to quantify associations between the time intervals of interest and times to CRPC or PCM, with times to CRPC or PCM defined beginning at the last time point used to construct the marker. For example, in the model to quantify association between time to T > 50 ng/dL and time to CRPC, time to CRPC begins when T > 50 ng/dL. Based on preliminary graphic examination, all time intervals of interest entered the models as continuous measures with the exception of time from T > 50 ng/dL to PSA rise, which was dichotomized as < 60 days versus ≥ 60 days. In addition to the time interval of interest, all models controlled for age at study entry and grade category (dichotomized as Gleason score ≤ 3 + 4 vs. ≥ 4 + 3).
After standard graphic diagnostic evaluation of model performance and formal testing of the proportional hazards assumption using Schoenfeld residuals, plots were constructed that illustrated predictions of corresponding models with each time interval binarized at the median (except for T > 50 ng/dL to PSA rise, which the analysis continued to binarize at 60 days). For illustrative purposes, the analysis adjusted for mean age (66 years) and the more common grade category (Gleason score ≤ 3 + 4).
Between June 1996 and September 2006, 100 patients were accrued to the IAD trial. Of those, 62 were eligible for this exploratory analysis ( Figure 2 ). Characteristics of the eligible patients are presented in Table 1 . At diagnosis, the median age was 61.2 years (range, 48.3-74.8 years), with a median PSA of 9.7 ng/mL (range, 3.9-130.5 ng/mL). The median Gleason score was 3 + 4 (range, 6-9). The treatment choices were as follows: 47 patients underwent radical prostatectomy, 14 received definitive radiation therapy, and 1 patient received primary AD. Of the 14 patients who received radiation, 13 experienced biochemical recurrence, fulfilling the contemporary Phoenix criteria. 6 Median time from primary treatment to biochemical recurrence was 3.3 years (range, 0.5-14.6 years).
|At Initial Diagnosis||Value|
|Age (year), Median (Range)||61.2 (48.3-74.8)|
|Gleason Score (n)|
|3 + 4||20|
|4 + 3||14|
|PSA (ng/mL) Median (Range)||9.7 (3.9-130.5)|
|Primary Treatment (n)|
|At Study Entry||Value|
|Age (year), Median (Range)||66.2 (51.2-81.1)|
|Baseline PSA (ng/mL), Median (Range)||3.9 (0.46-152.4)|
|Baseline T (ng/dL), a Median (Range)||350 (140-640)|
|Time to BR (year), Median (Range)||2.9 (0.5-14.6)|
|Prior AD (n)|
a In 49 of 62 patients, baseline testosterone levels were known; missing values were due to late enrollment.
Abbreviations: AD = androgen deprivation; BR = biochemical recurrence; PSA = prostate-specific antigen; T = testosterone.
At study entry, the median age was 66.2 years (range, 51.2-81.1 years), with median baseline pre-study PSA and T levels of 3.9 ng/mL (range, 0.46-152.4 ng/mL) and 350 ng/dL (range, 140-640 ng/dL), respectively ( Table 1 ). There were 52 patients who achieved a PSA nadir of < 0.1 ng/mL during the first treatment cycle, whereas the remaining 10 patients had a median PSA nadir of 0.2 ng/mL (range, 0.1-0.4 ng/mL). During the first off-treatment interval, the median time of recovery to first T > 50 ng/dL was 3.1 months (range, 0-5.1 months). The median time to PSA rise was 4.5 months (range, 0.9-92.3 months), and the median time to PSA rise after first T > 50 ng/dL was 1.0 month (range, −0.9 to 88.5 months). The median duration of the first off-treatment interval was 9.5 months (range, 3.4 to more than 47.5 months). At the time of this report, 5 patients were still in their first off-treatment interval because they had not yet reached the PSA threshold for initiating the second cycle of IAD, and 3 of these patients still had an undetectable PSA; for these patients, the times to CRPC and PCM were censored at the date of the last clinic visit. The median PSAdt during the first off-treatment period starting from the first PSA rise was 1.2 months (range, 0-8.3 months).
Of 62 patients, 40 are alive (23 remain on IAD, 11 have CRPC, and 6 are off study), and 22 have died. Of the 22 patients who died, 13 (59%) died of progressive CRPC and 9 (41%) died of other causes. There were 39 patients who came off study at some point after completing the first full cycle: 29 patients owing to progression to CRPC and 10 for other reasons. After the first full cycle, median time to CRPC was 4.0 years (range, 0.5-8.6 years), and median time to death was 6.6 years (range, 2.9-13.0 years). Median times from primary treatment to CRPC and to death were 9.7 years (range, 4.0-21.0 years) and 12.8 years (range, 5.5-21.6 years), respectively.
Results of the Cox proportional hazard models are presented in Table 2 . There is moderate evidence that time to PSA rise and time to PSA rise after T > 50 ng/dL were each associated with time to CRPC after controlling for age at study entry and Gleason category (P = .02 and .05, respectively). Each 30-day increase in the time to PSA rise was associated with a 21% decrease in the risk of CRPC (95% CI, 3%-36%). If a patient had a time to PSA rise of ≥ 60 days after their first T > 50 ng/dL, this was associated with a 71% decrease in the risk of CRPC (95% CI 92% decrease to 2% increase). A sensitivity analysis found that the association was similar for patients who had a time to PSA rise of ≥ 30 days after their first T > 50 ng/dL (57% decrease; 95% CI, 85% decrease to 28% increase) and for patients who had a time to PSA rise of ≥ 90 days after their first T > 50 ng/dL (69% decrease; 95% CI, 93% decrease to 37% increase). Associations between time to T > 50 ng/mL and PSAdt and time to CRPC are consistent with clinically important prognostic markers (each 30-day increase in time to T > 50 ng/dL is associated with a 32% decrease in the risk of CRPC, and each 30-day increase in PSAdt is associated with a 39% decrease in the risk of CRPC); however, this study had insufficient power to conclude statistical significance. No time intervals were associated with PCM. Figure 3 shows Kaplan-Meier survival curves predicted from the Cox models for time to CRPC and time to PCM for each time interval of interest.
|Castration-Resistant Prostate Cancer|
|End AD to T > 50 ng/dL||44||0.68||(0.41, 1.13)||.13|
|End AD to PSA Rise||54||0.79||(0.64, 0.97)||.02|
|T > 50 to PSA Rise||43||0.29||(0.08, 1.02)||.05|
|PSA Doubling Time||47||0.61||(0.36, 1.04)||.07|
|Prostate Cancer Mortality|
|End AD to T > 50 ng/dL||47||1.42||(0.59, 3.41)||.44|
|End AD to PSA Rise||57||0.94||(0.72, 1.22)||.65|
|T > 50 to PSA Rise||46||0.45||(0.08, 2.41)||.35|
|PSA Doubling Time||50||0.58||(0.25, 1.35)||.20|
Abbreviations: End AD = end of initial 9 months of androgen deprivation; HR = hazard ratio; PSA = prostate-specific antigen; T = testosterone.
Recent randomized phase III trial data support the concept that IAD is not inferior in terms of survival compared with CAD for men with biochemically recurrent disease after definitive or salvage radiation. 1 Patients on IAD have a net improved quality of life with fewer hot flashes, reduced sexual adverse effects, and long-term preservation of bone mineral density.1, 7, 8, 9, and 10Given the significant heterogeneity in long-term response to IAD, prognostic markers that distinguish those with indolent versus aggressive disease would be useful. Patients with early PSA rise could be considered for novel clinical trial designs, given that this study's data indicate that they have a worse prognosis if they simply continue on intermittent ADT. Those patients with late PSA rise might require less therapy and be apt to experience mortality from other causes, rather than prostate cancer. Therefore, early identification of these patients not only may stratify risk groups but also could affect future treatment.
Previously, the present authors found that the duration of the first off-treatment interval is prognostic for both time to CRPC and death in this patient population. 3 Drawbacks to using the duration of the first off-treatment interval as a prognostic factor are that it requires waiting for the off-treatment interval to end and it does not take into account the biologic relationship between T and PSA. Knowing that changes in PSA levels over time have been found to be an important prognostic factor in other prostate cancer disease states,11, 12, 13, 14, 15, and 16and hoping to find earlier indicators of prognosis than the duration of the first off-treatment interval, the present authors sought to evaluate the kinetics and relationships of PSA and T rise during the first off-treatment period.
The present analysis found that there is a significant association between a longer time to PSA rise during the first off-treatment interval and a longer time to CRPC. This is not surprising, given the prior results that defined the duration of the first off-treatment interval as prognostic for both CRPC and death. However, the time to PSA rise occurs at an earlier time point and can be used to inform subsequent treatment decisions. This analysis also found that those with a longer time (eg, ≥ 60 days) to PSA rise after first T > 50 ng/dL experience a longer time to CRPC. This is an important finding, because it confirms that a delay in PSA rise with a noncastrate T level is “good” and that a longer time from first T > 50 ng/dL to PSA rise has improved outcomes.
Although it is intuitive that a greater interval between T and PSA rise would lead to improved quality of life and long-term outcomes, this is the first study in which the concept has been confirmed. However, the explanation for this relationship is unclear. A simple explanation is that patients with a smaller overall tumor burden require greater overall stimulation from T to produce enough PSA to reach the threshold to start the next IAD cycle. Another more biologically relevant explanation relies on the known intratumoral production of androgens.17 and 18It is possible that those tumors that respond very quickly to T with a rise in PSA are tumors that are already producing androgens, requiring very little exogenous T stimulation to produce and increase PSA, and hence are closer to the clinical definition of CRPC. Conversely, those tumors that are making little to no androgens rely more on testicular sources of T before the neoplastic cells are stimulated and PSA begins to rise.
Numerous studies have reported that PSAdt values after primary treatment,11, 12, 19, and 20biochemical recurrence,13, 15, and 21and in the castration-resistant22 and 23and metastatic disease states16 and 24are associated with poorer prognosis. Although an increased PSAdt is associated with a clinically important reduction in time to CRPC or PCM in the present data, these relationships did not meet statistical significance, owing to inadequate patient numbers. One challenge in this analysis is that PSAdt may not be accurate when calculated at very low PSA values. Additionally, PSAdt is usually calculated to indirectly measure tumor growth at steady-state androgen levels. It may be challenging to determine the effect of PSAdt in a setting in which T levels are actively rising.
A number of factors may have contributed to the lack of prognostic significance in some of the present evaluations. The patient population size was likely insufficient to find a marker of marginal or moderate significance. Furthermore, the long duration of time and heterogeneity in the course of subsequent treatments after the development of CRPC, as well as the small number of patients who had PCM (n = 13), limited the statistical power to test for prognostic time intervals for PCM. Finally, studying prognostic time intervals during IAD is challenging, because some patients progress during the first treatment cycle of AD whereas others may remain chronically castrate in the off-treatment period after only 1 treatment cycle of AD.
In this trial, time to first PSA rise during the first off-treatment interval was prognostic for progression to CRPC. Hence, the use of PSA and T during the first off-treatment interval of IAD for evaluating prognostic potential is reasonable. Examination of these parameters from a larger data set, such as the phase III PR7 trial, would be of interest. If these data were to be validated, one might consider these evaluations when making decisions about when to resume AD on an intermittent schedule: those who have good risk characteristics may be able to defer AD beyond the empiric PSA threshold defined in this trial, whereas those with poor risk characteristics should be considered for innovative clinical trials.
Clinical Practice Points
The authors thank Ruth Etzioni, PhD, for her thoughtful insight in review of the manuscript.
This study was funded in part by SPORE NCI P50 CA097186, Drive Fore the Cure Northwest, US Department of Defense Prostate Cancer Research Program, No. W81XWH-09-1-0144.
Dr Higano's industry financial relationships over the past 3 years are as follows: consulting for AbbVie, Algeta, Amgen, Astellas, Bayer, BHR Pharma, Dendreon, Endo/Orion, Ferring, Fresenius, Genentech, Johnson & Johnson, Medivation, Novartis, and Pfizer; involvement in research with Algeta, Amgen, Aragon, AstraZeneca, Bayer, Cougar Technology, Dendreon, Exelixis, Genentech, ImClone, Johnson & Johnson, Medivation, Millennium, Novartis, OncoGenex, Sanofi-Aventis, and Teva Pharmaceuticals.
Dr Yu's industry financial relationships over the past 3 years are as follows: consulting for Amgen, Astellas, Bayer, Dendreon, Janssen, Medivation, Millennium, and Seattle Genetics; involvement in research with Agensys, Astellas, AstraZeneca, Bristol-Myers Squibb, Dendreon, GTx, ImClone, Janssen, Medivation, Novartis, and OncoGenex.
All other authors state that they have no conflicts of interest.