ADULT UROLOGY
`
`EFFECT OF PREDNISONE ON PROSTATE-SPECIFIC
`ANTIGEN IN PATIENTS WITH HORMONE-REFRACTORY
`PROSTATE CANCER
`
`OLIVER SARTOR, MARIBETH WEINBERGER, ANDREA MOORE, AILING LI, AND WILLIAM D. FIGG
`
`ABSTRACT
`Objectives. To evaluate the effects of prednisone on prostate-specific antigen (PSA) in a cohort of patients
`with “hormone-refractory” prostate cancer.
`Methods. Data were collected from 29 consecutive patients with hormone-refractory progressive prostate
`cancer who were treated with 10 mg of prednisone orally two times a day. Patients were included in this
`analysis only if other factors known to influence PSA levels (antiandrogen withdrawal, radiation, and/or other
`concomitant anticancer therapies) were definitively excluded as potentially confounding variables.
`Results. The mean and median PSA decline after initiating prednisone was 33% (95% confidence interval
`[CI] 20% to 46%) and 24% (range 0% to 99%), respectively. Ten patients (34%) had a PSA decline of more
`than 50% and 4 patients (14%) had PSA declines of more than 75%. The average and median time for
`progression-free survivals were 2.8 (95% CI 1.7 to 3.8) and 2.0 (range 0 to 11) months. Four (14%) patients
`had PSA declines lasting 6 months or more. Median survival was 12.8 months. Additional analyses indicated
`that a PSA decline of more than 50%, compared with less than 50%, was associated with a longer survival.
`Toxicities included steroid myopathy (n ⫽ 4), new-onset diabetes (n ⫽ 1), and dyspnea (n ⫽ 1).
`Conclusions. Prednisone (10 mg orally two times a day) can decrease PSA by more than 50% in approxi-
`mately one third of patients with hormone-refractory progressive prostate cancer. On the basis of compar-
`isons with other data sets, we hypothesize a dose-response relationship between glucocorticoid dose and
`PSA decline. UROLOGY 52: 252–256, 1998. © 1998, Elsevier Science Inc. All rights reserved.
`
`Glucocorticoids have significant palliative ac-
`tivity in patients with metastatic prostate can-
`cer whose previous therapy with surgical or
`medical orchiectomy failed. This activity in post-
`orchiectomy prostate cancer was initially recog-
`nized in the 1950s.1 Since that time, various glu-
`cocorticoids at a wide range of doses have been
`used in patients. Clear efficacy has been documented
`in some patients when using palliative end points.2
`In recent years investigators have recognized
`that hormone-refractory prostate cancer is com-
`prised of a relatively heterogeneous group of pa-
`tients.3 In fact, a significant proportion of these
`hormone-refractory patients may respond to sec-
`
`From the Departments of Urology and Medicine, Louisiana State
`University Medical Center, Shreveport, Louisiana and Medicine
`Branch, National Cancer Institute, Bethesda, Maryland
`Reprint requests: Oliver Sartor, M.D., Stanley S. Scott Cancer
`Center, Louisiana State University Medical Center, 2025 Gravier
`Street, Suite 620, New Orleans, LA 70112
`Submitted: November 10, 1997, accepted (with revisions): Feb-
`ruary 23, 1998
`
`ondary hormonal manipulations as measured by
`changes in objective markers such as prostate-spe-
`cific antigen (PSA) decline and/or tumor shrink-
`age.3,4 The PSA changes after glucocorticoid treat-
`ment are frequently difficult to interpret in the
`literature because of confounding variables such as
`radiation therapy,5 adrenal suppressive therapies,6
`suramin,7,8 or other concomitant therapies.9 In ad-
`dition, not all studies10 examining PSA changes
`after glucocorticoids were initiated before recogni-
`tion of antiandrogen withdrawal as a potentially
`active therapeutic maneuver.11
`Since the advent of PSA testing and the recogni-
`tion of the flutamide withdrawal as a potentially
`confounding variable, only four trials using regular
`PSA monitoring to ascertain glucocorticoids ef-
`fects in patients with hormone-refractory progres-
`sive prostate cancer have been published. Two
`trials used low doses of hydrocortisone (30 to 40
`mg/day) before suramin treatments12,13; another
`report used prednisone at 20 mg/day but included
`only 8 patients14; a recent report used 5 mg of pred-
`
`© 1998, ELSEVIER SCIENCE INC.
`252 ALL RIGHTS RESERVED
`
`Amerigen Exhibit 1114
`0090-4295/98/$19.00
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`
`

`
`nisolone orally two times a day.15 Additional series
`using glucocorticoid therapy have been reported in
`abstract form, but many details regarding these se-
`ries are incomplete.16,17 In this report, we review
`our experiences with prednisone 20 mg/day (10
`mg two times a day) in patients with progressive
`prostate cancer despite medical or surgical orchi-
`ectomy. No confounding variables known to effect
`PSA were present in any patient. No patients had
`concomitant treatment with radiation therapy, an-
`tiandrogen withdrawal, or any other known con-
`founding variables such as ketoconazole, suramin,
`aminoglutethimide, or chemotherapy. The effects
`of prednisone on PSA are emphasized because
`these data are limited in the peer-reviewed litera-
`ture.
`
`MATERIAL AND METHODS
`
`Patients were included in this review only if antiandrogen
`withdrawal could conclusively be excluded as a confounding
`variable. No patients had concomitant treatment with any
`medication or modality. All patients had been previously
`treated with surgical or medical castration (luteinizing hor-
`mone-releasing hormone [LHRH] analogue) and had evi-
`dence of a rising PSA at least 10 ng/mL above the previous
`nadir before initiating prednisone therapy. Thus all patients
`were classified as having hormone-refractory progressive
`prostate cancer. Twenty-nine consecutive patients meeting
`these criteria are included in this analysis.
`Treatment consisted solely of 10 mg of oral prednisone pre-
`scribed two times a day. If patients had previously received an
`LHRH analogue, this therapy was continued at the same dose
`as before. Serum PSA determinations were made at baseline
`(within 1 week of starting prednisone) and serially thereafter
`at each clinic visit. Patients were typically scheduled in clinic
`every 4 weeks. PSA responses were calculated according to the
`method of Tannock and colleagues,11 ie, the maximum ob-
`served decrease from baseline.
`We note that both Hybritech and Abbott assays were used to
`determine serum PSA levels in these studies. Although each
`patient consistently used only one methodology, there is the
`possibility of significant interpatient PSA variation because
`different assays were used.
`In analyzing the PSA response duration, progression was
`defined as a PSA rise of 10 ng/mL or more that was sustained
`on repeated measurements 2 or more weeks apart. We note
`that this is a more conservative criterion than that used by
`some investigators, ie, many analyses have required a PSA rise
`of 50% or greater than the nadir (or baseline) before declaring
`progressive disease.
`In addition to PSA end points, symptomatic end points were
`also evaluated. Patient symptoms of weight loss, pain, de-
`creased appetite, and fatigue were routinely documented in
`the chart. Formal quality of life assessments were not per-
`formed. Because pain management with narcotic and non-
`narcotic medications were optimized at each clinic visit, the
`investigators believe that improvements in symptomatic end
`points may or may not be attributed to prednisone.
`Potential statistical differences between survival curves
`were assessed by the log-rank test or by multivariate ap-
`proaches using a Cox proportional hazard analysis.18
`
`TABLE I. Patient treatments before initiating
`prednisone
`
`Treatment
`
`No. of Patients
`
`Medical or surgical castration
`Prior antiandrogens
`Bicalutamide
`Flutamide
`Initial CAB
`Subsequent CAB
`External beam radiation
`Chemotherapy
`Vitamin A
`Megace
`Ketoconazole
`Prednisone
`Intravenous radiation
`
`2
`15
`6
`11
`
`29
`17
`
`13
`3
`2
`2
`1
`1
`1
`
`KEY: CAB ⫽ combined androgen blockade using a combination of an antiandrogen
`and medical or surgical castration.
`
`RESULTS
`
`A total of 29 consecutive patients were included
`in this analysis. A review of prior therapies admin-
`istered to these patients (see Table I) indicated that
`all patients received prior orchiectomy or regular
`injections of an LHRH agonist. Seventeen patients
`had received prior antiandrogen therapy in addi-
`tion to medical or surgical castration. Six of these
`patients had received antiandrogens as part of ini-
`tial hormonal therapy; 12 patients received antian-
`drogens after progression of disease was initially
`documented. Radiation was previously adminis-
`tered to 12 patients. All patients completed radia-
`tion at least 1 month before starting prednisone.
`Chemotherapy had been previously administered
`to 3 patients and megestrol acetate to 2 patients;
`miscellaneous therapies had been administered in
`several other cases. When taken together, 13 pa-
`tients had been pretreated with only one previous
`hormonal therapy (orchiectomy or LHRH ana-
`logues), 13 patients had been treated with two hor-
`monal therapies (antiandrogens ⫹ medical/surgi-
`cal orchiectomy), and 4 patients had been treated
`with three or more hormonal therapies before
`prednisone. Flutamide withdrawal was not consid-
`ered a hormonal therapy in this compilation.
`Pretreatment characteristics of the patient popu-
`lation included the following (see Table II): me-
`dian patient age was 71 years, median Eastern Co-
`operative Oncology Group (ECOG) performance
`status was 1, median PSA was 158 ng/mL, and me-
`dian hemoglobin was 11.6 g/dL. Twenty-six pa-
`tients had previously documented metastatic dis-
`ease on a bone scan (n ⫽ 19), a computed
`tomography scan (n ⫽ 2), or both scans (n ⫽ 5); 2
`patients did not have a bone scan available for re-
`view, and 1 patient had a negative bone scan.
`
`UROLOGY 52 (2), 1998
`
`253
`
`

`
`TABLE II. Patient population in the
`prednisone study
`
`TABLE IV. Progression-free survival after
`initiating prednisone
`
`Total population
`Bone scan positive
`CT scan positive (soft tissue)
`Age (median yr)
`Performance status (median)*
`Hemoglobin (median g/dL)
`Alkaline phosphatase
`(median U/L)
`PSA (median ng/mL)
`
`29
`24
`7
`71 (range 50–85)
`1 (range 0–3)
`11.6 (range 7.4–14.2)
`134 (range 57–2260)
`
`158 (range 13–768)
`
`KEY: CT ⫽ computed tomography; PSA ⫽ prostate-specific antigen.
`* According to the criteria established by the Eastern Cooperative Oncology Group
`(ECOG).
`
`TABLE III. PSA responses after initiating
`prednisone
`
`PSA decline (average)
`PSA decline (median)
`ⱖ25% declines
`ⱖ50% declines
`ⱖ75% declines
`
`33% (95% CI 20%–46%)
`24% (range 0%–99%)
`14/29 (48%)
`10/29 (34%)
`4/29 (14%)
`
`KEY: PSA ⫽ prostate-specific antigen; CI ⫽ confidence interval.
`
`Twenty-six of the 29 patients had symptoms of
`some type including pain, loss of appetite, fatigue,
`and/or weight loss. Taken together, the majority of
`patients in this study had symptomatic, metastatic
`hormone-refractory prostate cancer.
`PSA responses are noted in Table III. The average
`PSA decline compared with baseline was 33% (95%
`confidence interval [CI] 20% to 46%); the median
`PSA decline was 24%. The range of PSA declines
`varied from 0% to 99%. Of the 29 patients, 14
`(48%) achieved a PSA decline of at least 25%, 10
`(34%) achieved a PSA decline of at least 50%, and 4
`(14%) achieved a PSA decline of at least 75% less
`than baseline. From an alternative point of view, 4
`patients achieved a PSA decline of at least 25% and
`less than 50%, 6 patients achieved a PSA decline of
`at least 50% and less than 75%, and 4 patients
`achieved a PSA decline of at least 75%. No PSA
`decline was documented in 10 patients; 4 patients
`had a documented PSA decline of less than 25%.
`The mean progression-free survival as deter-
`mined by PSA was 2.8 months (95% CI 1.7 to 3.8
`months); the median progression-free survival was
`2.0 months (see Table IV). The range of progres-
`sion-free survival was 0 to 11 months. Of the 29
`patients, 20 patients had a PSA progression-free
`survival of at least 2 months, 10 patients had a PSA
`progression-free survival of at least 4 months, and
`4 patients had a progression-free survival of at least
`6 months.
`Of the 26 symptomatic patients, 23 had im-
`proved appetite, weight gain, or pain relief. Be-
`
`Duration (average)
`Duration (median)
`Duration ⱖ2 months
`Duration ⱖ4 months
`Duration ⱖ6 months
`
`KEY: CI ⫽ confidence interval.
`
`2.8 months (95% CI 1.7–3.8)
`2.0 months (range 0–11)
`20/29 (69%)
`10/29 (34%)
`4/29 (14%)
`
`cause pain management was optimized concomi-
`tantly, the contributions of prednisone and/or pain
`management cannot be accurately ascertained.
`Analysis of survival revealed that the median sur-
`vival after starting prednisone was 12.8 months.
`The 25th and 75th percentiles for survival were 6.4
`and 21.4 months, respectively. To examine the re-
`lationship between PSA changes and survival, sur-
`vival was calculated for cohorts stratified by vari-
`ous percentages of PSA decline (Table V).
`Comparisons of survival for each cohort were then
`performed by log-rank testing. No differences in
`survival were noted for patients having a PSA de-
`cline of greater than 25% versus less than 25%. For
`patients having PSA declines of greater than 50%
`versus less than 50%, however, median survival
`differences of 17.4 versus 10.5 months (P ⫽ 0.027)
`were noted. The median survival of patients with a
`PSA decline of greater than 75% was 27.2⫹
`months; however, only 4 patients achieved this
`particular end point (making statistical analyses
`inappropriate).
`A multivariate analysis of PSA response (greater
`than 50% decline) was then performed and in-
`cluded the following independent variables: age,
`performance status, baseline hemoglobin, baseline
`alkaline phosphatase, and previous antiandrogen
`use. None of these variables predicted PSA declines
`of greater than 50% in these patients.
`A multivariate analysis of survival using Cox
`proportional hazards was performed on the follow-
`ing pretreatment
`laboratory variables: alkaline
`phosphatase (greater than 140 IU/L), hemoglobin
`(greater than 12 g/dL), PSA (greater than 100 ng/
`mL), or age (greater than 70 years). In this small
`study, none of these pretreatment variables were
`associated with survival.
`A review of prednisone-induced toxicities re-
`vealed 4 cases of proximal muscle weakness com-
`patible with steroid-induced myopathy, 1 case of
`new-onset diabetes in a man with no history of
`glucose intolerance, and 1 case of new-onset short-
`ness of breath and edema in a patient subsequently
`found to have heart failure and a left ventricular
`ejection fraction of less than 30%.
`
`254
`
`UROLOGY 52 (2), 1998
`
`

`
`TABLE V. Relationship between PSA decline and survival
`
`PSA Decline
`(%)
`
`No. of
`Patients
`
`Median Survival
`(25th to 75th Percentile)
`
`PSA ⬍25
`PSA ⬎25
`PSA ⬍50
`PSA ⬎50
`
`15
`14
`19
`10
`
`11.7 mo (5.7–17.6)
`14.8 mo (10.3–21.7)
`10.5 mo (5.9–15.9)
`17.4 mo (12.8–30.5)
`
`P Value
`
`0.131
`
`0.027
`
`KEY: PSA ⫽ prostate-specific antigen.
`P value determined by log-rank testing.
`
`TABLE VI. PSA response rates comparing 20 and 10 mg/day of
`prednisone and 30 mg/day of hydrocortisone
`
`P 20 mg/day (%)*
`
`P 10 mg/day (%)†
`
`HC 30 mg/day (%)‡
`
`25% declines
`50% declines
`75% declines
`
`14/29 (48)
`10/29 (34)
`4/29 (14)
`
`25/54 (46)
`12/54 (22)
`5/54 (9)
`
`5/22 (23)
`2/22 (9)
`0/22 (0)
`
`KEY: P ⫽ prednisone; HC ⫽ hydrocortisone.
`Note: The Tannock et al. study was uncontrolled for antiandrogen withdrawal until midway in their study; thus, their
`response rates could potentially be inflated by the inclusion of flutamide withdrawal responses. Hydrocortisone (30 mg/day)
`is the glucocorticoid equivalent of 7.5 mg/day of prednisone.
`* This study.
`† Tannock et al.11
`‡ National Cancer Institute data base.
`
`COMMENT
`
`These data clearly indicate that prednisone can
`decrease PSA levels in some patients whose initial
`hormonal therapy with medical or surgical castra-
`tion had failed. This review carefully excluded all
`patients with other known confounding variables.
`Prior hormonal therapy with an LHRH analogue or
`orchiectomy had failed in all patients. The average
`and median decline in PSA was relatively modest
`(33% and 24%, respectively); however, selected
`patients had a more robust PSA response. The av-
`erage and median progression-free survival were
`also quite modest (2.8 and 2.0 months, respec-
`tively) and consistent with previously published
`data.11 Symptomatic improvement was noted in
`most patients; however, pain management was op-
`timized during each clinic visit, and this undoubt-
`edly contributed to overall patient well-being.
`There has been only one previously published
`study of prednisone at 20 mg/day in patients with
`metastatic prostate cancer whose previous therapy
`with surgical or medical orchiectomy had failed. In
`that study, 3 of 8 patients had a decline in PSA of
`greater than 50%.14 Other details were not stated.
`These limited data are consistent with the data re-
`ported in this study.
`PSA changes induced by 30 mg of oral hydrocor-
`tisone a day (20 mg every AM, 10 mg every PM) in a
`similar group of patients with hormone-refractory
`prostate cancer (without confounding variables)
`are available from a data base established at the
`National Cancer Institute (Bethesda, Md). On an-
`alyzing PSA changes according to the same method
`
`used herein (the method of Tannock et al.11), 30
`mg/day of hydrocortisone induced PSA declines of
`at least 25% in 5 of 22 (23%) patients, at least 50%
`in 2 of 22 (9%) patients, and declines of at least
`75% in 0 of 22 (0%) patients (see Table VI).
`PSA changes after 5 mg of prednisone orally two
`times a day were published by Tannock and col-
`leagues.11 This trial did not recognize antiandro-
`gen withdrawal as a potentially active therapy until
`midway through the study; thus, response rates
`may be in part attributable to this maneuver. In the
`Tannock et al. report, a PSA decline of at least 25%
`was noted in 25 of 54 (46%) patients, a 50% or
`more decline was noted in 12 of 54 (22%) patients,
`and a 75% or more decline was noted in 5 of 54
`(9%) patients. As noted above, our method of cal-
`culating PSA changes was exactly the same as that
`used by Tannock and colleagues. A comparison of
`these data is shown in Table VI.
`A recent study evaluated the effects of 5 mg of
`prednisolone orally two times a day in patients
`with hormone-refractory prostate cancer.15 The in-
`vestigators stated that 55% of patients achieved a
`PSA decline; however, the percentage of patients
`achieving a greater than 25%, greater than 50%, or
`greater than 75% decline in PSA was not stated.
`After the first patient visit (6 weeks after treat-
`ment), patient follow-up was conducted at an in-
`terval of every 3 months. Differences in both data
`reporting and patient follow-up make these data
`difficult to compare with the other studies cited
`herein.
`Analysis of our data indicates that prednisone
`
`UROLOGY 52 (2), 1998
`
`255
`
`

`
`can decrease PSA in patients whose previous ther-
`apy of antiandrogens had failed. This suggests that
`antiandrogens and glucocorticoids are non-cross
`resistant in action, raising the possibility that the
`mechanism of glucocorticoid action in this disease
`may extend beyond adrenal suppression.
`The exact mechanism of PSA decline cannot be
`determined from these or other studies. We note,
`however, that in vitro studies in a PSA-secreting
`human prostate cancer cell line do not suggest that
`PSA secretion is directly altered by glucocorti-
`coids.19 Furthermore, our in vitro experiments
`(data not shown) detected no effects of glucocorti-
`coids on in vitro prostate cancer cell line cellular
`growth. These data suggest that the effects of glu-
`cocorticoids may be indirect, perhaps being medi-
`ated by glucocorticoid-induced inhibition of neo-
`vascularization.20 We conclude that additional
`experiments are necessary to understand the
`mechanism of glucocorticoid action in patients
`with prostate cancer.
`Our analysis of patient survival leads us to hy-
`pothesize that PSA declines of greater than 50%
`may be useful in predicting a relatively prolonged
`survival. We note that previously published inves-
`tigations have made similar conclusions when us-
`ing landmark methods of analysis.21
`Although the studies of PSA response rates with
`various glucocorticoids cannot readily be com-
`pared because of potential patient selection biases
`and other factors, note that the percentage of pa-
`tients with PSA declines is higher in patients re-
`ceiving higher doses of glucocorticoids (Table VI).
`These data suggest the possibility that a dose-re-
`sponse curve for glucocorticoids may be present in
`patients with hormone-refractory prostate cancer.
`It is also possible that differences between pred-
`nisone and hydrocortisone may contribute to the
`differences in observed outcome. We note that no
`prospective trial has ever compared various doses
`and schedules of glucocorticoids in this patient
`population. We suggest that randomized studies
`should be performed to establish the optimal dose,
`schedule, and route of glucocorticoid administra-
`tion.
`
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