`
`EFFECT OF PREDNISONE ON PROSTATE-SPECIFIC
`ANTIGEN IN PATIENTS WITH HORMONE-REFRACTORY
`PROSTATE CANCER
`
`OLIVER SARTOR, MARIBETH WEINBERGER, ANDREA MOORE, AILING Ll, 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 1 0 mg of prednisone orally two times a day. Patients were included in this
`ana lysis only if other factors known to influence PSA levels (antiartdrogen withdrawa l, radiation, and/or other
`concomitant anticancer therapies) were definitively excluded as p~tentially 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% Cl 1. 7 to 3.8) and 2.0 (range 0 to 1 ~ 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 ).
`Conclus ions. Prednisone ( 1 0 mg orally two times a day) can decrease PSt-. by more than 50% in approxi(cid:173)
`mately one third of patients with hormone-refractory progressive prostate cancer. On the basis of compar(cid:173)
`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 .
`
`G lucoconicoids have significant palliative ac(cid:173)
`
`tivity in patients with metastatic prostate can(cid:173)
`cer wh ose previous therapy with surgical or
`medical orchiectomy failed. This activity in post(cid:173)
`orchiectomy prostate cancer was initially recog(cid:173)
`ni7Prl in thP 1 QS()<; 1 "inrP th<:~t timp ""rin11<; crlll-
`..., ... . ._,._ .... . ........... . ... ,,._, ~ ~ ..... _ - ...... b .. ... ..
`.. ..__..__._ ..._,.. .
`... .......... - - ""'""' '
`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(cid:173)
`prised of a relatively heterogeneous group of pa(cid:173)
`tients .3 In fact, a significant proportion of these
`hormone-refractory patients may respond to sec-
`
`From the Departments of Uro logy and Medicine, Louisiana State
`University Medi cal Cente1·, Shreveport, Louisimta and Medicine
`Branch, Natio11al Cancer htstitute, Bethesda, .Maryland
`Reprint requests: Oliver Sartor, M. D., Stanley S. Scott Cancer
`Center, Louisiana State Untvasity Medical Center, 2025 Gravier
`SLreet, Suite 620, New Orleans, LA 70112
`Submitted: November 10. 1997, accepted (with revisions): Feb(cid:173)
`ruary 23, 1998
`
`lll L.laLUl (.. U\:..\..Q.U:)t.. VI. \..VlUUU.UU.1115 V(U. l~UI.~,-, i::JU\..lJ C4.;)
`
`ondary hormonal manipulations as measured by
`change$ in objective markers such as prostate-spe(cid:173)
`cific antigen (PSA) decline and/or tumor shrink(cid:173)
`age.3·4 The PSA changes after glucocorticoid treat(cid:173)
`ment are fTequently diflicult to interpret in the
`1 ~ .. n .... , ... .. .... n hr.~o,..,...,u .. , ,.,r ,..."._f. ... ~ .... 11Y"\,..1;V\n-,,".,.;..,.'h..lo.c- " "',....\., "lC
`radiation therapy,5 adrenal suppressive therapies,6
`suramin/ ·a or other concomitant therapies. 9 In ad(cid:173)
`dition, not all studies 10 examining PSA changes
`after glucocorticoids were initiated before re.cogni(cid:173)
`tion of antiandrogen withdrawal as a potentially
`active therapeutic maneuver. 1 1
`Since the advent of PSA testing and the recogni(cid:173)
`tion of the flutamide withdrawal as a potentially
`confounding variable, only four trials using regular
`PSA monitoring to ascertain glucocorticoids ef(cid:173)
`fects in patients with hor mone-refractory progres(cid:173)
`sive prostate cancer have been published. Two
`trials used low doses of hydrocortisone (30 to 40
`mglday) before suramin treatmentsll,l3; another
`report used prednisone at 20 mglday but included
`only 8 patients 14; a recent report used 5 mg of pred-
`
`© 1998, ELSEVIER Sci~NCE IN\.
`252 All RIGHT::. RESERVED
`
`0090-4295/98/$ 19.00
`PII 50090-4295(98)00 149-6
`
`WCK1006
`Page 1
`
`
`
`nisolone orally two times a day. L; Additional series
`using glucocorticoid therapy have been reported in
`.bstract form, but many details regarding these se(cid:173)
`ries are incomplete. 16 •17 In this report, we review
`our ex'Periences with prednisone 2.0 mgfday (10
`u1g rwo Limes a day) in patients with progressive
`prostate cancer despite medical or s urgical orchi(cid:173)
`eclOmy. No confounding variables known to effect
`?SA were present in any patient. No patients had
`concomitant treatment with radiation therapy, an(cid:173)
`tiandrogen withdrawal, or any othe:r known con(cid:173)
`founding variables such as ketoconazole, suramin,
`.aminoglutethimide, or chemotherapy. The effects
`of prednisone on PSA are emphasized because
`rhese data are limited in the peer-reviewed litera(cid:173)
`ture.
`
`MATERIAL AND METHO DS
`
`Patients were included in lhis review only if antiandrogen
`wit.hdrawal could conclusively be excluded as a confounding
`variable. No patients had concomitant ueaunent with any
`medication or modality. All patients had been previously
`ueated with surgical or medical castration (luteinizing 'hor(cid:173)
`mone-releasing hormone [LHRHI analogue) and had evi(cid:173)
`dence of a rising PSA at least lO nglmL above the previous
`nadir before initiating prednisone therapy. Tbus 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 lO mg of oral prednisone pre(cid:173)
`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 detenninations were made at baseline
`(within 1 week of starting prednisone) and ser-jall>• thereafter
`at each clinic visit. Patients were typically sc:heduled in clinic
`every 4 weeks. PSA responses were calculated ac~ording to the
`method of Tannock and coUeagues,l 1 ie, tine maximum ob(cid:173)
`served decrease from baseline.
`We note tharboth Hybritecb andAbbolt assays were used to
`determine serum PSA levels in these studie:s. Although each
`patient consistently used only one methodology, t.here 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 nglmL or more Chat was sustained
`on repeated measurements 2 or more weeks apart. We note
`that this is a more conservative criterion than t.hat 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 o[ weight Loss, pain, de(cid:173)
`creased appetite, and fatigue were routinely documented in
`the chan. Formal quality of life assessments were not per(cid:173)
`formed. Because pain management with narcotic and non(cid:173)
`narcotic medications were optimized at each clinic visit, the
`investigators believe that improvements in symptomatic end
`points may or may not be amibutecl to prednisone.
`Potential statistical differences between survival curves
`were assessed by the log-rank test or by multivariate ap(cid:173)
`proaches using a Cox proportional hazard analysis.t8
`
`TABLE I. Patient treatments before initiating
`prednisone
`
`Treatment
`Medical or surgical castration
`Prior antiandrogens
`Bicalutamide
`Flutamide
`Initial CAB
`Subsequent CAB
`External beam radiation
`Chemotherapy
`Vitamin A
`Megace
`Ketoconazole
`Prednisone
`Intravenous radiation
`
`No. of Patients
`29
`17
`
`2
`15
`6
`l I
`
`13
`3
`2
`2
`
`Ml~ CAB ~ tomblt~td androgrn blocJmde WlitJg cc combinatiml of an antiandrogr.>1
`ami mu/i(a/ or surgual castration.
`
`RESULTS
`A total of 29 consecutive patients were included
`in this analysis. A review of prior therapies admin(cid:173)
`istered w these patients (see Table l) indicated that
`all patients received prior orchiectomy or regular
`injections of an LHRH agonist. Seventeen patients
`had received prior antiandrogen therapy in addi(cid:173)
`tion to medical or surgical castration. Six of these
`patients had received antiandrogens as part of ini(cid:173)
`tial hormonal therapy; 12 patients received antian(cid:173)
`drogens after progression of disease was initially
`documented. Radiation was previously adminis(cid:173)
`tered to 12 patients. All patients completed radia(cid:173)
`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(cid:173)
`tients had been pretreated with only one p revious
`hormonal therapy (orchiectomy or LHRH ana(cid:173)
`logues), 13 patients had been treated with two hor(cid:173)
`monal therapies (antiandrogens + medical!surgi(cid:173)
`cal orchiectomy), and 4 patients had been treated
`with three or more hormonal therapies before
`prednisone. Flutamide withdrawal was not consid(cid:173)
`ered a hormonal therapy in tl1is compilation.
`Pretreatment characteristics of the patient popu(cid:173)
`lation included the following (see Table II): me(cid:173)
`dian patient age was 71 years, median Eastern Co(cid:173)
`operative Oncology Group (ECOG) performance
`status was 1, median PSA was 158 ng/mL, and me(cid:173)
`dian hemoglobin was 11.6 g/dL. Twenty-six pa(cid:173)
`tients had previously documented metastatic dis(cid:173)
`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(cid:173)
`view, and l patient had a negative bone scan.
`
`UROLOGY 52 (2), 1998
`
`253
`
`WCK1006
`Page 2
`
`
`
`TABLE IV. Progression-free survival after
`initiating prednisone
`Duration (average)
`2.8 months (95% Cl 1 .7-.>.8}
`2.0 months (range 0-11)
`Duration (median}
`Duration ~ 2 months
`20/29 (69%)
`Duration :::!:4 months
`1 0/29 (34%)
`Duration ~6 months
`4/29 ( 1 4%)
`
`krr. Cl • conjidct1u bum•al.
`
`cause pain management was optimized concomi(cid:173)
`tantly, the contributions of prednisone and/or pam
`management cannot be accurately ascertained.
`Analysis of survival revealed that the median sur(cid:173)
`vival after starting prednisone was 12.8 montl~..>.
`The 25th and 75th percenliles for survival were 6 4
`and 2l.4 months, respectively. To examine there(cid:173)
`lationship between PSA changes and survival, sul(cid:173)
`vival was calculated for cohorts stratified hy vari (cid:173)
`ous percentages of PSA decline (Table V).
`Comparisons of survival for each cohort were t.lll.n
`performed by log-rank testing. No differences i11
`survival were noted for patients having a PSA de(cid:173)
`cline of greater than 25% versus less than 25%. For
`paLient.S having PSA declines of greater than 50°~
`versus less than 50%, however, median survival
`differences of17. 4. versus 10.5 months (P = 0.02 1)
`were noted. The median survival of patients wit!-> 1
`PSA decline of greater than 75% was 27.2 +
`months; however, only 4 patients achieved th LS
`particular end point (making statistical analyse.;,
`inappropriate).
`A mullivariate analysis of PSA response (greater
`than 5
`% decline) was then performed and in
`eluded; the following independent variables: age,
`performance status, baseline hemoglobin, baseline
`alkaline phosphatase, and previous antiandroger
`use. N<bne of these variables predicted PSA decline'>
`of greater than 50% in these patients.
`A multivariate analysis of survival using Co
`proportional hazards was performed on the follow(cid:173)
`ing pretreatment laboratory variables: alkaline
`phosphatase (greater than 140 lUlL), hemoglobi .
`(greater than 12 gldL), PSA (greater than 100 ng/
`mL), or age (greater than 70 years). In this small
`study, none of these pretreatment variables we1
`associated with survival.
`A review of prednisone-induced toxicities re(cid:173)
`vealed 4 cases of proximal mu cle weakness con
`patible wiLh steroid-induced myopathy, 1 case (1f
`new-onset diabetes in a man with no history ol
`glucose intolerance, and 1 case of new-onset shor
`ness of breath and edema in a patient subsequen tlv
`found to have heart failure and a left ventricular
`ejection fraction of less than 30%.
`
`10
`
`TABLE II. Patient population in the
`prednisone study
`29
`24
`7
`71 (range 50-85)
`1 (range 0-3)
`11.6 (range 7.4-14.2)
`134 (range 57-2260)
`
`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)
`
`158 (range 13-768)
`
`Kn CT • 'omputtd tomograph)·. PSA ; pro,tatc·~pwfit anugru.
`• Accordrn~ Ia the cntcria established b) the E11stcrn Coopcmme O>tcology vrmrp
`IECOV)
`
`TABLE Ill. PSA r esponses after initiating
`prednisone
`PSA decline (average)
`33% (95% Cl 20%-46%)
`PSA decline (median)
`24% (range 0%-99%)
`~ 25% declines
`14/29 (48%)
`:::!:50% declines
`I 0/29 (34%)
`:::!: 75% declines
`4/29 ( 14%)
`
`Krr PSA - pr~Y.>tau-spccafic anngm; Cl ; confidtncr l>tlr l'\al.
`
`Twenty-six of the 29 patients had symptoms o[
`some tY1Je 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 111. The average
`PSA decline compared with baseline was 33% (95%
`confidence interval [ Cl] 20% to 46%); the median
`PSA decline was 24%. The range of PSA declines
`vatied from 0% to 99%. or 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
`paiit:.nts achieved a PSA decline of at leasi 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(cid:173)
`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 LV). The range of progres(cid:173)
`sion-free survival was 0 to 11 months. or 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(cid:173)
`proved appetite, weight gain, or pain relief. Be-
`
`254
`
`UROLOGY 52 (2).1998
`
`WCK1006
`Page 3
`
`
`
`TABLE V. ReJ'ationship between PSA decline and survival
`PSA Decline
`Median Survival
`No. of
`(25th to 75th Percentile)
`(%)
`Patients
`PSA < 25
`11.7 mo (5.7-17 .6)
`IS
`PSA > 25
`14
`14.8 mo (I 0.3-21.7)
`PSA <50
`19
`10.5 mo (5.9-15.9)
`PSA > 50
`17.4 mo ( 12.8-30.5)
`10
`1\n. P.s.A • fli051tllr·•tJCcojic ""''gt"
`P • cllu~ d<Lcrm ~t~cd by log-rank ttStmg.
`
`P Value
`0. 131
`
`0.027
`
`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 (%) t
`HC 30 mg/day (% )*
`25% declines
`1•4/29 (48)
`25/54 (46)
`5/22 (23)
`I 0/29 (34)
`12/54 (22)
`2/22 (9)
`50% declines
`75% declines
`0/22 (0)
`·4/29 ( 14)
`5/54 (9)
`Kt r: P • pt tdnlsrmc; I-IC ~ hyd!'o.rortlsonc. I
`Note: 'fill' 1'mlllucl: "l al . .>~udy wa< «IlCON II ollec/ for antiwrdrogcu withdrawal urrtil midway lu Orcu <ltuly; Ows, tlotit
`' l!.'l"'lt" •·otr< couldfiVIcntlal/y be 1injlmcd by the i11clu.sfon ofjluwmid~ withdrawn/ t't:SfiOII<e> llvrl•·oconi>ottt (30 tttw'llay)
`Is rhc glucocolllcoid cqui~ule111 oj ;1.5 mglday of prcduisout.
`<
`• Tlris m •dy.
`' Tcmnoch e1 al. ll
`' Ntllimwl Canur /tutllult dttta lnt<r.
`
`COMMENT
`
`1 hese data clearly indicate Lhat prednisone can
`d ~ rease PSA levels in some patients whose initial
`hormonal therapy with medical or surgical castra(cid:173)
`tion had failed . This review carefull y excluded all
`p:>•ients with other known confounding variables.
`Prior hormonal therapy with an LH RH analogue or
`otchiectomy had fai led in all patients. The average
`aPd median decline in PSA Was relaltively modest
`(33% and 24%, respectively); however, selected
`patients had a more robust PSA respon~e. The av(cid:173)
`en ge and median progression-free su~vival were
`also quite modest (2.8 and 2.0 months . respec(cid:173)
`li ¥ely) and consistent with previously published
`dnta. 11 SymptOmatic improvement was noted in
`most patients; howeve r, pain management was op(cid:173)
`lt nized during each clinic visit, and Lhis undoubt(cid:173)
`edly contributed to overall patienl well-being.
`f here has been on ly one previoUlsly published
`s J dy of prednisone at 20 mglday in patients with
`metastatic prostate cancer whose previous therapy
`Wtth surgical or medical orchiectomy had failed. In
`tr at study, 3 of 8 patients had a decline in PSA of
`greater than 50%.'"' Other deLails were not stated.
`1 hese limited data are consistent wilh the data re(cid:173)
`f " rted in this study.
`PSA changes ind uced by 30 mg of oral hydrocor(cid:173)
`tl~one a day (20 mg every AM, 10 mg every PM) in a
`similar group of patients with hormone-refractory
`prostate cancer (without confound ing variables)
`a:e avai lable from a data base estalblished at the
`National Cancer lnstitute (Bethesda, Md). On an(cid:173)
`alyzing PSA changes according to the: same method
`
`used herein (the method of Tannock et a/. 11) , 30
`mglday 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 Vl) .
`PSA changes after 5 mg of prednisone orally two
`limes a day were published by Tannock and col(cid:173)
`leagues.11 This trial did not recognize antiandro(cid:173)
`gen withdrawal as a potentially active therapy until
`midway through the study; thus, response rates
`may be in pan attributable Lo this maneuver. ln the
`Tannocl< 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 no1.ed in 5 of 54
`(9%) patients. As noted above, our method of cal(cid:173)
`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 Limes a day in patients
`with hormone-refraclOry prostate cancer. 15 The in(cid:173)
`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 paliem visit (6 weeks after treat(cid:173)
`ment) , patient follow-up was conducted at an in(cid:173)
`terval of every 3 months. Differences in both data
`reporting and paLient follow-up make these data
`dW1cult to compare with the other studies cited
`herein .
`Analysis of our data indicates tha t prednisone
`
`l tROLOGY 52 (2), 1998
`
`255
`
`WCK1006
`Page 4
`
`
`
`can decrease PSA in patients whose previous ther(cid:173)
`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, rhat in vitro studies in a PSA-secreting
`human prostate cancer cell line do not suggest that
`PSA secretion is directly altered by glucoconi(cid:173)
`coids.19 Furthermore, our in vitro experiments
`(data not shown) detected no effects o( glucocorti(cid:173)
`coids on in vitro prostate cancer cell line cellular
`growth. These data suggest that the effects of glu(cid:173)
`cocorticoids may be indirect, perhaps being medi(cid:173)
`ated by glucocorticoid-induced inhibition of neo(cid:173)
`vascularization.10 We conclude that additional
`experiments are necessary to understand the
`mechanism of glucocorticoid action in patients
`with prostate cancer.
`Our analysis of patiem survival leads us to hy(cid:173)
`pothesize that PSA declines of greater than 50%
`may be useful in predicting a relatively prolonged
`survival. We note that previously published inves(cid:173)
`tigations have made similar conclusions when us(cid:173)
`ing landmark methods of analysis.21
`Although the studies of PSA response rates with
`various glucocorticoids caru1ot reaclily be com(cid:173)
`pared because of potential patient selection biases
`and other factors, note that the percentage or pa(cid:173)
`tients with PSA declines is higher in patients re(cid:173)
`ceiving higher doses of glucocorticoids (Table Vl).
`These data suggest the possibility that a dose-re(cid:173)
`sponse curve for glucocorticoids may be present in
`patients with hormone-refractory prostate cancer.
`It is also possible that differences between pred(cid:173)
`nisone and hydrocortisone may contribute to the
`differences in observed outcome. We note that no
`prospective trial has ever compared various doses
`and schPrlules of glucocorticoirl<> L11 this patient
`population. We suggest that randomized studies
`should be performed to establish the optimal dose,
`schedule, and route of glucocorticoid administra(cid:173)
`tion.
`
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