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`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`REVIEW ARTICLE
`
`Second-Line Hormonal Therapy for Advanced Prostate
`Cancer: A Shifting Paradigm
`
`By Eric J. Small and Nicholas J. Vogelzang
`
`Purpose: To discuss the evolution of new concepts in
`the use of second-line hormonal therapy for patients with
`progressive prostate cancer despite androgen depriva-
`tion.
`Design: Pertinent contemporary prostate-specific an-
`tigen [PSAl-bosed reports of the utility of secondary hor-
`monal maneuvers after treatment with combined andro-
`gen blockade {CAB} were reviewed.
`Results: The use of PSA as an end point in hormone-
`relractory prostate cancer [HRPC] trials is more widerr
`accepted, but still remains somewhat controversial. Us-
`ing PSA as an end point, it is clear that a variety of sec-
`ondary hormonal maneuvers can result in responses.
`Antiandrogen withdrawal
`is efiicocious in approxi-
`materr 20% of patients and can be observed with a vari-
`ety of antiandrogens, including llutamide, hicolutamide,
`and megestrol acetate. A variety of regimens, including
`
`megestrol, bicalutarnide, giucocorticoids, aminoglutethi-
`mide, and ketacanozole, retain activity “4% to 75% PSA
`response proportion] even in patients who have failed
`to respond to CAB and flutamide withdrawal.
`Canciust'on: Once CAB [suppression of gonadal and
`adrenal androgenl is undertaken, further hormonal ma-
`neuvers remain efficacious in some patients with pro-
`gressive prostate cancer. Antiandrogen withdrawal is
`now a mandatory maneuver before proceeding to other
`regimens. It is clear that certain patients will continue to
`respond to hormonal maneuvers even after antiondro-
`gen withdrawal. An understanding of the molecular ba-
`sis of these responses may result in the development of
`a more targeted therapy in the future.
`J Clin Oncol‘ 15:382-388. {t3
`i997 by American So»
`ciety of Clinicat‘ Oncology.
`
`DEF-ABIRA-0000321
`
`ROSTATE CANCER is the most common malig—
`nancy in men. and in l996, will account For more
`than 41.000 deaths in the United States.' Unfortunately,
`no hormonal therapy is capable of producing durable rc—
`sponscs in any but a slnall minority of patients with inclu—
`static prostate cancer. The median duration of response
`to androgen dcpt'ivatitm is approximately 18 months.2 The
`development ol'antiandrogcns such as liutaniitlc and bica-
`ltttainitic for use in combination with gonadal androgen)
`ablation (combined androgen blockade [CARD appears
`to have improved survival in some patients.-U However.
`all advanced prostate cancer patients treated with andro—
`gen deprivation eventually develop progressive hormone-
`insensitive disease, as evidenced by increasing prostate—
`specilic antigen {PSA} levels. progressive disease on
`imaging studies. or progression) of symptoms, usually
`pain. Virtually all prostate cancer fatalities are due to
`the development of honnone-rcl'ractory prostate cancer
`
`(HRPC). The approach to advanced prostate cancer pa—
`ticnts who have failed to respond to therapy with andro-
`gen deprivation has undergone a significant and funda—
`mental transfonnation over the last 2 to 3 years and is
`the subject of this report. This changing paradigm is in
`part a consequence of the development of novel therapeu-
`tic interventions for this group of patients. but is in no
`small part also due to the redefinition of HRPC.
`
`END POINTS IN ADVANCED PROSTATE CANCER
`TRIALS
`
`An evolution in the understanding of the end points
`that are used to describe the effect of treatment of HRPC
`
`patients has contributed in part to the development of this
`new paradigm. Several reviews have commented on the
`difficulty in drawing conclusions from the literature re-
`garding the most appropriate therapies for hormone—resis—
`lant prostate cancer because of the differing criteria for
`study inclusion and response assessment.5"' The earliest
`clinical trials for advanced prostate cancer reported objec—
`live or subjective responses. although criteria for qualiti-
`fication of these results were not specified. Subsequently.
`the National Prostate Cancer Project (N PCP) established
`rigid response criteria. Since most patients who entered
`these trials had clinically progressive disease. stabiliza-
`lion of disease. presumably as a consequence of therapy.
`was considered an objective response. However,
`these
`criteria have been roundly criticized. and most investiga—
`tors today do not use either the stable disease category or
`the NPCP criteria.” Some investigators have advocath
`
`
`
`i-‘t'ttm the Dr’pttt'tttirirt of r'rirriic'ittt‘. and tile Urviogt'c' ()ttc‘niogt
`Program.
`t_.-"trircr.\'it_\' of California. Sun Fritttt't'n'tro. and Mt Zion
`(‘ttnt-trr (Tourer. San Ft'turr'fs't'tt. CA: and Dt’fli’tt’t‘tttt‘tti tat-tidcdt't'itrc.
`l.-"tli1‘c‘t'.tt't_\' tel-(‘itit'ttgrz Chicago. FL.
`.S'rttattiitteti March 6, i990: art-rpm! .tmttr tF. N915.
`Address reprint requests to Eric J. Stimti. MD, Umtogt't‘ Uni-otngr
`Program. University of C'ntt'fitmia. Sat: Francisco/iii: Zion Caricer
`(hirer. 2356 Stttter St. 5th Hoar. .S'tm Francisco. CA Witfi: Ettmii
`r’t'it'_ttttttii({-'-‘ Qi."i(fiKM/l it“ {.-'(-'.§'i".tttitt.
`-'s;- NU? in American Strrt'rflr (git-titrin Gaming):
`0.7.43- ltlj'_1’.\’t")7ft5t’tt-UUBIEii‘JNth
`
`382
`
`Journal of Clinicoi Oncoiogy, Vol 15, No l {January}, I997: pp 382-388
`
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`
`
`SECOND-UNE HORMONES lN PROSTATE CANCER
`
`383
`
`inclusion in clinical trials only of patients with measur-
`able disease as a means to dctertnine true response propor—
`tions. However.
`this is an impractical approach, since
`80% to 90% of patients with HR PC do not have measurn
`able disease. There is also disagreement as to whether
`patients with bidiniensionally measurable disease repre—
`sent a subset of patients with a worse prognosis?
`More recently. a decline in PSA level has been advo—
`cated as an intermediate marker of response. and a surro—
`gate marker for survival in patients with I—lRl’C.“-‘J While
`it seems clear that a greater than 50% [or in some series.
`75%) decrease in PSA level appears to define a group of
`patients with improved survival. controversy remains as
`to the validity of decreased PSA as a surrogate marker
`of response or survival in patients treated with suramin."'
`Prospective validation ofthe percentdecline in PSA level,
`as well as duration of PSA decline. as a variable predictive
`of outcome (ie. survival) is warranted. Furthermore.
`it
`should be noted that novel therapeutic agents. cg,
`im~
`mune-modulating or differentiating agents. and possibly
`even surainin. cannot be assumed to have a similar impact
`on PSA as more conventional cytotoxic agents.
`Despite growing sophistication with the use of PSA as
`a predictive outcome variable.
`in one sense. we have
`come a full circle in assessing responses to therapy for
`advanced prostate cancer. in that patient-derived tie. sub-
`jective) measures of clinical benelit have been recognized
`as reasonable (and in fact. critically important) end points.
`For example. a recent report that compared prednisone
`alone versus prednisone plus mitoxantrone failed to dem—
`onstrate a survival advantage for the chemotherapy arm,
`but demonstrated a dramatic improvement in quality of
`life (QOLl when mitoxantronc was included.” It is clear
`that future evaluations of therapy for HRPC must. in some
`fashion. measure changes in quality of life or pain.
`in
`addition to more conventional measures of response.
`However. the utility of many of these measures may be
`limited by the fact that an increasing reliance on PSA—
`defined disease progression has resulted in the treatment
`of more and more asymptomatic HRPC patients in whom
`no discernible changes in QOL would be anticipated.
`
`THE OLD PARADIGM
`
`An understanding of the adrenal contribution to the
`total testosterone pool.2 coupled with the observation that
`clinical responses occur in men with relapsed prostatic
`carcinoma after castration when an antiandrogen is
`added,'2 have suggested that adrenal androgens provide
`continued stimulus to target cells still responsive to andro—
`gens. This hypothesis prompted several randomized trials
`in the late l980s that compared CAB (the addition of an
`
`antiandrogen to the interruption of testicular androgen
`production) versus testicular androgen deprivation aloltt-3.'l
`The largest reported series to date is the National Cancer
`lnstittltc llttergt’oup study. which was initiated in |985.1
`This was a double-blind. placebo—controlled trial in which
`603 patients with stage D2 prostate carcinoma were ratt—
`domizcd to receive leuprolide acetate alone versus leu-
`prolide acetate plus flutatnide. Titne to progression (16.5
`months tr 13.9 months), as well as overall survival (35.6
`months it 28.3 months). was superior in the combination
`therapy arm. Of interest. the superiority ot'combined ther-
`apy over leuprolide alone was most apparent in patients
`who had been prospectively stratified into a good—perfor—
`mancet’minitnal—disease category. These patients experi—
`enced a greater than 20-month survival advantage when
`treated with combined therapy. An important point to be
`made about this trial is that it was. by design. a crossover
`trial that allowed patients with progressive disease who
`had been on the placebo arm to then add flutantide to
`their regimen. In essence. this trial showed that immediate
`CAB was preferable to the delayed addition of an antian—
`drogen on progression.
`While several other randomized trials have also shown
`
`a survival advantage to CAB. enthusiasm for this ap—
`proach has been tempered by the fact that several smaller.
`yet moderately sized trials.
`well as a meta—analysis,
`have failed to show an advantage to this approach.4
`Whether individual physicians are convinced of the utility
`of initial CAB. it is fair to say that either initial CAB or
`the late addition of an antiandrogen after progression after
`gonadal androgen ablationu'” has become the standard
`of care in the United States for patients with advanced
`prostate cancer.
`Until recently. second—line hormonal therapy For HRPC
`had been used in the setting of an attempt to suppress
`adrenal androgen production in a patient who had not
`yet undergone total androgen blockade tic, delayed total
`androgen blockade). This approach was based on the be—
`lief that the development ot‘ progressive disease reflected
`the capacity of certain clones of cells to grow in the
`presence of only minute concentrations of androgens. and
`that disease regression could be achieved by targeting
`previously untreated sources of androgenic stimulation.
`This was accomplished with ketoconazole. atninogluteth—
`imide. or antiandrogens. such as megestrol acetate. flu-
`tamide. or bicalutamide. Ketoconazole and aminogluteth—
`imide block steroidogenesis by inhibiting the conversion
`of cholesterol to pregnenolone. Thus. they are potent in—
`hibitors of adrenal steroid production. including adrenal
`androgens, and replacement (loses of hydroeortisone are
`required. Overall. objective partial responses have been
`
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`384
`
`SMALL AND VOGELZANG
`
`reported in 9% (aminogiutethimidel and I6% lketocona—
`role} of patients. with stable disease (NPCP criteria) in
`23% and 30%. respectively.H The role of patient selection
`in virtually all of these trials cannot be overstated: most
`were conducted bel‘ore an understanding of the role of
`CAB. and virtually all of these patients had not undergone
`prior adrenal androgen deprivation.
`Similarly.
`r'negestt'ol aeetate (Megace. Bristol-Myers
`Squibb Company. Princeton. NJ) appears to have activity
`in HRPC by inhibiting release of luteinizing hormone
`(Ll-I). blockade of the androgen receptor. anti inhibition
`of 5—r.r-I'eductase_ Some investigators suggest that it may
`be cytotoxic at high doses. Response proportions of ap-
`proximately 4{]% have been reported. but again.
`these
`reports have all predated the more widespread use of
`CAB.” Other hormonal maneuvers that have been re
`
`ported to hav‘ antiturnor activity in HRPC patients not
`yet treated with CAB include glueocorticoids. high-dose
`
`estrogens. and antiestrogcns High~dose estrogens sup—
`press pituitary gonadotrophins. compete for the androgen
`receptor. and may have a direct cytotoxic et'l'ect.
`Glucocorticoids restrlt
`in a medical adt'enaleetomy.
`with resulting decreased adrenal androgen production. A
`recent review of pttblished clinical trials of patients who
`had progressed after primary honnone treatment. and
`whose subsequent treatment included glucoeortieoids, re—
`ported a wide range of response proportions (0% to 66%).
`Of 19 trials reviewed. live included fiutamide as one of
`
`the prior hormone therapies, but only one prospectively
`controlled for the potential contribution of llutaniide with—
`drawa]."< The diversity of response and entry criteria
`makes it
`impossible to draw generic conclusions about
`the tttility of corticosteroids for the treatment of HRPC.
`
`While both objective and symptomatic improvements can
`be. achieved with these approaches. their efficacy in pa—
`tients who have already been treated with an antiandrogen
`is not known.
`
`The interest generated by recent reports of a new gener—
`ation of agents for the treatment of HRPC.
`including
`sur‘antinmw and estramnstine—based regimensfun re—
`sulted in the recommendation that second-line hormonal
`
`therapy be reserved for patients who were not eligible for
`or declined therapy with investigational agents”?! These
`recommendations have been bolstered by the perception
`held by some investigators that secondary hormonal mas
`ncuvers. particularly those aimed at adrenal androgen
`deprivation. While of utility in patients who were being
`treated only with gonadal androgen deprivation, were un—
`likely to be efficacious for patients already on CAB.
`
`THE NEW PARADIGM
`
`The recommendations described are being reevaluated
`as it becomes clear that HRPC is a heterogeneous disease.
`with varying degrees of retained hormonal sensitivity.
`The sentinel report that resulted in a fundamental restruc—
`turing or the way in which HRPC is conceptualized was
`published by Kelley et at“ in I993. A follow—up study
`of this report and two subsequent confirmatory studies
`have described the benclits ol‘ the discontinuation of flu—
`
`tamide in patients whose metastatic prostate cancer had
`become hor'ntone—refractoryyk’ This syndrome has been
`termed the “antiartdrogen withdrawal syndrome.” These
`reports included a total of I39 patients (Table I]. Overall.
`approximately 209:.- of patients with progressive (hor—
`mone—re fractory) prostate cancer treated with CAB had a
`significant decrease in serum PSA level when fiutarnidc
`
`Va riohle
`
`
`Table 1. Summary Data of Antiundragen Withdrawal
`First Author
` Scher)‘ Figgz" Smoll“ Total
`
`
`
`36
`2t
`32
`139
`Total no. oi: patients
`63
`66 {mean}
`71
`70.]
`Median age [years]
`103
`N5
`116
`N/A
`Median stort PSA [ng/rnL]
`25 [69%]
`NS
`57 trees]
`8'2
`Prior concomitant ilutomide therapy
`rt [31%;
`NS
`25 lacs}
`35
`Prior nonconcomilant ilutomide therapy
`10/35 :2933}
`rm {33%}
`12/82 [15%;
`rows tats.)
`Overall PSA response proportion
`5
`3.7+
`3.5
`N/A
`Median duration oi responses [months]
`was 140%}
`NS
`8X5? [14%]
`13/32 [22‘s]
`Response proportion in patients with prior concomitant Huton‘tide therapy
`0/11 test
`NS
`4/25ll6%]
`4/36 ttt'sr
`Response proportion in patients with prior nonconcomitont llulomicle therapy
`13
`23.3
`2t
`N/A
`Median duration oi: prior Huton‘tide therapy in responders [months]
`
` la? 1213 N/A
`
`
`Median durotion oi prior Flutomide therapy in nonrespondcrs {months}
`NOTE. Concomitant ilutctmide is defined as the simultaneous use oi on LHRH ogonisl or orchiectomy along with Hutomide [CAB]. Noneoncomiml'”
`liutomide Iheropy is defined as rnonotl'leropyr with on LHRH ogonist or orchieclomy with the late addition at ilulomide at progression, or as monotholopy
`with flutomide with or without the Inter addition oi [HRH ogonist or orchiectomy.
`Abbreviations: N/A, aggregate median data could not be determined irom available eloto; NS, not speciiied.
`
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`

`SECOND-LINE HORMONES IN PROSTATE CANCER
`
`385
`
`was discontinued. and some of the patients experienced a
`cl tar symptomatic or objective improvement. The median
`duration of PSA decline in these studies ranged from 3.5
`to 5 months. Since the initial report of this syndrome. it
`has become clear that it can be observed in a wide variety
`of patients. including those initially treated with CAB. as
`well as patients initially treated with an LH—releasin‘l:I
`hormone (LHRHJ agonist or orchiectomy alone. in whom
`flutamide was added later}5 The benefits of discontinua-
`lion ol‘ an antiandrogen have also been observed in pa—
`tients treated with antiandrogens other than t‘lutamide.
`including bicalutamide (:Casodex. checa Pharmaceuli~
`cals. Wilmington, DE)” and niegestro] acetate (Meg—
`aeeid“ The observed response to megestrol withdrawal
`may provide an explanation for the exacerbation of syrup—
`toriis reported in some trials of this agent. In a blinded.
`randomized trial ofan Ll-IRl-l analog plus either i'lutamide
`or bicalutamide, a small subset of patients was available
`for evaluation of blinded antiandrogen withdrawal. In 14
`patients on bicalutarl'lide. the PSA response proportion to
`antiandrogen withdrawal appeared to be the same as that
`seen for eight patients on fltltamide (29% 160%}. interest-
`ingly. the tilne to PSA decline after antiandrogen with—
`drawal appears to be shorter with fltttamidc than with
`bicalutamide. perhaps reflecting the longer hall-life ob-
`served with bicalutamide (1 week 1‘ 5.2 hours}?
`It has recently been shown that
`the steroid-binding
`domain of the androgen receptor is mutated in sortie pa-
`tients with HRPC.”J Functional studies indicate that rather
`
`than being inhibited. these mutant receptors can be stimu—
`lated by some antiandrogens. The relationship between
`these androgen receptor mutations and the antiandrogen
`withdrawal syndrome is under study. While the mecha-
`nisms involved are not understood. nor is it clear if the
`
`fluctuation of PSA levels is always clinically signifi ‘ant,
`these observations mandate a trial of antiandrogen with-
`drawal before therapy for HRPC‘ is initiated. Furthermore,
`the impact of the eftect ot' antiandrogen withdrawal on
`previously reported results from trials for the therapy of
`HRPC must also be evaluated.
`
`The unexpected antitumor activity manifested by the
`withdrawal of antiandt'ogens has prompted a reexamina—
`tion of the previously held belief that other hormonal
`maneuvers undertaken after CAB are not likely to be of
`utility.
`It
`is now apparent that there exists tremendous
`heterogeneity in the HRPC patient population, and that
`some patients previously labeled as resistant to hormones
`may in fact retain a certain degree of hDITI‘IOt‘ltll sensitivity.IS
`While the use of additional hormonal manipulations in
`the treatment of a cancer that has been termed hormonally
`refractory appears paradoxical. a variety of secondary
`
`manipulations of the hormonal milieu have been reported
`to result in PSA decline. and in some cases. objectiv -‘ and
`symptomatic responses. Subsequent hormonal maneuvers
`after anliandrogen withdrawal fall under two categories:
`(I) the Lise of a second antiandrogen. and (2) adrenal
`androgen ablation.
`The use of a second antiandrogen is predicated on the
`possibility that despite their ftlrtctional similarities. dil'l'er-
`cnt antiandrogens interact differently with the androgen
`receptor. There is evidence.
`for example,
`that
`in the
`LNC‘aP cell line. llutamide acts as a par1ia| agonist (and
`not an inhibitor). whereas bictllutamide maintains an in—
`
`hibitory functions“ Liebertz. et a!” have evaluated the
`impact of high—dose biealtttainide (200 mgi'dl in patients
`who had previously undergone ilutamide withdrawal. and
`have reported in preliminary fashion that PSA responses
`are seen in patients previously on flulamide, whether or
`not they had a response to ll utamide withdrawal. A second
`study reported a PSA response in four of 10 androgen-
`independent patients treated with 150 maid of bicaltrtarn—
`ide. although the number ol‘ patients previously treated
`with flutamide and fitttumide withdrawal was not speci—
`lied?" The converse situation.
`ie.
`the use of llutamide
`in patients who failed to respond to con\-'entional-Llose
`biealutamide. has not yet been reported.
`The Cancer and Leukemia Group B (CALGB) has re—
`ported a randomized trial of low—dose versus high-dose
`mcgestrol acetate in HRPC patients.“ Data on antiandro—
`gen withdrawal before megestrol administration was
`available on I I9 of I49 patients. The objective response
`proportion to tnegestrol was low (4 2%), but PSA re—
`sponses occurred in l4‘i’c- of patients. There was no clear
`association between prior response to ilutantide with—
`drawal and subsequent response to megestrol (P = .23.
`Fisher‘s exact test}. although this study was not designed
`with sufficient power to assess adequately this question.
`The overall median survival was comparable to that of
`historical controls. and there was a trend toward improved
`survival in patients who experienced a PSA response to
`megestrol “7.4 months 1'
`l2.? months; P = .61,
`log—
`rarrk test.) These data suggest that second—line megestrol
`acetate has modest. but clear activity in advanced prostate
`cancer patients previously treated with CAB.
`It
`is assumed that a certain proportion of androgen
`receptors expressed in tumor specimens from prostate
`cancer patients who have had progressive disease despite
`CAB will have a mutant phenotype. For these receptors,
`an antiandrogen may act as a partial agonisl. and anlian—
`drogea withdrawal would be predicted to result
`in an
`improvement in PSA and possibly a reduction in tumor
`burden. However. it appears likely that either these mu—
`
`DEF-ABIRA-0000324
`
`MYLAN PHARMS. INC. EXHIBIT 1112 PAGE 6
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`DEF-ABIRA-0000324
`
`MYLAN PHARMS. INC. EXHIBIT 1112 PAGE 6
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`

`

`386
`
`SMALL AND VOGELZANG
`
`tant receptors retain sensitivity to androgens, or there
`remains a population of wild-type androgen receptors that
`retain sensitivity to androgenic stimulation. so that sup—
`pression of adrenal androgens in these patients might re—
`sult
`in a clinical benefit. Adrenal androgen suppression
`can be achieved by aminoglulethimide, ketoconazole. and
`perhaps glucocorticoids. While many previous reports
`have detailed the use of these agents. their use during
`or after antiandrogen withdrawal has only been recently
`reported. The first report to evaluate the utility of adrenal
`androgen suppression at the time of tlutarnide withdrawal
`undertook adrenal androgen deprivation with aminoglu-
`tethimide and ltydrocot‘tisonc. and reported a PSA rev
`sponsc proportion of 48%..35 considerably higher than that
`reported for [lutarnide withdrawal alone. Other investiga-
`tors have examined the role of liutantide withdrawal in
`
`prostate cancer patients. some of whom were already re—
`ceiving attrinoglutethirnide and hydrocortisone. and have
`reported a PSA response proportion ol‘ 80%.""
`More recently. a second inhibitor of adrenal steroido-
`genesis. ketocorrazole. has been trsed in patients who had
`progressive disease after flutamide withdrawal." Fifty
`consecutive prostate cancer patients with documented
`progressive prostate cancer after
`liutaniide withdrawal
`were treated with ketoconazole and hydrocortisone. A
`surprisingly high PSA response proportion of 62.59?- was
`reported. The median duration of PSA decline was 3.5
`months. These data suggest that evetr in the face of dis—
`ease progression or antiandrogen withdrawal. certain hor-
`monenrefractory patients retain hormonal sensitivity.
`The efficacy of corticosteroids in the treatment of ad-
`vanced prostate cancer has long been appreciated and was
`recently reviewed.” The exact rnechanistnts} of action
`are not fully known. but almost certainly there is an anti-
`inflanrmatory effect. as evidenced by the capacity ofcorti—
`coster'oids to palliate pain front bone metastascs. How—
`ever.
`a second mechanism of action that has been
`
`proposed has been a reflex inhibition of adretral steroido—
`genesis. which also affects adrenal androgen production.
`There are numerous reports on the efficacy of corticoste-
`roids, but one of the first reports to describe QOL benefits
`of corticosteroids as second—line therapy in patients with
`advanced prostate cancer was reported 111
`|989 by Tan-
`trock et all“ Among 39 HRPC patients treated with a
`median of two prior endocrine maneuvers. 37 were treated
`with low—dose prednisone (7.5 to 10 mgfd). This report
`predated the wide use of anliandrogens. and was under—
`taken morc than 4 years before the appreciation of the
`antiarrdrogen withdrawal phenomenon. Nonetheless. 38%
`of patients were found to have an improved QOL at
`]
`trronth. and 19% tnaintaincd their improved QOL for a
`
`median of 4 months. with a range of 3 to 30 months.
`Adrenal androgens were measured and found to be sup-
`pressed. These data were the basis of a more recent ran—
`domized trial that compare prednisone alone versus pred-
`nisone plus tnitoxantrone in patients with HRPC. In this
`trial. while survival was not different in the two treatment
`arms. the addition of miloxantrone appeared to confer a
`QOL advantage. Of note. when prednisone alone was
`used. a greater than 50% decrease in PSA level was ob—
`served in 22% of patietrts.‘l
`Other investigators have evaluated the eflicacy of gluco~
`conjcoid administration while controlling for the possible
`contribution of flutamide withdrawal. Kelley et al'” reported
`30 such patients who were treated with 40 mg of hydrocorti—
`sone daily. {Twenty—two had undergone prior flutamide
`withdrawal. while eight never received tlutarnide.) A 20%
`PSA response proportion was observed. with a median re—
`sponse duration