International Journal of Urology (2001) 8, 290–294
`
`Original Article
`
`Treatment of androgen-independent prostate cancer
`with dexamethasone: A prospective study in
`stage D2 patients
`
`Abstract
`
`TAKASHI SAIKA,1 NOBUYUKI KUSAKA,1 TOMOYASU TSUSHIMA,1
`TOYOKO YAMATO,2 TERUHISA OHASHI,3 BUNZO SUYAMA,4 RYOJI ARATA,1
`YASUTOMO NASU,1 HIROMI KUMON1 AND OKAYAMA UROLOGICAL CANCER
`COLLABORATING GROUP (OUCCG)
`Departments of Urology, 1Okayama University Medical School, 2Okayama City Hospital and
`3Okayama Red-Cross Hospital, Okayama and 4Mitoyo General Hospital, Toyohama, Japan
`
`Purpose: In order to evaluate the efficacy of dexamethasone in the treatment of Japanese men with
`androgen-independent prostate cancer, a prospective study was conducted using prostate-specific
`antigen (PSA) as a primary end-point.
`Methods: Nineteen Japanese men with stage D2 androgen-independent prostate cancer were regis-
`tered and treatment was started. After ruling out anti-androgen withdrawal syndrome, they were
`treated with dexamethasone (1.5 mg daily). Patients were monitored for PSA, symptoms, radiologic
`response, survival rate, time to disease progression, time to treatment failure and complications.
`Results: Prostate-specific antigen levels decreased in nine patients (50.0%); five (27.8%) showed
`a 50% or greater decrease and two (11.1%) showed an 80% or greater decrease. For the nine
`patients, the mean duration of PSA response was 7.3 months and the median duration was 2.1
`months (range, 1.2–27.5+). Bone pain, which was noted in 13 patients at study entry, improved in
`seven patients (53.8%). Of nine patients who had serial radiographic examinations with bone scan,
`three (33%) showed partial response, two (22%) were stable and four (44%) showed disease pro-
`gression. Treatment was well tolerated, except for one patient who suffered a severe pulmonary
`infection.
`Conclusion: Dexamethasone decreased PSA levels and produced subjective symptomatic improve-
`ment in the patients with stage D2 androgen-independent prostate cancer.
`
`Key words
`
`androgen-independent prostate cancer, dexamethasone.
`
`Introduction
`
`treatment for advanced prostate
`Initial hormonal
`cancer has a beneficial effect in the majority of
`patients. However, many patients eventually progress
`to androgen-independent disease. Once the cancer
`becomes androgen-independent, further systemic treat-
`ments achieve only modest benefits. It is not clear
`
`Correspondence: Takashi Saika MD PhD, Okayama
`University Medical School, 2-5-1 Shikatacho, Okayama,
`Japan. Email: takasaika@aol.com
`Received 18 April 2000; revision 28 July 2000; accepted
`22 December 2000.
`
`whether chemotherapy for such patients has an impact
`on the survival rate or palliation of symptoms.
`Corticosteroids may act through a variety of ways in
`patients with prostate cancer. Recently, the use of cor-
`ticosteroids has been regarded as a treatment option
`which is minimally toxic, low cost and which demon-
`strates mild anticancer activity1,2 and which has an
`apparent beneficial effect on quality of life.3 Several
`studies have reported the use of corticosteroids alone
`as a second-line therapy following failure of primary
`hormonal therapy. Nishiyama and Terunuma recom-
`mended that patients whose disease continued to
`progress after discontinuation of oral hormonal agents
`should be treated with corticosteroids.4 As a decline in
`
`Amerigen Exhibit 1121
`Amerigen v. Janssen IPR2016-00286
`
`

`
`PSA from baseline is related to survival in patients
`with androgen-independent prostate cancer,5
`in this
`trial we examined the effect of dexamethasone on PSA
`as a primary end-point of response for the patients
`with androgen-independent stage D2 prostate cancer.
`
`Methods
`
`Patients were eligible for this study if they had
`metastatic prostate cancer (stage D2) and had under-
`gone no less than one prior anti-androgen treatment
`but had subsequent disease progression or disease
`exacerbation. Patients were required to have adequate
`hepatic and renal function; however, those with dia-
`betes mellitus or active infectious disease were not
`eligible. Performance status had to be 0–3, and the
`patient’s expected survival should have been over 3
`months. Before entry into the trial, it was necessary
`that the patient’s serum testosterone levels be less than
`1 ng/mL to confirm repression of testicular androgen;
`also required was subsequent documented disease
`progression more than 4 weeks after stopping anti-
`androgen administration to rule out anti-androgen
`withdrawal syndrome. Continued use of luteinizing-
`hormone releasing hormone (LHRH) agonist was
`required for those who had not undergone orchiectomy.
`Dexamethasone was administered orally at a dose of
`1.5 mg per day. The treatment was conducted for at
`least 12 weeks and continued unless disease progres-
`sion or severe complications occurred.
`From June 1997 to May 1999, 19 patients were
`registered for this clinical study. Patients ranged from
`46 to 82 (median 72) years of age at study entry.
`Histologically, adenocarcinoma was initially diagnosed
`as well differentiated in two patients, moderately dif-
`ferentiated in eight and poorly differentiated in nine.
`The median duration from the initiation of first-line
`hormonal therapies to the study entry was 24.5 months
`(range, 6.3–96.3 months). Prior hormonal therapies
`were surgical castration in five patients, medical cas-
`tration in 14, flutamide in 12, chloromadinone acetate
`in seven, and DES-P in 14. Other prior therapies, such
`as chemotherapy or radiation therapy, were estramus-
`tine in 17, intravenous chemotherapy in five, orally
`administered chemotherapy using VP-16 or fluoro-
`uracil in seven, and external beam radiation in five. All
`patients had bone lesions detected on radionuclide
`bone scans and elevated serum PSA (median 219.9,
`range 26.0–3503.0). Thirteen cases had bone pain that
`required some analgesic before the treatment. No other
`subjective complaints, such as loss of appetite or diffi-
`culty of urination, were recognized.
`
`Treatment of prostate cancer with dexamethasone 291
`
`Prostate-specific antigen levels, as a primary end-
`point, were used to determine response to the therapy.
`Serum PSA levels were measured every 4 weeks and
`judged PSA response at 12 weeks after the initiation of
`the therapy or at the best response. The rates of PSA
`decline from baseline were classified into four groups:
`over 80%, from 50% to 80%, declined but under 50%
`and no decline. Disease progression was also defined
`as a continuous elevation of PSA in at least three con-
`secutive measurements separated by more than 2 weeks
`each. In addition to the PSA end-point, radiographic
`findings and subjective symptoms, especially pain,
`were evaluated. Bone scan was performed at 12 weeks
`after the initiation of the therapy if possible. The
`patients were evaluated every 2 weeks for subjective
`symptoms: for pain with the necessity, kinds and vol-
`ume of pain-relief drugs; for urinary voiding disorders
`with the International Prostate Symptom Score; and
`for other complaints with question and answer. Formal
`quality of life assessments were not performed. We
`regarded improvement in symptoms as attributable to
`dexamethasone in this study. The evaluation of compli-
`cations was done by routine clinical examination,
`physical findings and blood and urine examination.
`All patients consented to treatment after being
`informed about their condition, disease status, the
`treatment schedule, side-effects and expectation of
`treatment results.
`Statistical analysis of survival curves was performed
`using the log–rank test.
`
`Results
`
`All patients were treated with dexamethasone for at
`least 12 weeks but one patient could not continue
`because of an infected decubitus and was excluded
`from the evaluation. Seventeen (89.5%) of the patients
`could be treated with dexamethasone in an outpatient
`clinic. Only two cases were treated in hospital in order
`to receive other medications for their cancer pain.
`Median duration of treatment was 6.2 months (range,
`0.9–21.0+ months).
`Of the evaluable 18 patients, a decline in PSA was
`recognized in nine (50%). The range of decline in PSA
`varied from 0% to 98.2%. Of the nine patients, five
`achieved at least 50% and two achieved at least 80%
`lower PSA than their prestudy baseline. In analyzing
`the PSA-response duration of the responders, progres-
`sion was defined as a re-elevation of the PSA; median
`duration was 2.1 months and mean duration was 7.3
`months (range, 1.2–27.5+ months). Patient characteris-
`tics and the PSA results are shown in Table 1. Of the
`
`

`
`292 T Saika et al.
`
`Table 1 Patients characteristics and the results of PSA
`
`Case
`
`Age
`(years)
`
`Histology*
`(differentiation)
`
`Castration
`
`Prior
`hormone
`therapy
`
`Chemotherapy/
`radiation therapy
`
`PSA
`decline
`rate (%)
`
`Response
`duration
`(months)
`
`Survival
`duration
`(months)
`
`Survival
`outcome
`
`1
`2
`
`3
`
`4
`5
`
`6
`
`7
`
`8
`
`9
`
`46
`64
`
`70
`
`72
`82
`
`79
`
`76
`
`70
`
`82
`
`Poor
`Well
`
`Moderately
`
`Poor
`Poor
`
`Poor
`
`Moderately
`
`Surgical
`
`Medical
`
`Poor
`
`Poor
`
`EPM, VP-16
`EPM, UFT
`
`EPM
`
`EPM
`EPM, XRT
`
`21.0
`73.7
`
`73.3
`
`25.8
`Increase
`
`EPM, VP-16, XRT Increase
`
`Increase
`
`Increase
`
`35.8
`
`1.3
`3.3
`
`2.0
`
`3.8
`0.0
`
`0.0
`
`0.0
`
`0.0
`
`1.9
`
`20.4
`> 13.1
`
`7.2
`
`5.5
`2.5
`
`Dead
`Alive
`
`Dead
`
`Dead
`Dead
`
`> 11.3
`
`Alive
`
`6.1
`
`8.3
`
`Dead
`
`Alive
`
`> 3.0
`
`Alive
`
`Medical DES
`Medical DES,
`flutamide
`Medical DES,
`flutamide
`Medical DES
`Medical DES,
`flutamide
`Medical DES,
`flutamide
`CDDP, IFM, EPM,
`CMA,
`UFT
`DES
`CDDP, IFM, EPM,
`CMA,
`flutamide UFT, VP-16, XRT
`Medical DES,
`XRT
`flutamide
`Surgical DES
`Medical DES,
`flutamide
`CMA,
`flutamide
`Surgical DES,
`flutamide
`CDDP, IFM, EPM,
`Surgical DES,
`flutamide VP-16
`Medical DES
`EPM, VCR, IFM,
`PEP
`0.0
`EPM, CDDP, IFM Increase
`EPM
`Drop out Drop out
`
`XRT
`EPM
`
`EPM
`
`Medical
`
`Increase
`70.9
`
`0.0
`2.9
`
`84.3
`
`> 27.5
`
`EPM, UFT
`
`17.6
`
`Increase
`
`Stable
`
`1.2
`
`2.2
`
`0.0
`
`CMA
`Medical
`Surgical DES,
`flutamide
`CMA
`
`Medical
`
`1.0
`7.8
`
`Dead
`Dead
`
`> 27.5
`
`Alive
`
`> 12.2
`
`Alive
`
`7.0
`
`Dead
`
`17.2
`
`Dead
`
`2.5
`> 6.1
`
`Dead
`Alive
`
`10
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`17
`
`18
`
`19
`
`82
`80
`
`71
`
`79
`
`63
`
`65
`
`75
`71
`
`66
`
`79
`
`Moderately
`Moderately
`
`Moderately
`
`Poor
`
`Moderately
`
`Moderately
`
`Poor
`Well
`
`Moderately
`
`Poor
`
`Medical
`
`EPM, VCR, IFM,
`PEP
`Flutamide EPM
`
`98.2
`
`> 26.1
`
`> 26.1
`
`Alive
`
`Increase
`
`1.0
`
`1.0
`
`Dead
`
`* All patients were stage D2.
`PSA, prostate-specific antigen; DES, fosfestrol; CMA, chloromadinone acetate; EPM, estramustine phosphate; VP-16,
`etoposide; UFT, tegaful-uracil; XRT, radiation therapy; CDDP, cis-diamminodichloroplatinum; IFM, ifosphamide; VCR, vin-
`cristine; PEP, peplomycin.
`
`nine patients who could be evaluated for bone scan
`findings at 3 months after the start of dexamethasone
`therapy, three showed partial response (PR), two
`showed no change (NC) and four showed progression
`(PD) in comparison with findings before therapy. Of
`the 12 evaluable patients with bone pain that required
`analgesia, two were able to decrease the dose and five
`were able to stop their analgesic. Overall, seven
`(58.3%) patients experienced subjective improvement
`
`in bone pain by using dexamethasone. In analyzing the
`duration of symptomatic improvement, the median
`duration was 3.0 months and the range was 1.3–7.3
`months. Survival curves, as shown in Fig. 1, revealed a
`median survival after starting dexamethasone of 7.2
`months. No statistical differences in survival were
`noted for those patients having a PSA decline of
`greater than 50% compared to less than 50% (P =
`0.132). As complications, newly developed diabetes
`
`

`
`Treatment of prostate cancer with dexamethasone 293
`
`study was also performed after confirming the absence
`of anti-androgen withdrawal syndrome
`in
`these
`patients. These facts show that the cancers in our
`patients had re-growth under maximum androgen
`blockade (adrenal androgen suppression) when they
`entered this study. No confounding variables known to
`effect PSA were present in any patients as no concomi-
`tant treatment had been given. Our results clearly indi-
`cate that dexamethasone can decrease PSA levels in
`50% of patients in whom maximum androgen block-
`ade therapy has failed and that dexamethasone can
`contribute to subjective symptom improvement, espe-
`cially bone pain, in a greater percentage of patients.
`This result suggests that anti-androgens and dexa-
`methasone are non-cross resistant in action, raising the
`possibility that the mechanism of dexamethasone
`action in androgen-independent prostate cancer may
`extend beyond adrenal suppression.
`The exact mechanism of PSA decline cannot be
`determined from our results. Montgomery et al.
`showed that glucocorticoids could not induce suppres-
`sive regulation on LNCaP cells in an in vitro study.11 In
`addition, the effects of glucocorticoids may be indirect
`and may be mediated by an inhibition of neovascular-
`ization.12 Further basic and clinical studies should be
`done to understand the mechanism of dexamethasone
`action in patients with androgen-independent prostate
`cancer.
`Clinically, our series showed some effect on objec-
`tive response and subjective symptoms, although pre-
`vious ineffective treatments did not. In our small study,
`there were no statistically significant differences in sur-
`vival rate among patients demonstrating PSA decline;
`however, Scher et al. reported that a decline in PSA of
`50% or greater from baseline is related to survival in
`patients with androgen-independent prostate cancer.5
`From these results, dexamethasone is expected to
`have a good effect on the quality of life of terminal-
`stage prostate cancer patients. We believe that a
`prospective study of dexamethasone for larger num-
`bers of patients which both evaluates the response and
`investigates quality of life as a formal standard should
`be undertaken.
`In conclusion, dexamethasone decreased PSA
`levels in half of the patients with stage D2 androgen-
`independent prostate cancer. Moreover, symptomatic
`improvement was recognized in over half of the patients.
`
`References
`
`1 Storlie JA, Buckner JC, Wiseman GA, Burch PA,
`Hartmann LC, Richardson RL. Prostate specific anti-
`
`6
`
`12
`
`18
`
`24
`
`Time (Months)
`
`1
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`
`Survival rate
`
`Fig. 1 Survival rate due to prostate-specific antigen
`(PSA) decline-rate. Decline in PSA of 50% or greater
`from baseline following dexamethasone treatment may
`show a tendency of survival improvement in patients with
`androgen-independent prostate cancer, although the statis-
`tical significance was not clear (P = 0.132). 䊏, Decline
`≥ 50%, n = 5; 䉬, decline < 50%, n = 13.
`
`mellitus, which required insulin administration, was
`seen in one patient and both pneumo-cryptococcosis
`and a gastric ulcer were seen in another patient. The
`latter patient died due to pneumonia.
`
`Discussion
`
`The efficacy of glucocorticoids has been documented
`in some patients with hormone-refractory prostate
`cancer using palliative end-points.3 Moreover, some
`reports show that glucocorticoids can decrease PSA
`levels and tumor size.1,2,4,6,7 However, as Sartor et al.
`mentioned,2 reported PSA changes with glucocorticoid
`treatment are frequently difficult to interpret because
`of confounding variables from concomitant therapies.
`Most reports investigating PSA change after therapy
`with glucocorticoids were initiated before recognition
`of the anti-androgen withdrawal syndrome as a poten-
`therapeutic maneuver.8
`In addition,
`tially active
`hormone-refractory prostate cancer is comprised of a
`relatively heterogeneous group of patients. Repression
`of the serum androgen level in hormone-refractory
`patients to the level of surgical castration should be
`confirmed, because some reports have shown that
`androgen re-elevation was observed in spite of the
`regular injection of LH-RH agonist.9,10 For the pre-
`sent study, androgen-independent prostate cancer was
`defined as a disease that progressed despite a low level
`(1 ng/mL) of testosterone with medical or surgical
`castration; testosterone levels were confirmed in all
`patients. Additionally, previous treatment with anti-
`androgen had failed for all patients in this study. Our
`
`

`
`294 T Saika et al.
`
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`N, Matsumoto K. Enhancement by androgen of the
`angiogenic ability of androgen-responsive Shionogi
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