2570
`
`Low Doses of Oral Dexamethasone for Hormone-
`Refractory Prostate Carcinoma
`
`1
`Kazuo Nishimura, M.D.
`1
`Norio Nonomura, M.D.
`1
`Yutaka Yasunaga, M.D.
`1
`Natsuki Takaha, M.D.
`2
`Hitoshi Inoue, M.D.
`3
`Hideki Sugao, M.D.
`4
`Seiji Yamaguchi, M.D.
`5
`Osanu Ukimura, M.D.
`5
`Tsuneharu Miki, M.D.
`1
`Akihiko Okuyama, M.D.
`
`1 Department of Urology, Osaka University Medical
`School, Suita, Japan.
`
`2 Department of Urology, Osaka Rosai Hospital,
`Sakai, Japan.
`
`3 Department of Urology, Mino Municipal Hospital,
`Mino, Japan.
`
`4 Department of Urology, Ikeda Municipal Hospital,
`Ikeda, Japan.
`
`5 Department of Urology, Kyoto Prefectural Univer-
`sity of Medicine, Kyoto, Japan.
`
`Address for reprints: Kazuo Nishimura, M.D., De-
`partment of Urology, Osaka University Medical
`School, 2-2 Yamadaoka, Suita-City 565-0871, Ja-
`pan;
`Fax:
`(011)
`81-6-6879-3539;
`E-mail:
`kazu@uro.med.osaka-u.ac.jp
`
`Received March 1, 2000; revisions received June
`7, 2000, and August 17, 2000; accepted August
`17, 2000.
`
`© 2000 American Cancer Society
`
`BACKGROUND. Although glucocorticoids have been used to treat patients with
`hormone-refractory prostate carcinoma (HRPC), reports have varied regarding the
`
`types and doses of glucocorticoids used as well as their clinical benefits. In the
`
`current study, low doses of dexamethasone were investigated for their specific
`
`beneficial effects and the feasibility of long term treatment.
`METHODS. Thirty-seven patients diagnosed with HRPC were treated with oral
`dexamethasone (0.5–2 mg/day). The patients ranged in age from 53– 89 years
`
`(median, 74 years). Thirty-two patients, including 6 with lymph node metastases,
`
`had bone involvement whereas only 5 patients were found to have elevated serum
`
`prostate specific antigen (PSA) levels.
`RESULTS. Twenty-three patients (62%) who received no other concomitant therapy
`demonstrated a decline in their serum PSA level of ⱖ 50%, which was confirmed by
`
`a second PSA value obtained ⱖ 4 weeks later. The median time to PSA progression
`
`was 9 months. Among 18 patients with bone pain, 11 (61%) had improvement and
`
`in 5 patients (28%) the pain became stable. Among 21 patients with interpretable
`
`bone scans, 4 (19%) showed improvement and 8 (38%) achieved stable disease.
`
`Both symptomatic and objective responses of bone metastases were correlated
`
`with declines in the serum PSA level of ⱖ 50%. Ten patients achieved an increase
`
`in their hemoglobin level of at least 2 g/dL. Patients whose PSA level declined by
`
`ⱖ 50% with therapy had significantly prolonged survival (median, 22 months). As
`
`pretreatment markers, a longer interval before the initial evidence of disease
`
`progression appeared was found to correlate significantly with posttherapy PSA
`
`declines of ⱖ 75%. All side effects of the glucocorticoids were reported to be mild.
`CONCLUSIONS. Low doses of dexamethasone were found to be beneficial in the
`treatment of HRPC, decreasing the severity of anemia and osseous disease as well
`
`as reducing serum PSA levels. A posttherapy serum PSA decline of ⱖ 50% appears
`
`to be a reliable marker of improved survival with this therapy. Cancer 2000;89:
`
`2570 – 6. © 2000 American Cancer Society.
`
`KEYWORDS: prostate carcinoma, hormone-refractory, dexamethasone, prostate
`specific antigen.
`
`P rostate carcinoma is the second leading cause of death in Amer-
`
`ican men1 and is a growing worldwide problem. The majority of
`patients with advanced prostate carcinoma will respond to testicular
`androgen blockades such as castration or luteinizing hormone-releas-
`ing hormone (LH-RH) analogue with or without antiandrogens. How-
`ever, the median duration of response after hormonal therapy is ⬍ 2
`years.2,3 Once the disease becomes hormone-refractory, it is difficult
`to cure the patient because to our knowledge no effective therapy has
`been established.
`To our knowledge to date no clinical trial has resulted in a clearly
`prolonged survival among patients with hormone-refractory prostate
`carcinoma (HRPC). Instead, a palliative role for cytotoxic chemother-
`
`Amerigen Exhibit 1123
`Amerigen v. Janssen IPR2016-00286
`
`

`
`Dexamethasone for Hormone-Refractory Prostate Carcinoma/Nishimura et al.
`
`2571
`
`apy in the treatment of HRPC has been reported.4,5
`The antineoplastic agent mitoxantrone in combina-
`tion with a corticosteroid (either prednisone or hydro-
`cortisone) has shown clinical efficacy as palliative
`treatment in approximately 35– 40% of patients diag-
`nosed with HRPC.
`The clinical efficacy of glucocorticoids in the
`treatment of patients with advanced prostate carci-
`noma has been reported previously.6-10 Although sub-
`jective and objective response rates varied,6 clear ef-
`fects in patients with HRPC have been documented in
`terms of a decreased prostate specific antigen (PSA)
`level7-9 or palliative activity.10 Although to our knowl-
`edge the exact mechanism of action for decreasing the
`PSA level is not understood, suppression of adrenal
`androgens has been proposed. Indeed, adrenal andro-
`gens were reported to be suppressed in 22% of pa-
`tients achieving a ⱖ 50% decrease in the PSA level.5 In
`addition, an antiinflammatory effect may play a key
`role in the palliation of pain from bone metastases.
`There are several types of glucocorticoids that
`have been used in different doses for clinical trials. We
`chose dexamethasone for its very intense glucocorti-
`coid activity with little mineralocorticoid activity. To
`our knowledge no reports to date have shown a clear
`dose-response effect
`for dexamethasone. Further-
`more, high doses of dexamethasone possibly produce
`adverse effects such as Cushing syndrome. Therefore,
`we administered low doses of dexamethasone for the
`treatment of HRPC. In addition, we found oral admin-
`istration to be the most attractive option for the ma-
`jority of patients with HRPC in view of their advanced
`age and poor physical condition. The objective of this
`prospective study was to evaluate the clinical useful-
`ness of oral dexamethasone in the treatment of pa-
`tients with HRPC.
`
`MATERIALS AND METHODS
`Patient Selection
`Thirty-seven patients were enrolled in this clinical trial
`performed at Osaka University Hospital, Kyoto Prefec-
`tural University Hospital, and three affiliated hospitals
`between January 1996 and November 1999. Informed
`consent was obtained from all patients in this study.
`Eligibility criteria included: HRPC, defined as serial
`rising PSA values on ⱖ 3 occasions at least 2 weeks
`apart or radiologically detected new or extensive le-
`sions; a castration level of serum testosterone while
`receiving hormonal therapy; a Karnofsky performance
`status (KPS) of ⱖ 40%; and a life expectancy of ⱖ 3
`months.
`Pretreatment characteristics of the patients are
`shown in Table 1. The age of the patients ranged from
`53– 89 years (median, 74 years). The majority of pa-
`tients primarily had moderately to poorly differenti-
`
`TABLE 1
`Patient Characteristics
`
`Age (yrs) (n ⫽ 37)
`Pretreatment PSA (ng/mL) (n ⫽ 37)
`Interval before initial evidence of disease progression
`(mos) (n ⫽ 37)
`Karnofsky performance status (%) (n ⫽ 37)
`Pretreatment hemoglobin level (g/dL) (n ⫽ 32)
`
`Median (range)
`
`74 (53–89)
`38 (2.4–3570)
`
`23 (3–48)
`80 (40–100)
`11.8 (7.9–16.3)
`
`(n ⴝ 37)
`
`No. of patients (%)
`
`Histologic grade of primary tumor
`Well differentiated adenocarcinoma
`Moderately differentiated adenocarcinoma
`Poorly differentiated adenocarcinoma
`Indeterminate
`Progressive disease site
`Bone
`Lymph nodes
`Prostate
`Biologic failure (PSA)
`Symptomatic status
`Bone pain
`Dysuria
`
`PSA: prostate specific antigen.
`
`TABLE 2
`Prior Therapies
`
`(n ⴝ 37)
`
`Primary hormonal therapy
`LH-RH analogue plus other hormonal agentsa
`Castration plus other hormonal agentsa
`Antiandrogen alone
`Prior use of antiandrogen
`Prior radiation therapy
`Prior chemotherapy
`Estramustine plus other cytotoxic agentsb
`Estramustine alone
`
`1 (3%)
`14 (38%)
`19 (51%)
`3 (8%)
`
`32 (86%)
`6 (16%)
`5 (14%)
`5 (14%)
`
`18 (49%)
`4 (11%)
`
`No. of patients (%)
`
`29 (78%)
`7 (19%)
`1 (3%)
`15 (41%)
`10 (27%)
`
`17 (46%)
`3 (8%)
`
`LH-RH: luteinizing hormone–releasing hormone.
`a Other hormonal agents included chlormadinone acetate, estrogen, estramustine, and flutamide.
`b Other cytotoxic agents included cyclophosphamide, 5-fluorouracil prodrug, and etoposide.
`
`ated adenocarcinoma of the prostate with metastases.
`Prior therapies are shown in Table 2. As a primary
`hormonal therapy, 36 patients received medical or
`surgical castration plus an antiandrogen, estrogen, or
`estramustine, whereas 1 patient received bicalutamide
`alone followed by estramustine. The antiandrogen
`was discontinued at least 4 weeks before the admin-
`istration of dexamethasone. There were four patients
`who had demonstrated a decline in the serum PSA
`after antiandrogen withdrawal.
`Estramustine-based chemotherapies were admin-
`istered in 20 patients. Although 2 patients had re-
`
`

`
`2572
`
`CANCER December 15, 2000 / Volume 89 / Number 12
`
`ceived estramustine combined with initial hormonal
`therapy, 18 received estramustine-based regimens for
`between 1–27 months (median, 3 months) after dis-
`ease progression subsequent to initial hormonal ther-
`apy.
`With regard to the sites of progressive disease that
`were evaluated by bone scan, computed tomography
`(CT), or magnetic resonance imaging (MRI), 32 pa-
`tients had bone disease, 6 had lymph node involve-
`ment, and 5 had local disease progression (prostate)
`whereas 5 patients had only biochemical disease pro-
`gression evaluated by PSA.
`
`Assessability, Toxicity, and Response Criteria
`In general, patients underwent a physical examination
`and laboratory studies including complete blood cell
`count, blood chemistry, and PSA at a minimum of
`every 4 weeks. Posttherapy PSA decline was used to
`determine primary response to therapy. The percent-
`age of PSA decline and the time to PSA progression
`was calculated using the guidelines suggested by the
`PSA working group.11 Both a PSA decline of ⱖ 50% and
`a PSA decline of ⱖ 75% were confirmed by a second
`PSA evaluation at least 4 weeks later. Because a de-
`cline in the serum PSA occasionally was observed after
`the dose escalation of dexamethasone in patients with
`an initial posttherapy PSA decline, no PSA decline
`after the dose escalation was considered to be treat-
`ment failure.
`The difference from baseline to the highest hemo-
`globin level at least 4 weeks after treatment with dexa-
`methasone was calculated in evaluable patients, who
`then were divided into 4 groups: those with a hemo-
`globin increase ⱖ 2 g/dL, those with a hemoglobin
`increase ⬍ 2 g/dL but ⱖ 1 g/dL, those with a change in
`hemoglobin ⬍ 1 g/dL, and those with a decrease in
`hemoglobin ⱖ 1 g/dL.
`Symptomatic response in terms of bone pain was
`assessed by comparing the analgesic dose at the time
`of the lowest PSA level after therapy and the pretreat-
`ment dose. The response was categorized as “im-
`provement” ( reduced analgesic dose), “stability” (the
`same analgesic dose), or “progression” (increased an-
`algesic dose).
`Chest X-ray, bone scan, CT scan, or MRI was per-
`formed according to the clinical evolution. If assess-
`able, posttherapy bone scans were graded as “im-
`provement” (a decrease in the number of lesions
`without the development of new lesions), “stability”
`(no change in the number of lesions without the de-
`velopment of new lesions), or “progression” (an in-
`crease in the number of lesions or the emergence of
`new lesions relative to the baseline scan). Measurable
`disease as assessed by CT scan and/or MRI was cate-
`gorized as partial response (PR) (defined as an at least
`
`50% reduction in the sum of the products of the great-
`est perpendicular dimensions), stable (either a ⬍ 50%
`reduction or a ⬍ 25% increase in the sum of the
`products of the greatest perpendicular dimensions
`without the appearance of new lesions), or progres-
`sion (either an at least 25% increase in the sum of the
`products of the greatest perpendicular dimensions or
`the appearance of new lesions).
`Toxicities were assessed every 4 weeks based on a
`medical history, physical examination, and laboratory
`studies. Dose reduction or discontinuation of dexa-
`methasone was employed if a serious adverse effect
`developed.
`Survival times were established from the date of
`study entry until the date of death or last follow-up.
`Survival rates were calculated using the Kaplan–Meier
`method and comparisons were made using the log
`rank test.
`The associations between pretreatment or post-
`treatment parameters and posttreatment PSA decline
`were evaluated by the Mann–Whitney U test. A P value
`of 0.05 was taken to indicate statistical significance. All
`statistical analyses were performed using StatView
`software (SAS Institute Inc., Cary, NC).
`
`Treatment
`The treatment, which was administered on an outpa-
`tient basis, was comprised solely of oral dexametha-
`sone starting from 0.5–1 mg/day. Patients typically
`received 0.5 mg twice daily whereas those with PSA
`failure alone received 0.5 mg once daily. If a patient
`had demonstrated an initial decline in PSA after dexa-
`methasone therapy, a dose escalation of 0.5 mg/day
`was administered to observe further response when
`the PSA serially rose from the nadir. If a patient had no
`posttherapy decline in PSA on the initial two occa-
`sions, this therapy was discontinued. Thus, oral ad-
`ministration of dexamethasone was continued to a
`maximum of 2 mg/day until disease progression or
`unacceptable side effects. To prevent the rebound ef-
`fects of dexamethasone withdrawal, the dose was re-
`duced by 0.5–1 mg/day at least 2 weeks apart. All
`patients receiving an LH-RH analogue continued ther-
`apy.
`
`RESULTS
`Treatment
`Five asymptomatic patients initially received 0.5 mg of
`dexamethasone once daily whereas the other patients
`received 0.5 mg twice daily. Limited dose escalation of
`dexamethasone was used in 25 patients 2–12 months
`after the start of therapy. The maximum doses varied
`from 0.5 mg/day in 2 patients to 1 mg/day in 13
`patients, 1.5 mg/day in 19 patients, and 2 mg/day in 3
`patients.
`
`

`
`Dexamethasone for Hormone-Refractory Prostate Carcinoma/Nishimura et al.
`
`2573
`
`TABLE 3
`PSA Decline after Dexamethasone Therapy
`
`Initial PSA
`decline
`
`No. of
`patients (%)
`
`ⱖ 75%
`ⱖ 50%a
`⬍ 50%
`Elevation
`
`19 (51%)
`23 (62%)
`9 (24%)
`5 (14%)
`
`Time to PSA
`progression
`(mos) Median
`(range)
`
`10 (6–21)
`9 (3–21)
`3 (1–9)
`0 (0)
`
`Further PSA decline
`(no. of patients)
`
`Dose escalation
`(No. of patients)
`
`2/12
`3/16
`2/9
`—
`
`PSA: prostate specific antigen.
`a The row includes the number of patients with a decline in the prostate specific antigen ⱖ 75%.
`
`The duration of dexamethasone treatment ranged
`from 1–22 months (median, 7 months). Twenty-seven
`patients discontinued dexamethasone at the time of
`disease progression or the development of side effects
`and then underwent chemotherapy or symptom con-
`trol.
`
`Clinical Response
`Biochemical responses evaluated by serum PSA levels
`are shown in Table 3. Twenty-three patients (62%) had
`a PSA decline of ⱖ 50% and 19 patients (51%) had a
`PSA decline of ⱖ 75%. Their median times to PSA
`disease progression were 9 months and 10 months,
`respectively. A greater decline in the PSA level was
`found to be correlated with a longer median time to
`PSA disease progression. Conversely, five patients
`demonstrated PSA elevation and then underwent
`other therapy. Those patients who had not shown a
`trend toward an increasing PSA value at the time of
`assessment were excluded from the assessment for the
`time to PSA disease progression.
`Among the 25 patients who were treated with dose
`escalation, 5 experienced additional PSA declines.
`Among the four patients who had experienced
`antiandrogen withdrawal syndrome, all had a PSA de-
`cline of ⱖ 75% after dexamethasone therapy.
`To assess the association between a PSA decline of
`ⱖ 50% and clinical response in bone metastases, an
`assessment of bone pain and a bone scan were per-
`formed, as shown in Table 4. Among the 18 patients
`with symptomatic bone metastases, the majority with
`a PSA decline of ⱖ 50% showed improvement in bone
`pain whereas 6 of 9 patients with a PSA decline of
`⬍ 50% were found to have stability or progression in
`pain. Thus, the majority of symptomatic patients
`achieved improvement or stability of their bone pain.
`Among the 21 patients assessable for bone scan, 9 of
`10 patients with a PSA decline of ⱖ 50% showed im-
`provement or stability whereas 8 of 11 patients with a
`
`PSA decline of ⬍ 50% were found to have progression
`based on bone scan changes. A PSA decline of ⱖ 50%
`was associated significantly with a good outcome on
`both bone pain (P ⫽ 0.0167) and bone scan (P
`⫽ 0.0021).
`With regard to for measurable disease, five pa-
`tients were assessable for metastatic lymph nodes.
`Among these patients, only 1 showed a PR with a PSA
`decline of ⱖ 50%, 2 were considered stable (one with
`a PSA decline of ⱖ 50% and the other without this
`decline), and 2 were found to have disease progression
`without this decline.
`Because a significant number of patients experi-
`enced an improvement in anemia during therapy with
`dexamethasone, the posttherapy change in the hemo-
`globin level was evaluated as shown in Table 5. Thirty-
`two patients were assessable for a change in their
`hemoglobin level after dexamethasone therapy. Twen-
`ty-one patients (65%) had an increase in their hemo-
`globin level of at least 1 g/dL and 10 patients (31%)
`had an increase of at least 2 g/dL, whereas only 2
`patients (6%), including 1 patient with rectal bleeding,
`demonstrated a decrease in their hemoglobin level of
`ⱖ 1 g/dL. The majority of patients with a change in
`their hemoglobin level of ⬍ 1 g/dL had a hemoglobin
`level of ⱖ 13 g/dL at baseline.
`To determine any predictors of a better PSA re-
`sponse, pretreatment factors at baseline (age, KPS,
`interval before the initial evidence of disease progres-
`sion, hemoglobin level, serum PSA, histologic grade,
`and bone pain) were stratified into 2 groups based on
`the level of PSA decline (ⱖ 50% vs. ⬍ 50% or ⱖ 75% vs.
`⬍ 75%). None of these pretreatment factors were
`found to be associated significantly with a PSA decline
`of ⱖ 50% (data not shown). Conversely, as shown in
`Table 6, a longer interval before the initial evidence of
`disease progression (median, 32.5 months) was found
`to have a statistically significant association with a PSA
`decline of ⱖ 75% (P ⫽ 0.0217). KPS was found to be of
`borderline statistical significance (P ⫽ 0.0684).
`
`Survival Analysis
`The overall survival time after dexamethasone treat-
`ment ranged from 3–28 months (median, 20 months).
`The 1-year and 2-year survival rates were 66% and
`27%, respectively.
`To determine whether a posttherapy PSA decline
`correlated with survival, overall survival rates were
`stratified by a posttherapy PSA decline of 50% and
`were analyzed as shown in Figure 1. The median sur-
`vival times were 22 months in patients with a PSA
`decline of ⱖ 50% versus 8 months in patients without
`this decline. The difference in the probability of sur-
`vival between the two groups was statistically signifi-
`cant (P ⫽ 0.0002).
`
`

`
`2574
`
`CANCER December 15, 2000 / Volume 89 / Number 12
`
`TABLE 4
`Assessment of Bone Metastasis Stratified by PSA Decline
`
`Bone pain (n ⴝ 18)
`
`No. of patients
`
`Bone scan (n ⴝ 21)
`
`No. of patients
`
`PSA decline
`
`Improvement
`
`Stability
`
`Progression
`
`Improvement
`
`Stability
`
`Progression
`
`ⱖ 50%
`⬍ 50%a
`Total (%)
`
`8
`3
`11 (61%)
`
`1
`4
`5 (28%)
`
`0
`2
`2 (11%)
`
`P ⫽ 0.0167
`
`4
`0
`4 (19%)
`
`5
`3
`8 (38%)
`
`1
`8
`9 (43%)
`
`P ⫽ 0.0021
`
`PSA: prostate specific antigen.
`a The row includes the number of patients with an elevation in their prostate specific antigen level.
`
`TABLE 5
`Improvement in Anemia (n ⴝ 32)
`
`Change in hemoglobin level
`
`No. of patients (%)
`
`Increase ⱖ 2 g/dL
`2 g/dL ⬎ increase ⱖ 1 g/dL
`Change ⬍ 1 g/dL
`Decrease ⱖ 1 g/dL
`
`10 (31%)
`11 (34%)
`9 (28%)
`2 (6%)
`
`TABLE 6
`Univariate Analysis of Pretreatment Markers for PSA Decline
`
`PSA decline
`
`Factor
`
`> 75%
`
`< 75%
`
`P value
`
`Median
`
`Interval before initial evidence of
`disease progression (mos) (n ⫽ 37)
`Karnofsky performance status (%)
`(n ⫽ 37)
`Age (yrs) (n ⫽ 37)
`Pretreatment hemoglobin level
`(g/dL) (n ⫽ 32)
`Pretreatment PSA level (ng/mL)
`(n ⫽ 37)
`
`32.5
`
`80
`76
`
`12.1
`
`27
`
`No. of patients
`
`Histologic grade (n ⫽ 34)
`Well differentiated adenocarcinoma
`Moderately differentiated
`adenocarcinoma
`Poorly differentiated adenocarcinoma
`
`Bone pain (n ⫽ 37)
`Symptomatic
`Asymptomatic
`
`PSA: prostate specific antigen.
`
`1
`
`8
`8
`
`7
`9
`
`16.5
`
`80
`72
`
`11.1
`
`54
`
`0
`
`6
`11
`
`11
`10
`
`0.0217
`
`0.0684
`0.0827
`
`0.186
`
`0.763
`
`0.259
`
`0.608
`
`In addition, the overall survival rates stratified by
`a posttherapy PSA decline of 75% were analyzed. A
`statistical difference was observed between patients
`with a PSA decline of ⱖ 75% and those without this
`decline (P ⫽ 0.0234). The median survival times were
`22 months and 9 months, respectively. Because the
`
`FIGURE 1. Overall survival stratified by 50% decrease in the prostate specific
`antigen (PSA) level; patients who achieved a posttherapy PSA decline of ⱖ 50%
`
`(n ⫽ 23) versus those patients who did not (n ⫽ 14).
`
`follow-up period for patients with a PSA decline of
`⬎ 75% was short (median, 11 months), their median
`survival time was the same as that of patients with a
`PSA decline of ⱖ50%.
`To elucidate prognostic markers, survival rates
`stratified by pretreatment factors were compared. The
`factors examined included age (ⱖ 75 years vs. ⬍ 75
`years), interval before the initial evidence of disease
`progression (ⱖ 12 months vs. ⬍ 12 months or ⬎ 24
`months vs. ⱕ 24 months), PSA (ⱖ 20 ng/mL vs. ⬍ 20
`ng/mL), and bone pain (symptomatic vs. asymptom-
`atic). Only freedom from bone pain was associated
`significantly with better survival (P ⫽ 0.0133), whereas
`the other factors had no statistical significance. Al-
`though it is not statistically significant, a long interval
`before the initial evidence of disease progression ap-
`peared to be associated with prolonged survival. For
`patients in whom this interval was ⬎ 24 months, the
`median survival difference was 22 months versus 16
`months in patients in whom this interval was ⱕ 24
`months (P ⫽ 0.0723).
`
`

`
`Dexamethasone for Hormone-Refractory Prostate Carcinoma/Nishimura et al.
`
`2575
`
`Toxicity
`All toxicities were mild and manageable on an outpa-
`tient basis. There were two cases of hypertension, two
`cases of mental confusion, one case of cataracts, and
`one case of diabetes. Of of the 12 patients assessable
`for serum cholesterol, 8 showed hypercholesterol-
`emia, which was able to be managed with 3-hydroxy-
`3-methylglutaryl coenzyme A (HMG-CoA) reductase
`inhibitors. No patients developed severe infectious
`disease.
`
`DISCUSSION
`In the current study, we examined the efficacy of low
`doses of dexamethasone in the treatment of patients
`with HRPC. Dexamethasone is considered to be a
`more potent agent than prednisone or hydrocortisone
`because of its stronger glucocorticoid activity and less
`mineralocorticoid activity. Glucocorticoids bind to
`glucocorticoid receptors (GR) in their target cells, after
`which ligand-bound GR initiates the actions of glu-
`cocorticoids. In the majority of cells, glucocorticoids
`exert antiproliferative effects, which have prompted
`the clinical use of these drugs in anticancer therapy for
`lymphoproliferative disorders and solid tumors.12-14
`Dexamethasone was reported to have an inhibitory
`effect on cell growth mediated by intrinsic GR in an
`androgen-independent prostate carcinoma cell line,
`PC3.15 Therefore, we hypothesized that glucocorti-
`coids have direct growth-inhibitory effects on prostate
`tumors, in addition to any effects resulting from the
`suppression of adrenal androgen production or anti-
`inflammatory action. However, because GRs generally
`are down-regulated by glucocorticoids in a dose-de-
`pendent manner,16,17 their effectiveness eventually
`will be lost. Indeed, our in vitro experiments using PC3
`cells have indicated that their intrinsic GRs were
`down-regulated by high doses of dexamethasone
`(data not shown). Thus, low dose dexamethasone is
`considered desirable for achieving a sufficient re-
`sponse duration and minimizing side effects. The trial
`presented in the current study continued for 22
`months with no patients reported to have developed
`severe side effects.
`Assuming that patients with only PSA elevations
`have a better prognosis than those with osseous le-
`sions or other radiologically measurable indicators of
`progressive disease, the minimum dose was given to
`the former group of patients. When we tried limited
`dose escalation to augment glucocorticoid effects in
`initial responders, 20% (5 of 25 patients) demon-
`strated a second PSA decline subsequent to the dose
`escalation.
`There have been several reports regarding glu-
`cocorticoids for the treatment of HRPC. However, the
`
`majority of studies used prednisone or hydrocortisone
`to achieve suppression of adrenal androgen.5-8,10 Ac-
`cording to these studies, a PSA decline of ⱖ 50% was
`noted in 9 –34% of patients4,5,7,8 and pain relief was
`noted in 12–38%.5,10 Overall median survivals were
`reported to be approximately 12 months.4,7 To our
`knowledge, only one previous report9 is comparable
`with regard to low doses of dexamethasone; the find-
`ings of this study demonstrated a PSA decline of at
`least 50% in 61% of patients and pain relief in up to
`63%.9 These results are similar to the findings of the
`current
`study. The overall median survival
`(20
`months) in the current study was higher than that
`reported in prior studies using prednisone or hydro-
`cortisone. Although comparisons among trials are not
`justified because of potential patient selection biases
`and different response criteria, the prolonged survival
`reported in the current study is noteworthy because
`approximately 50% of the patients had symptomatic
`bone pain, a feature usually associated with end stage
`disease. Thus, the results suggest that dexamethasone
`is superior to other steroids for the treatment of pa-
`tients with advanced HRPC.
`Many current studies have used PSA as a marker
`of response,18 –23 demonstrating an association be-
`tween PSA decline after treatment and improved pa-
`tient outcome.22,23 In the current study, 23 patients
`(62%) achieved PSA declines of ⱖ 50%, which was
`found to correlate significantly with survival time as
`well as osseous disease response.
`A recent survey20 demonstrated marked variability
`in the determination of disease response or progres-
`sion in the treatment of HRPC based on changes in the
`PSA level. Accordingly, the PSA working group sug-
`gested defining response duration and the time to PSA
`progression.12 Because the current study demon-
`strated an additional PSA decrease after dose escala-
`tion of dexamethasone, the time to PSA progression
`was evaluated using the guidelines, indicating that a
`longer time to PSA progression was correlated with a
`PSA decline of ⱖ 50%.
`Anemia in patients with HRPC has been linked to
`both poor physical status and poor prognosis.22 It is
`interesting to note that we observed a marked im-
`provement in anemia in approximately 31% of pa-
`tients during dexamethasone therapy. Although to our
`knowledge the mechanisms by which dexamethasone
`improves anemia remain unknown, an increase in
`appetite may be one reason.
`The relatively few patients in this trial who had
`measurable disease showed no definite response; be-
`cause of the small number of assessable patients, we
`were unable to determine the efficacy of dexametha-
`sone against measurable disease.
`No pretreatment factor studied demonstrated a
`
`

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`2576
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`CANCER December 15, 2000 / Volume 89 / Number 12
`
`significant association with a PSA decline of ⱖ 50%,
`whereas long term initial hormonal therapy (median
`duration, 32.5 months) was identified as a significant
`predictor of a PSA decline of ⱖ 75%. Such decreases
`were found to be associated significantly with longer
`survival in the current study as well as in other stud-
`ies.5,22 Among the prognostic factors analyzed, only
`bone pain, which is widely accepted as an indicator of
`poor prognosis, was found to have a significant asso-
`ciation with poor survival. However, a larger clinical
`trial is required to determine the prognostic signifi-
`cance of other pretreatment factors.
`Because no control arm was established in the
`current study trial, we were unable to determine
`whether low dose dexamethasone itself prolonged
`survival. This is the limitation of the current study
`because establishing a no treatment arm involves eth-
`ical difficulties.
`In the current study we found clear benefits with
`low dose dexamethasone as demonstrated by clinical
`improvement with regard to symptoms, bone scan,
`hemoglobin level, and PSA decline. Furthermore, a
`PSA decline of ⱖ 50% was shown to be a significant
`prognostic factor when using dexamethasone in the
`treatment of HRPC.
`
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