Am J Clin Onto! (CCT) [2(4): 353—360, 1989,
`
`© I989 Raven Press Ltd.. New York
`
`A Study of Aminoglutethemide and
`Hydrocortisone in Patients with Advanced
`and Refractory Prostate Carcinoma
`
`Alex Y. C. Chang, M.D., John M. Bennett, M.D.,
`Kishan J. Pandya, M.D., Robert Asbury, M.D.,
`and Craig McCune, MD.
`
`We have studied aminoglutethemide (AG) combined with
`hydrocortisone in 28 patients with advanced and refractory
`prostate carcinoma. All the patients had failed at least one
`endocrine therapy. Six patients received only one prior hor-
`monal treatment. Five patients were off study within 3 weeks
`due to early death and toxicity, l4 had progressive disease,
`and 9 had stable disease. No objective partial remission was
`observed, but the nine stable patients had therapeutic benefit,
`with improvement in bone pain and performance status for
`a median duration of 153 days. Three patients withdrew be-
`cause of postural hypotension, dizziness, weakness, and leth-
`argy. The median survival of the entire group was 186 days
`(range 41—606 days). Our results suggest that aminogluteth-
`emide and hydrocortisone can be an alternative treatment
`for patients with advanced and refractory prostate carcinoma.
`Key Words: Aminoglutethemide—Hydrocortisone—Prostate
`carcinoma.
`
`carcinoma and metastatic disease (stage D2) that had
`
`Patients with stage D2 metastatic adenocarcinoma
`of the prostate gland are usually managed with hor-
`monal manipulation to ablate androgen for controlling
`symptoms (1-3). Androgen ablation can be achieved
`either by giving patients additive hormones, such as
`estrogen, progestational agent
`(4),
`luteinizing hor-
`mone—releasing hormone agonist (LH-RH) (5), or bi-
`lateral orchiectomy (6). Although the majority of pa-
`tients will respond to the initial hormonal therapy, al-
`most all patients will relapse with disease progression
`within 2—3 years. Then, the disease assumes a more
`rapid and progressive downhill course. The median
`survival
`in this group of patients with hormone-re-
`fractory prostate carcinoma is only about 6 months
`(2,7,8). These patients do not usually respond to sec-
`ondary hormone treatment, such as megestrol acetate,
`leuprolide (9,10), or chemotherapy (11). The mecha-
`nism of the resistance to therapy remains largely un-
`known.
`
`The adrenal steroid production is also a source of
`serum androgen and is not affected by most primary
`hormonal therapy directed to suppress the testicular
`androgen (12). Aminoglutethemide inhibits the syn-
`thesis of adrenal androgen (l3), and hydrocortisone
`suppresses the compensatory increase of adrenocorti-
`cotropin. It is prudent to employ secondary hormonal
`manipulation with a different mechanism of action
`from the first one. Hence, we evaluated the palliative
`effect of the combination of aminoglutethemide and
`hydrocortisone in 28 patients with advanced and re-
`fractory prostate carcinoma.
`
`MATERIALS AND METHODS
`
`Patients with histologically documented prostate
`
`From the Department of Medicine and Cancer Center, School of
`Medicine and Dentistry, University of Rochester, Rochester, New
`York,
`Address correspondence and reprint requests to Dr. Alex Y. Chang,
`Division of Oncology/Hematology. Genesee Hospital, University of
`Rochester Cancer Center, 224 Alexander Street, Rochester, NY
`14607, U.S.A.
`
`358
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`TABLE 2. Toxicity of aminogiutethemide
`and hydrocortisone
`
`No. of patients (°/a)
`
`Ataxia
`Peripheral edema
`Skin rash
`Fever
`Postural hypotension
`Nausea/vomiting
`Dizziness. lethargy
`
`1 (3.6)
`2 (7.1)
`3 (1 0.7)
`4 (14.3)
`4 (14.3)
`6 (21 .4)
`8 (28.6)
`
`patients had failed hormonal treatment. The toxicity
`of treatment is shown in Table 2. The side effects of
`dizziness, lethargy, weakness, and postural hypotension
`were severe enough that three patients withdrew from
`the study in spite of the use of mineralocorticoid (Flor-
`inef acetate, 0.1-0.3 mg/day). Dizziness, nausea, and
`vomiting were common, but tolerable, except in one
`patient who refused further therapy. Skin rash occurred
`transiently in three patients. Fourteen patients had
`progressive disease without any response. Nine patients
`had stable disease and obtained significant improve-
`ment ofbone pain and performance status for a median
`duration of 153 days (range 90—380 days). Four of these
`patients experienced less bone pain and a sense of well-
`being in the first month of treatment. Three patients
`showed dramatic improvement of their performance
`status, which changed from bedridden to ambulatory
`within the first 2 weeks on study. The mean age of
`patients with stable disease was 71 (range 63—85), which
`was the same as that in patients with progressive dis-
`ease.
`
`No objective partial remissions were observed. Two
`patients had a reduction of serum acid phosphatase of
`more than 50% from the pretreatment level, and one
`patient’s acid phosphatase returned to the normal range
`after treatment. The median times to treatment failure
`and survival for the entire group were 80 and 186 days,
`respectively, and for the stable patients alone, they were
`153 and 331 days, respectively.
`
`DISCUSSION
`
`Most of our patients had disease refractory to mul-
`tiple treatment modalities. Only six patients had failed
`from one endocrine treatment. Our results demonstrate
`the therapeutic benefit of improving bone pain and
`performance status from aminoglutethemide and hy-
`drocortisone in 9 of 28 (32%) heavily pretreated pa-
`tients. Two of six patients with prior chemotherapy
`also had improvement ofbone pain. The toxicities were
`similar to those previously reported. They were not
`negligible, but were tolerable most of the time by our
`patients. It is possible that toxicity could be less if we
`
`Age (range)
`Performance status (no. of patients)
`1
`2
`3
`4
`Prior therapy (no. of patients)
`Orchiectomy
`Diethylstilbestrol
`Chemotherapy
`Tamoxifen
`Megestrol Acetate
`Disease sites (no. of patients)
`Osseous only
`Visceral only
`Osseous and visceral
`No. of prior therapies (no. of patients)
`
`71 (46-85)
`
`12
`9
`4
`3
`
`24
`0
`4
`
`6 (a)'
`10 (a)
`7 (1)
`4 (2)
`1 (0)
`
`‘ The number in parentheses denotes patients with improvement
`of bone pain.
`
`AG IN PROSTATE CARCINOMA
`
`RESULTS
`
`All patients registered on the study were included in
`the analysis of response and toxicity. Five patients had
`an inadequate trial of treatment and were viewed as
`treatment failures (one each with subdural hemorrhage,
`cardiac arrest, and pneumonia; two patients died within
`21 days on study). The characteristics of the patients
`were shown in Table l. The median performance status
`and number of prior therapies were both 2. All the
`
`TABLE 1. Patients characteristics
`
`become refractory to hormonal management were eli-
`gible. Patients with uncontrolled congestive heart fail-
`ure, cardiac arrhythmia, or hypertension were ex-
`cluded. Prior chemotherapy was allowed for patient
`entry.
`All patients received aminoglutethemide (Cytadren,
`supplied by CIBA Co., Summit, NJ, U.S.A.), 250 mg
`p.o., q.i.d., and hydrocortisone, 20 mg q.i.d., at the
`same time. After the first week of treatment, the dose
`of hydrocortisone was reduced to 10 mg q.i.d. in pa-
`tients with stable disease so as to reduce the potential
`side effects of hypercorticism. Patients were evaluated
`once a week for the first 4 weeks, with history, physical
`examination, and performance status. If the patient’s
`condition was stable after 4 weeks, he was then followed
`every 4 weeks until disease progression occurred.
`Complete blood counts, chemistry, and acid phospha-
`tase were done every month and bone scan every 3-6
`months. We applied the response criteria of the Na-
`tional Prostate Cooperative Projects (NPCP) to eval-
`uate treatment results (14).
`
`Am J Clin Oneal (CCT), Vol. 12, N0. 4, I989
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`exclude patients with poor performance status and
`multiple treatment failures.
`Drago et al. (15) have reported that aminogluteth-
`emide had a 16% objective response and 24% stable
`disease in 43 patients with metastatic prostate carci-
`noma after initial treatment failure. Ahmann et al. (16)
`also reported a 13% objective partial remission and
`48% stable disease in 86 patients who had failed only
`from orchiectomy. Thus, both studies employed ami-
`noglutethemide and hydrocortisone as the second hor-
`monal
`treatment with moderate success. However,
`Block et a1. (17) reported no objective or subjective
`response in 23 patients, but only 4 of their patients
`were first-line failures. Our patient population is similar
`to those in Block‘s report. The observation of subjective
`symptomatic relief in our patients is different from their
`report. The reason for this discrepancy is unknown.
`Those reports by Lippman et a1. (18) and Rostom et
`a1. (19) showed subjective improvement of bone pain
`in 50% and 75% of patients, respectively, and are con-
`sistent with our findings. As only four patients in our
`study had an objectively measurable disease, we did
`not expect to observe any objective partial response.
`Bilateral adrenalectomy has also been reported to pro-
`duce 20—40% clinical response (20). Hence, we regard
`adrenal androgen ablation is an alternative treatment
`for patients with hormone-refractory prostate carci-
`noma. We believe that the combination of aminoglu-
`tethemide and hydrocortisone can be used as second-
`line hormonal therapy and in place of bilateral adre-
`nalectomy.
`It is unclear which is the best second-line hormonal
`treatment in patients with metastatic prostate carci-
`noma, although most investigators agree that second
`endocrine manipulation seldom produces objective re-
`mission (21). Considering available agents, amino—
`glutethemide and hydrocortisone olfer the advantage
`of costing less than leuprolide (9). estramustine phos-
`phate (22). or Ketoconazole (23) and are possibly more
`beneficial in relieving symptoms than leuprolide (9) or
`megestrol acetate (10). However, definite conclusion
`requires future randomized studies that should also in-
`clude a placebo control arm to accurately assess the
`therapeutic effect of second-line hormonal treatment.
`(E
`
`REFERENCES
`I. Byar DB. The VACURG's studies of cancer of the prostate.
`Cancer 1973;32:1126—30.
`
`Am J Clm Onwl {CCT}. Vol. I2, No. 4. 1989
`
`360
`
`A. Y. C. CHANG ET AL.
`
`. Klein LA. Prostate carcinoma. N Engl J Med 1979;300:824-33.
`. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect
`of castration, of estrogen and of androgen injection on serum
`phosphatase in metastatic carcinoma ofthe prostate. Cancer Res
`1941;]:293—7.
`. Catalona WJ. Scott W. Carcinoma of the prostate: a review.
`J Urol 1978;119:1—8.
`. The Leuprolide Study Group. Leuprolide versus diethylstilbestrol
`for metastatic prostate cancer. N Eng! J Med 1984:3112
`1,281-6.
`. Blackard CE, Byar DP. Jordan WP Jr. Orchiectomy for advanced
`prostatic carcinoma: a re-evaluation. Urology 1973;]:553—60.
`. Glick J H, Wein A, Padavic K, et al. A Phase ll trial of tamoxifen
`in metastatic carcinoma of the prostate. Cancer 1982;49:1,367—
`72.
`. Lyss AP. Systemic treatment for prostate cancer. Am J Med
`1987;83: l ,120-8.
`. Soloway MD. Newer methods of hormonal therapy for prostate
`cancer. Urology 1984;24(suppl 5):30—8.
`. Crombie C, Raghavan D, Page J. et al. Phase 11 study of megestrol
`acetate for metastatic carcinoma of the prostate. Br J Ural
`1987;59:443-6.
`. Tannock IF. is there evidence that chemotherapy is of benefit
`to patients with carcinoma of the prostate? J Clin Oncol 19853:
`1,0 l 3,
`. Geller J , Albert J, Vik A. Advantages of total androgen blockade
`in the treatment of advanced prostate cancer. Semin Oncol
`1988;15:53-6l.
`. Salhanick HA. Basic studies on aminoglutethemide. Cancer Res
`1982;2c3,3155—215.
`. Murphy GP, Slack NH. Response criteria for the prostate car-
`cinoma of the USA National Prostatic Cancer Project. Prostate
`1980,1375.
`. Drago JR. Santen RJ, Lipton A, et al. Clinical effect of amino-
`glutethemide, medical adrenalectomy, in treatment 01‘43 patients
`with advanced prostatic carcinoma. Cancer 1984;53:1,447-50.
`. Ahmann FR, Crawford ED, Kreis W, Levasseur Y. Aminoglu-
`tethemide Study Group. Adrenal steroid levels in castrated men
`with prostatic carcinoma treated with aminoglutethemide plus
`hydrocortisone. Cancer Res 1987;47:4,736—9.
`. Block M, Trump D, Rose DP, Cummings KB, Hogan TF. Eval-
`uation of aminoglutethemide in stage D prostate cancer: an as-
`sessment of efficacy and toxicity in patients with tumor refractory
`to hormonal therapy. Cancer Treat Rep 1984;36:719-22.
`. Lippman A. Cohen F, Samojlik E, Enel N, Park Y, Kirschner
`M. Aminoglutcthemide for metastatic prostatic cancer (abstr).
`Proc Am Soc Clin Oneal l983;2:144.
`. Rostom AY, Folkes A, Lord C. Notley RG, Schweitzer PAW,
`White WF. Aminoglutethemide therapy for advanced carcinoma
`of the prostate. Br J Ural 1982;54:552-5.
`. Bhanalaph T, Varkarakis MH. Murphy GP. Current status of
`bilateral adrenalectomy for advanced prostatic carcinoma. Ann
`Surg 1974;179:17—23.
`. Labrie F, Dupont A, Giguere M, et al. Combination therapy
`with flutamide and castration (orchiectomy or LHRH agonist):
`the minimal endocrine therapy in both untreated and previously
`treated patients with advanced prostate cancer. Prog Clin Biol
`Res 1988;260:41—62.
`. Benson RC. Loear J B. Gill GM. Treatment of stage D honnone-
`resistant carcinoma of the prostate with estramustine phosphate.
`J Ural 1979; 12 12452-4.
`. Johnson DE, Babaian RJ, von Eschenbach AC, Wishnow Kl,
`Tenney D. Ketoconazo1e therapy for hormonally refractive met-
`
`astatic prostate cancer. Urology 1988;81:132-4.
`
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