Volume 146
`
`December 1991
`
`Number 6
`
`T
`
`J --------
`I
`r
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`®
`
`Official Journal of the American Urological Association, I~c.
`Founded In 1917 By Hugh Hampton Young
`
`Annual Meeting, American Urological Association, Inc., Washington, D. C., May 10-14, 1992
`
`JANSSEN EXHIBIT 2049
`Mylan v. Janssen IPR2016-01332
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`

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`The Journal of
`
`®.
`
`Editor
`John T. Grayhack
`1120 North Charles Street
`Baltimore, Maryland 21201
`
`Associate Editor
`Terry D. Allen
`Dallas, Texas
`
`Section Editor
`Stuart S. Howards
`Charlottesville, Virginia
`
`Associate Editor
`Jay Y. Gillenwater
`Charlottesville, Virginia
`
`Section Editor
`Patrick C. Walsh
`Baltimore, Maryland
`
`EDITORIAL BOARD
`
`Mid-Atlantic
`A. Barry Belman
`Washington, D. C.
`
`New England
`Bernard Lytton
`New Haven, Connecticut
`
`New York
`Michael J. Droller
`New York, New York
`
`North Central
`Joseph W. Segura
`Rochester, Minnesota
`
`Northeastern
`Abraham T. K. Cockett
`Rochester, New York
`
`South Central
`Robert E. Donohue
`Denver, Colorado
`
`Southeastern
`Floyd A. Fried
`Chapel Hill, North Carolina
`
`Western
`Duncan E. Govan
`Stanford, California
`
`BOARD OF CONSULTANTS
`
`Marc Garnick
`Boston, Massachusetts
`
`Ryoichi Oyasu
`Chicago, Illinois
`
`Allyn W. Kimball
`Baltimore, Maryland
`
`Bruce McClennan
`St. Louis, Missouri
`
`William M. Murphy
`Memphis, Tennessee
`
`Howard Pollack
`Cheltenham, Pennsylvania
`
`William U. Shipley
`Boston, Massachusetts
`
`Lynwood H. Smith, Jr.
`Rochester, Minnesota
`
`Colin White
`New Haven, Connecticut
`
`FORMER EDITORS
`
`Hugh H. Young
`1917-1945
`
`J. A. Campbell Colston
`1945-1966
`
`Hugh J. Jewett
`1966-1977
`
`William W. Scott
`1977-1983
`
`Herbert Brendler
`1983-1985
`
`The Journal of Urology (ISSN 0022-5347) is the Official Journal of the American Urological Association, Inc., and is published monthly by
`Williams & Wilkins, 428 East Preston Street, Baltimore, MD 21202. Second class postage paid at Baltimore, MD, and at additional mailing
`offices. Subscription rates individual $169.00 ($234.00 foreign); institutions $189.00 ($254.00 foreign); in-training $83.00 ($148.00 foreign); single
`copy $23.00 ($28.00 foreign).
`Subscription prices subject to change. The GST number for Canadian subscribers is 123394371. To m;der call 1-800-638-6423 from anywhere in
`the U.S.; in Maryland call1-800-638-4007. POSTMASTER: Send address changes to The Journal of Urology, 428 East Preston Street, Baltimore,
`MD 21202. Indexed by Current Contents and Index Medicus. Copyright© 1991 by American Urological Association, Inc.
`A4
`
`

`

`LETTERS TO THE EDITOR
`
`1621
`
`mate interchange might possibly be misinterpreted and misused. I,
`therefore, asked Dr. H. Logan Holtgrewe, whose opinions I value highly
`as a urologist and as a leader in the interactic>ns on the social scene,
`about his reaction to publication of the Letter. I received the following
`Letter in reply and believe that it warranted sharing with all of you.
`
`3. Bruskewitz, R. C., Iversen, P. and Madsen, P. 0.: Value ofpostvoid
`residual urine determination in evaluation of prostatism. Urol(cid:173)
`ogy, 20: 602, 1982.
`
`Note by Dr. H. Logan Holtgrewe. The thrust of the paper by Katz et
`al was to extol the virtue of transurethral incision over transurethral
`resection of small prostate glands. They dealt lightly, if at all, with the
`indications for the operation. As Doctor Rohlf notes, the only specific
`reference was "patients were candidates for incision if they had a
`clinically benign prostate, peak urinary flow rate of less than 15 mi.
`per second and an estimate 15 gm. or less of resectable prostatic tissue."
`Katz et al may well have insisted upon other criteria before operating
`but if they did so, their paper fails to state these additional criteria,
`leaving the reader with the assumption that a slow stream was the sole
`indication for the operation.
`Doctor Rohlf is right on! A flow rate of less than 15 cc per second is
`certainly not of itself an indication for a prostate operation. Doctor
`Rohlf also is correct that variation in practice styles of urologists
`accounts for the variation in the .incidence of prostatic surgery in age(cid:173)
`adjusted populations in different geographic areas of our co.untrY_-~he
`variation is as great as 3-fold. He is equally correct that this vanatwn
`in the incidence of prostate surgery has brought this operation to the
`attention of the Government and its health care agencies, including
`the Health Care Financing Administration. It also may account for the
`fact that benign prostatic hyperplasia was among the first 3 diseases
`for which the Federal Government decreed there would be guidelines
`of treatment. Fortunately, due to the fact that the American Urological
`Association was already well along in a scholarly construction of
`guidelines for the treatment of benign prostatic hyperplasia, the gov(cid:173)
`ernmental agency that the Congress created to oversee guideline de(cid:173)
`velopment literally hired the existing American Urological Ass?ci~tion
`committee chaired by Dr. John McConnell to complete these guidelmes,
`which were in the hands of the Federal Government by December 1,
`1990.
`
`Reply by Authors. Our patients were not selected for transurethral
`incision of the bladder neck and prostate based on a single parameter.
`We agree with Doctor Rohlf that a transurethral operation should not
`be performed solely for a slow urinary stream. We evaluated men 50
`years and older who presented with symptoms of prostatism. As noted
`in the Methods Section, our patient assessment included a symptoms
`questionnaire, physical examination, urine culture, uroflowmetry and
`cystoscopy. The symptoms evaluated included force of stream, hesi(cid:173)
`tancy, intermittency, daytime and nighttime urinary frequency and
`urgency /incontinence. The symptom scoring system is given in table 1
`in the article. Treatment recommendations were based on this evalua(cid:173)
`tion and not on a single factor. After evaluation those patients who
`decided to proceed with surgical intervention underwent examination
`while they were under anesthesia. The decision was then made to
`proceed with either transurethral prostatectomy or, for patients with a
`small prostate, incision.
`Except for a total outflow obstruction, the indications for a bladder
`outlet operation are not absolute. We excluded symptomatic patients
`with peak urinary flow rates of greater than 15 mi. per second because
`they are less likely to have bladder outlet obstruction and have signif(cid:173)
`icantly lower success rate after a prostatic operation than those with
`lower preoperative flow rates. 1 Doctor Rohlf discusses other criteria for
`bladder outlet obstruction, including residual urine without stating
`what volume he considers to be significant. However, residual urine
`may occur in the absence of bladder outflow obstruction and markedly
`3
`obstructed bladders may empty completely. 2
`•
`We believe that our selection criteria were appropriate in identifying
`symptomatic patients with bladder outlet obstruction. With a mean
`followup of more than 2 years, the incisional procedure resulted in a
`statistically and clinically significant decrease in total symptom scores
`(table 3 in article) and an increase in peak flow urinary flow (table 2
`in article).
`
`1. Jensen, K. M.-E., J0rgenson, J. B. and Mogensen, P.: Urodynamics
`in prostatism. I. Prognostic value of uroflowmetry. Scand. J.
`Urol. Nephrol., 22: 109, 1988.
`.
`2. Abrams, P. H. and Griffiths, D. J.: The assessment of pros.tatlc
`obstruction from urodynamic measurements and from residual
`urine. Brit. J. Urol., 51: 129, 1979.
`
`RE: PROSTATE SPECIFIC ANTIGEN FOR ASSESSING
`RESPONSE TO KETOCONAZOLE AND PREDNISONE IN
`PATIENTS WITH HORMONE REFRACTORY METASTATIC
`PROSTATE CANCER
`
`G. S. Gerber and G. W. Chodak
`
`J. Urol., 144: 1177-1179, 1990
`
`To the Editor. Since so much of the literature pertaining to prostate
`· cancer is directed toward treating potentially curable or endocrine
`responsive tumors, it was gratifying to read an article directed toward
`endocrine unresponsive carcinoma of the prostate. This is an area that
`requires much more basic and clinical research. In 1973 the Veterans
`Administration Cooperative Urological Research Group suggested that
`when a patient with advanced prostate cancer became refractory to 1
`form of androgen deprivation and had relapse it was unlikely he would
`respond significantly to any other form of endocrine therapy. 1 In 1976
`Prout et al suggested that prostate cancer consists of a heterogeneous
`population of cancer cells, some of which are androgen sensitive and
`others that are not. 2 The further proliferation and spread of the latter
`group of cells eventually causes endocrine refractory prostate cancer.
`The authors reported on 15 patients with endocrine refractory met(cid:173)
`astatic carcinoma of the prostate who were treated with ketoconazole
`and prednisone. All patients had been treated previously with bilateral
`orchiectomy alone or with luteinizing hormone-releasing hormone ag(cid:173)
`onist alone. Of the 15 patients 10 had also received radiotherapy. None
`of these 15 patients showed a significant improvement in terms of
`increased survival, or an objective or subjective response except for a
`decrease in prostate specific antigen (PSA) and bone pain. Since
`ketoconazole presumably acts by inhibiting gonadal and adrenocortical
`steroid synthesis, the authors have again substituted 1 form of endo(cid:173)
`crine therapy for another. Therefore, one would not expect a significant
`improvement unless the new therapy had an effect beyond androgen
`deprivation, for example a direct cytotoxic effect. Eichenberger et al
`recently suggested a direct cytotoxic effect for ketoconazole. 3 Perhaps
`a reason why estramustine phosphate has not been too successful in
`the treatment of endocrine refractory prostate cancer patients is that
`the principal activity of this drug has been largely through its estradiol
`moiety.4
`It is likely that the effects of ketoconazole and prednisone in decreas(cid:173)
`ing PSA levels have little or nothing to do with clinical improvement.
`All of us who treat prostate cancer patients have noted an increasing
`PSA value when a patient has a relapse after radical prostatectomy or
`radiation therapy. After androgen ablation the PSA level often de(cid:173)
`creased or returned to normal even though the prostate cancer was
`progressing clinically. Kaplan et al suggested that this phenomenon
`might occur partly because "testosterone is required to drive the syn(cid:173)
`thesis of PSA by prostatic tissue."5 Therefore, a decrease in the PSA
`level after endocrine intervention is not necessarily synchronous with
`clinical improvement.
`Reduction in bone pain is largely subjective and difficult to evaluate.
`The reduction in bone pain reported by the authors could have been
`related partly to bed rest, simultaneously administered analgesics and/
`or the prednisone. Almost all of us can treat organ-confined disease or
`prostatic carcinoma still responsive to androgen deprivation but what
`can we do for the patient with endocrine unresponsive carcinoma of
`the prostate? We definitely need more research in this area.
`
`Respectfully,
`Clyde E. Blackard
`Park Nicollet Medical Center
`Minneapolis, Minnesota 55416
`1. Hurst, K. S. and Byar, D. P.: An analysis of the effects of changes
`from the assigned treatment in a clinical trial of treatment for
`prostatic cancer. J. Chron. Dis., 26: 311, 1973.
`2. Prout, G. R., Jr., Kliman, B., Daly, J. J., MacLaughlin, R. A.,
`Griffin, P. P. and Young, H. H., II: Endocrine changes after
`diethylstilbestrol therapy; effects on prostatic neoplasm and
`pituitary-gonadal axis. Urology, 7: 148, 1976.
`.
`3. Eichenberger, T., Trachtenberg, J., Toor, P. and Keatmg, A.:
`Ketoconazole: a possible direct cytotoxic effect on prostate car(cid:173)
`cinoma cells. J. Urol., 141: 190, 1989.
`4. McMillin, J. M., Seal, U. S. and Doe, R. P.: Effect of oral estra-
`
`

`

`1622
`
`LETTERS TO THE EDITOR
`
`mustine phosphate on pituitary, gonadal, and adrenal function
`in the green monkey (Cercopithecus aethiops sabaeus). Invest.
`Urol., 15: 151, 1977.
`·
`5. Kaplan, 1., Prestidge, B. R., Cox, R. S. and Bagshaw, M. A.:
`Prostate specific antigen after irradiation for prostatic carci(cid:173)
`noma. J. Urol., 144: 1172, 1990.
`
`Reply by Authors. Doctor Blackard raises important questions about'
`the significance of our observations regarding the effect of ketoconazole
`in patients with hormone refractory prostate cancer. Secondary hor-
`. monal therapy in various forms has been used for many years with a
`small but real response rate of approximately 20%. As cited in our
`paper, other studies observed an objective response in approximately
`20% of the patients treated with ketoconazole using other objective
`tests. The focus of our report was to show that perhaps this subset can
`be identified more easily by following serum PSA levels, thereby
`obviating the need for the other studies and identifying nonresponders
`more rapidly. Doctor Blackard suggests that a decrease in PSA may
`have no clinical significance and he states that the PSA level often
`decreases or returns to normal when the patient has clinical progres(cid:173)
`sion. This latter comment is an uncommon event, however, since less
`
`than 10% of the patients demonstrate progressive disease without first
`having an increasing PSA level. Furthermore, we have not said that
`survival was unaffected but, rather, we have insufficient data to deter(cid:173)
`mine the impact on survival. We acknowledge that the improvement
`in bone pain is subjective and may be due to the simultaneous admin(cid:173)
`istration of prednisone. However, the clear reduction in analgesics by
`many of these patients would argue that the benefit is real, even if
`short-lived. Furthermore, a recent report by Trachtenberg provides
`evidence that ketoconazole is effective in the absence of steroids.1
`Finally, although radiation had been previously administered to some
`of these patients, the timing of the ketoconazole and the demonstration
`of an increase in PSA after radiation but before the medication argue
`for attributing this response to the drug. We certainly agree that more
`research is needed but the observations by others as well as our own
`findings suggest that more investigation with ketoconazole or its ana(cid:173)
`logue appears to be warranted, since the drug does appear to have some
`clinical benefit in these patients in addition to its effect on serum PSA.
`
`1. Trachtenberg, J.: Ketoconazole therapy in advanced prostatic can(cid:173)
`cer. J. Urol., 137: 959, 1987.
`
`