This material may be protected by Copyright law (Title 17 U5. Code)
`
`THE JOURNAL 01* UROLOGY
`Vol. 72, No. 3, September 1954
`Printed in U.S.A..
`
`CORTISONE TREATMENT IN ADVANCED CARCINOMA OF THE
`PROSTATE
`
`GERALD M. MILLER AND FRANK HINMAN, JR.
`
`From the Sub-Department of Urology, University of California School of Medicine, San
`Francisco, Calif.
`
`Intense interest has arisen in the role of the adrenal glands in carcinoma of the
`prostate, stimulated by Huggins’ work with bilateral adrenalectomy.‘! 2' 3
`In 1950, Sprague“ in reviewing and discussing the physiologic effects of corti-
`sone brought out, first, that cortisone causes a depression of the endogenous
`production of adrenal cortical hormone, second, that experimentally, cortisone
`causes atrophy of the adrenal cortices in rats and, third, that a depression of
`urinary 17-ketosteroids occurs with the administration of cortisone. Wilkins et
`al.5v 6 demonstrated this clinically by showing excellent results with cortisone in
`children masculinized by congenital adrenal hyperplasia.
`It therefore seemed reasonable to us that the use of relatively large doses of
`cortisone in patients with advanced prostatic carcinoma might produce a
`“medical adrenalectomy” that could be as effective as actual surgical bilateral
`adrenalectomy. We also believed that this would give us an opportunity to
`study some of the still unknown factors existing in the hormonal interrelation-
`ship present in prostatic cancer. Taylor et al.7' 3~ 9 in 1950 had reported on the
`use of ACTH and cortisone in a wide variety of malignancies including a few
`cases of prostatic cancer but no detailed and extensive studies of carcinoma of
`the prostate had been reported at the time we undertook this study. Since then,
`there has been a case report in the literature” and more recently Harrison, Thorn,
`Read at annual meeting, Western Section of American Urological Association, San
`Francisco, A ril 27-30, 1953.
`Supporte by Institutional Grant, American Cancer Society. Cortisone acetate (Cor-
`tone) was generously supplied by Merck & Co. Inc.
`1 Huggins, C. and Scott, W. W.: Bilateral adrenalectomy in prostatic cancer; clinical
`features and urinary excretion of 17-ketosteroids and estrogens. Ann. Surg., 122: 1031-1041,
`1945.
`
`2 Huggins, C. and Bergenstal, D. M.: Surgery of the adrenals. J.A.M.A., 147: 101-106,
`1951.
`
`3 Huggins, C. and Bergenstal, D. M.: Inhibition of human mammary and prostatic
`cancers by adrenalectomy. Cancer Research, 12: 134-141, 1952.
`4 Sprague, R. G. and others: Observations on the physiologic efi’ects of cortisone and
`ACTH in man. Arch. Int. Med. 85: 199-258, Feb. 1950.
`5 Wilkins, L., Lewis, R. A., Klein, R. and Rosemberg, E.: The suppression of androgen
`secretion by cortisone in a case of congenital adrenal hyperplasia; preliminary report. Bull.
`Johns Hopkins Hosp., 86: 249-252, 1950.
`3 Wilkins, L. and others: Further studies on the treatment of congenital adrenal hyper-
`plasia with cortisone. J. Clin. Endocrin. & Metab., 12: 257-295, 1952.
`7 Taylor, S. G. III, Ayer, J. P. and Morris, R. S., Jr.: Cortical steroids in treatment of
`cancer; observations on efi’ects of pituitary adrenocorticotropic hormone (ACTH) and corti-
`sone in far advanced cases. J.A.M.A., 144: 1058-1064, 1950.
`3 Taylor, S. G. III and others: Effect of ACTH and cortisone on advanced malignant
`disease. Abstr. of ACTH Adrenocortical Steroid Conference, Am. Coll. Surg., October 1950.
`9 Taylor, S. G. III and Morris, R. S., Jr. : Efi’ect of ACTH in certain types of malignancy.
`Proc. 1st Clin. ACTH Conf., Philadelphia: The Blakiston Co., 1950, p. 331.
`1° Hayward, W. G.: The treatment of late relapse in prostatic carcinoma by cortisone.
`J. Urol., 69: 152-156, 1953.
`1‘ Harrison, J. H., Thorn, G. W. and Jenkins, D. : Total adrenalectomy for reactivated
`carcinoma of the prostate. N. Eng. J. Med., 248: 86-92, 1953.
`485
`
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`

`
`486
`
`GERALD M. MILLER AND FRANK HINMAN, JR.
`
`and Jenkins“ in their paper on bilateral adrenalectomy mentioned that they
`treated 9 patients with cortisone and all but one had some relief of pain and an
`increased sense of well-being but without objective evidence of regression of
`neoplastic tissue. They used an average of 25 to 37 mg. of cortisone a day after
`initial doses of 100 mg. for several days. Valk” has also recently reported on the
`use of cortisone combined with estrogens.
`METHODS
`
`Choice of patients. Ten patients with far advanced disseminated carcinoma of
`the prostate were treated with cortisone (table 1). All had been treated previously
`with orchiectomy and estrogens with remissions of varying duration and extent,
`and were in severe exacerbation at the time cortisone was started. Stilbestrol
`
`was stopped at least one week before baseline studies were obtained and cortisone
`begun. Estrogens were not given during cortisone therapy to any of these pa-
`tients but we are now determining on another series of patients any possible
`supplemental effect that estrogens might have in combination with cortisone.
`Dosage. All but one of the patients were started on 50 mg. of cortisone per day
`by mouth in four divided doses. Most of the beneficial effects were obtained on
`this dosage schedule, although a few needed 100 mg. per day. As soon as the
`initial desirable effect lessened or if it did not occur within one month, the original
`50 mg. dose was doubled. One patient was eventually given as much as 200 mg.
`per day for a prolonged period. It would be expected that adrenal suppression
`would be more complete if intramuscular injection of cortisone were used in-
`stead of the oral route.“
`
`RESULTS
`
`1. Symptomatic improvement. Eight out of the 10 patients in our series had
`tremendous subjective,
`in some objective,
`improvement
`in symptoms. This
`beneficial effect included: 1) complete loss to marked decrease in pain, 2) im-
`provement in appetite and in 5 patients weight gain, 3) increased sense of well-
`being with increased strength, and 4) increased use of extremities.
`It was most gratifying to see some of the patients who had been taking fre-
`quent and large doses of narcotics no longer need them'and be able to walk with-
`out pain and stiffness. Some would come back to the clinic after 3 to 4 weeks
`stating that they were able to walk miles, drive their cars again, and in general
`felt better than they had in many months.
`2. Improvement in local prostatic lesions. Six out of 10 patients showed moderate
`to marked improvement in their local lesion by rectal palpation. In 3, there was
`complete disappearance of any palpable prostatic tissue but palpable tumor re-
`turned in 2 patients after 4 and 5 months. The rest had softening, loss of nodu-
`larity, and decrease in size of the lesion.
`We have x-ray evidence of regression in the local lesion in one of our patients.
`The initial right hydronephrosis (fig. 1, A) cleared on cortisone therapy as the
`local
`lesion markedly decreased in size (fig'. 1, B), but became progressively
`more severe as the local lesion again enlarged (fig. 1, C’).
`
`1’ Valk, W. and Owens, R. H.: Effect of cortisone on patients with carcinoma of prostate.
`J. Urol., 71: 219-225, 1954.
`
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`

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`r
`
`PROSTATIC CARCINOMA
`
`487
`
`3. Acid and alkaline phosphatase findings. Four of the 10 patients initially had
`elevated serum acid phosphatase and 3 of these showed definite and consistent
`decrease, in one to normal levels. Two of these patients had improvement in
`their local lesion but one of the two had no symptomatic improvement. Two of
`the 10 had a marked progressive increase in acid phosphatase and yet both had
`wonderful symptomatic relief and improvement in their local lesion. The re-
`mainder had no essential change in acid phosphatase. Thus there seems to be no
`particular relationship between changes in the acid phosphatase and sympto-
`matic improvement or change in the local lesion.
`Two of the patients with initially elevated levels of serum alkaline phosphatase
`had a definite and progressive increase, while the remainder had no essential
`change.
`4. Improvement in bony metastases by :v—ray. None of our patients showed im-_
`provement in their bony metastases, as determined by serial x-ray studies. In
`fact, 6 actually had an increase in the number and size of metastases. The others
`showed no real change.
`
`HORMONAL STUDIES
`
`1. 17—Ketosteroid excretion. The excretion of 17—ketosteroids was followed in
`
`all of our patients. Four of the 10 patients had a definite decrease in their urinary
`17-ketosteroids. In the others, all of whom had very low levels to begin with
`(below 2 mg./24 hrs.) there was no change. It is of interest that all but one
`patient had initial 17-ketosteroid levels of 4.1 mg./24 hrs. or less, the exception
`having an initial level of 6.8 mg./24 hrs. The relationship between changes in
`17-ketosteroids and clinical improvement can be summarized as follows:
`
`.
`.
`.
`.
`.
`Decrease in 17-ketosteroids and clinical improvement .
`.
`.
`.
`.
`No change in 17-ketosteroids and clinical improvement .
`No change in 17-ketosteroids and no clinical improvement. .
`
`.
`.
`
`.
`.
`
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`. .. 4 cases
`. .. 4 cases
`.
`.
`. 2 cases
`
`2. Protein-bound iodine. Serial determinations of the protein-bound iodine as
`a measure of pituitary thyrotropic and thyroid function were done on 4 of our
`10 patients. All 4 showed a consistent and steady decrease from an average con-
`trol level of 6.5 micrograms/100 cc to an average of 3.8 micrograms/ 100 cc.
`This is consistent with reported results.13v 14
`3. Pituitary gonadotropin excretion (FSH + LH). The urinary excretion of
`gonadotropin was followed in 3 of the patients, with initial levels on 2 more. In
`all 5, the reactions were initially zero. The 3 patients which were followed had
`marked increases in gonadotropin excretion while on cortisone, their levels rang-
`ing between 80 and 220 M.U. /24 hrs. This rise of gonadotropin during cortisone
`(and ACTH) therapy has been previously described during treatment of arthritis
`and other diseases.”
`
`13 Wolfson, W. Q. and others: Corticogenic hypothyroidism; its regular occurrence and
`clinical significance during prolonged therapeutic administration of ACTH or cortisone.
`J. Lab. & Clin. Med., 36: 1005-1006, 1950.
`14 Hardy, J. D., Riegel, C. and Erisman, E. P.: Experience with protein bound iodine
`(PBI); effect of ACTH and cortisone on thyroid function. Am. J. M. Sc., 220: 290-292, 1950.
`15 Sohval, A. R. and Soffer, L. J. : The influence of cortisone and adrenocorticotropin on
`urinary gonadotropin excretion. J. Clin. Endocrin., 11: 677-687, 1951.
`
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`
`
`B E
`C0nl?1‘‘i;(‘)ENE
`5: 5?‘
`STARTED
`Z E
`AND nos):
`3 :2:
`8 E E min D3‘!
`8
`ms
`
`SYMPTOMATIC
`CHANGE (SUBJECTIVE
`AND oapzcrrvz)
`
`CHANGE IN LOCAL
`i>nosrAr1c LESION
`
`ACID
`rnosmurnsa
`
`ALKALINE
`PHOSPHATASE
`
`ME1¥A::AYSES
`
`17'K"°5““°m5 sub_
`i_ec-
`txve
`
`0b_
`39¢-
`tlve
`
`I:Iil:I(i-élsilglg
`
`turnove-
`mmr
`
`8817
`
`TABLE 1
`
`3-30-52:
`100
`
`No decrease in pain.
`Some increase in
`appetite. No weight
`change.
`
`6-19-52:
`50
`7-22-52:
`100
`8-2-52:
`200
`11-1-52:
`150
`
`8-8-52: 50
`
`5
`<
`E
`E
`as
`
`GW'
`59
`
`FC1
`52
`
`ML
`77
`
`RS
`76
`
`x
`
`x
`
`x
`
`x
`
`Complete disappear-
`ance of palpable
`prostatic tissue-
`originally there was
`stony hard 2 cm.
`nodule.
`Complete relief of se- Complete disappear-
`vere pain for 1
`ance of palpable
`month with
`prostatic tissue—-
`marked increase of
`was originally large,
`appetite 6: 12 lb.
`stony and nodular.
`weight gain. Then
`After 5% months
`mild intermittent
`began to reappear.
`pain for 1-2 days
`every 2 \veeks. Im-
`proved urination.
`Tremendous im-
`provement in
`strength, appetite.
`Loss of pain. 10 lb.
`weight gain, ability
`to walk, increase of
`urinary.stream.
`8-3-52: 50 Complete loss of pain
`in back and legs,
`allowing him to
`walk miles each
`day. Tremendous
`improvement in
`appetite-before
`severe anorexia.
`Weight gain 17 lb.
`in 6 wks.
`Increased appetite,
`decreased pain, in—
`creased strength.
`
`Decreased
`45 -> 18 —>
`33 —> 26
`(KA)
`
`Increased
`29 -> 37 -—>
`55 -> 73 —>
`96
`(KA)
`
`Increased
`
`Low to begin
`(1.2 mg./24°).
`No change.
`
`Increased
`
`Increased
`6 -> 11 --
`13 —> 15
`(B)
`
`Definite fall
`(4.1 —> 1 mg./
`24°).
`
`Increased af-
`ter 3
`months,
`1 -0 6 -0
`11 —o 22
`
`(B)
`
`Decrease,
`then same
`22 -+ 10 -+
`20
`(B)
`
`(B)
`
`No change
`
`‘
`a Down (3.9 -—> 2
`mg./24°).
`'
`I
`
`Increased
`
`Low to begin
`~ with (1.9
`mg./24°). No
`change.
`
`0
`
`x
`
`x
`
`x
`
`x
`
`x
`
`x
`
`None except local
`lesion and im-
`provement in
`phosphatases.
`Bilateral adre-
`nalectomy done.
`Six months. Bilat-
`eral adrenalec-
`tomy then done.
`
`0
`
`I
`I Ten weeks. Died
`10-26-52, bron-
`'
`chopneumonia.
`
`x
`
`Three months.
`
`Softening and shrink- Slight in—
`ing of nodules. (At
`crease
`post, gland very
`1 —> 5
`small and soft.)
`
`Softening of gland
`with disappearance
`of nodularity.
`Smaller. Marked
`improvement in
`urination. Residual
`from 300 cc to less
`than 80 cc.
`
`No change.
`
`x
`
`GD
`62
`
`10-4-52:
`50
`10-18-52:
`
`75
`
`' Able to get out of
`,
`bed where before.
`
`Increased
`then de-
`creased,
`
`No change
`14 -> 20 ->
`24 —> 18
`
`then slight
`increase
`
`(KA)
`
`Increased in
`size‘. Col-
`lapsed verte—
`brae
`
`Low to begin
`with (2.0
`mg./24°). No
`change.
`
`x
`
`0
`
`2% weeks.
`
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`
`I
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`"Hf‘NVWNIH}INV}I..-I(INV}I5I’I"IIW‘I/\I(I’IV1I5I€)
`
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`

`
`11-24-52:
`50
`1-14~53:
`100
`
`he could not. De-
`creased swelling of
`legs by measure-
`ment. All very
`transient. Collapsed
`vertebrae—-para-
`plegia after 2%
`weeks.
`Complete disappear-
`ance of pain, in-
`crease of strength
`and appetite.
`No cliange—on1y
`mild pain to begin
`with. No improve-
`ment in weight or
`appetite, or sense
`of Well-being.
`Disappearance of se-
`vere pain & stiff-
`ness. No longer
`required pain med-
`ication. Able to
`walk well, climb up
`& dow-n—before
`had to lift rt. leg
`with hands. In-
`creased appetite &
`strength. Gained 10
`lbs.
`Some decrease in dif-
`ficulty of urination.
`Nocturia from
`7-8X to 3X; resid-
`ual from 300 cc to
`90 cc. Disappear-
`ance of back pain.
`Increased appetite.
`Marked increase in
`strength, sense of
`well—being, appe-
`tite. Loss of nausea
`and vomiting.
`
`’ Referred by Dr. Frederick S. Howard
`‘I’ Referred by Dr. Miley B. Wesson.
`t Referred by Dr. Sidney Olsen.
`
`No change.
`
`No change.
`
`I
`
`: Increased (De-
`veloped path.
`fracture of
`pubic ramus).
`No change
`
`l
`
`Slight in-
`crease
`0.8 —» 2.6
`(B)
`Essentially
`unchanged.
`6.5 —> 5.9
`(KA)
`
`No change
`2.5 —> 2.0
`(B)
`
`No change
`10.5 -0 11
`(KA)
`
`Complete disappear-
`ance of three fixed
`stony nodules. Two
`returned after four
`months.
`
`Increased
`7 -5 11 —> 17
`(B)
`
`No change
`7 —> 9 —> 8
`(B)
`
`Progression
`
`Not done. Were
`3.4 mg./24°
`before adre-
`nalectomy.
`Low to begin
`with (1.0
`mg./24°). No
`change.
`
`Decreased (6.8
`-’ 1.9 mg./24°).
`
`8 weeks. Bilateral
`adrenalectomy
`done.
`
`No remission.
`
`455 months.
`
`Shrinking of gland
`from 3+ to 1+
`with loss of nod-
`ularity and marked
`softening. After 3
`months began to
`increase in size.
`
`No change.
`
`Decreased
`7 -9 1
`(B)
`
`No change
`5—>7
`(B)
`
`No change
`
`1.0. No change.
`
`Decreased
`22 —- 8
`
`Not done
`
`Progression
`
`Decreased
`(2. 4 —» 1 . 8)
`
`3 months. (Still
`doing _well.)
`
`
`
`VWONIOHVOOILVLSOHJ
`
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`
`GER.-\LD .\I. ?\1ILI.l-ZR AND F‘I{.~\.\'K I-II\'.\I.\N, JR.
`
`l"1(;.1. Ax-.xt:1~<-.l uI‘_\_.‘ lII'ogr:11n slniawiiig l1}'tlroImphrosis. ser'riml:1r_\' to l.lI'(‘ll!r.'1l iiivolvtmteiit
`by pi'nst:tt:(‘ t-.iu‘cu1o11m. B, after r(:n11ssIon on mrtisolit-.
`lll(‘I':|])_\', slmwmg rt-gt‘:-.ss1oi1 of
`diI:1l::I|on. (.‘,:1ftm‘1‘:a|:1psv.
`
`[’f\'(‘I‘(‘ll(JII of
`1ll'i1::u‘_\_'
`'l‘lIt‘
`fconipritirid F)
`c=.'rcrc£'i'on
`I7-Nyu'r0.t'_i;-('0:'i'ir:0i(i
`3}.
`an‘:-1':Lg<‘.<l 13
`trnmpound I“ \\'a.s studied in 5 of the pil.l'i(!l1t!-§. The initial
`l(!\-'(‘.l.‘-‘.
`mg./24 hm. and all \\'eI'e ('.0I1Sldel'e(l witliiri the normal r:1ngt*.. F0ll0win;_.r, the ad-
`minist1'at.ion of cortisone they all had the {‘.X})(’(‘-led increase in I?'—l1_ytli'oxy—
`{tortivoid {‘.X(’]‘{!t-i()lI.
`
`C{J1\’l PI. I {IA 'l‘I U N5
`
`in our svrivs \\':1:.«‘
`'l‘ht>. only t:omplit:a.t.ion from Cort-isone thempy (‘.I1(‘.()1ll1'(.(!]‘[‘(l
`the I'vatrti\-':1t.ion of an old lll('.E‘.I' in one pat-lent. His symptoms l't‘H])tJI](lE‘lll to tax-
`t-oiisivte ltltadical
`t.l1m‘ap_V tlespite the t.*.0ntinual'.i01) of (.*oI'tisoi1v. No l‘|£‘II1()I'I'llEl§I,tE
`or pvrfoi-at.ion (J(!('.llI'['(‘d, alt-hough this danger should he kept. in mind. ’I‘lu~r<-t'm-t-,
`it \\'0Lll{l l)t! lll]\\-'iH(P to t'1'{‘.a-t.
`:3, pat-i(‘.nl with a known £u'.ti\'(‘. or 1'ot'vIit|_\' urtivv 11lt‘tPI'
`\\‘it.h cortisone.
`
`])l1I.{’{‘[l on :1 low sotlillm diet to p1‘(-.\'<'11t tho po.-'sil)lt‘.
`All of our pativnts ‘.\'t‘I‘(‘.
`0t'.t'.11r1'e11(tt: of vtltélna from the sodium l'(‘.llE‘.lIli03l avtion of t'o1'tisom-.
`'l'l1ost- who
`
`did not have fmilk ('a1'diat* tlisvziso xvere pla.{:ed on 21 diet t':01“1taini11g.§ I gm._,-"24 hrs.
`of sodium, and the nt..|wi's on 300 mg./'da_v. The patients on .30 mg. {-011 is-som‘ a
`day we1'e §I,iven 3 gm. of ]}(Jtaé-5.‘-iilln‘1 chloride (t'ahlets) by month each day. Wlion
`the ('.()I'li:-i(}I}(P close was I‘ai.~:vd to I00 mg.,-"rla_v, the potassium cliloridu \\':1.'-:
`in-
`creased to [5 gm. in tlivitlvd (l(J5~'('H. If stillwstrol should he gi\'mi along‘ with vorti-
`sonv, thou tho (l'.u1g('I‘.~; of salt ]'{‘t(‘IItl()ll and :-;I1l)sm|11(\11t- (‘.(llI?I'n3. woultl l){'
`l1’IllI‘lI
`il1f!l‘I?(‘lSC(.l. Froqlimit injm-tions of :1 Inch-.1irial diuretir-.mi,r_r,l1t than he I1(‘('{'t~Zt-={tl'_\_-'.
`N0 diflivult_\' with l]_\_']l[‘I'l('l1Sl{}]1 \\':1;~:
`[‘Il(!tJllI1l('I‘(‘(l. One paI.l(‘I1L \\'a.s :1 mild
`tlizllwtiv but no a(l\'('1’:-:0 uIl"v<‘.I:-; \\'('I'[? notvd.
`
`The danger.-L: of s-tiidden \\'ll'l1(lI'E1\\':I.l of vortisom-.
`
`:ift'i~r 21, pi-olongecl cotirse are
`
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`
`PROSTATIC CARCINOMA '
`
`Iflflohl Iltnlluloffldi
`
`iv
`
`FIG. 2. Cortisone‘ and bilateral adrenalectomy: comparative results ‘(adrenalectomy
`figures are from the combined series,of Huggins and Bergenstal, ‘ West et al.” Harrison et
`al.“ and Leberman et al.")
`
`real inasmuch as such patients would be temporarily in a state of adrenal in-
`sufliciency. By gradual withdrawal, this complication can be avoided.
`
`THE NUMBER OF PATIENTS OBTAINING” REMISSION AND
`OF THIS REMISSION
`
`LENGTH
`
`We feel that 8 out of the 10 patients had a clinical remission on cortisone
`therapy and in 6 out of these 8 there was some‘evidence of'tumor regression by
`change in the local prostatic lesion ‘or acid phosphatase decrease.
`However, the length of the remission was relatively short and varied from 17
`to 180 days with an.average of 82 days.
`
`PILBLISHED CASES OF BILATERAL ADBENALECTOMY
`COMPARISON
`Since we have attempted by means of large doses of cortisone to produce a
`“medical adrenalectomy,” a comparison of our results with the effects of surgical
`bilateral adrenalectomy is important. We have drawn on the published results
`of four series, those of Huggins’ (University of Chicago), West“ (Memorial
`Hospital, New York), Harrison“ (Peter Bent Brigham Hospital), and Leberman"
`(University of Pennsylvania). Together these give a total of 26 patients available
`for analysis, omitting 4 additional patients who died in the immediately post-
`operative period -(fig: 2).
`1. Symptomatic improverneht. Twenty-two out of the 26 patients had sympto-
`matic improvement. Again, here as in our coftisone series, the most striking thing
`noted was the relief of severe and often crippling bone pain.
`2. Improvement in local prostatic lesion. Nine out-of the 26 patients were noted
`to have marked decrease in the size of their local‘pelvic lesions.
`3. Acid and alkaline phosphatase. Six of the 26 patients had a consistent de-
`crease in acid phosphatase following ‘adrenalectomy. Alkaline phosphatase data
`are diflicult to interpret.
`" West, C. D., Hollander, V. P., Whitmore, W. F., Jr., Randall, H. T) and Pearson,
`O. H.: The efiect of bilateral adrenalectomy upon neoplastic disease in man. Cancer, 6:
`1009-1018, 1952.
`" Leberman, P.: Bilateral adrenalectomy inprostatic carcinoma. (In press.)
`
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`GERALD M. MILLER AND FRANK HINMAN, JR.
`
`4. Changes in bony metastases by 2:-ray. As was seen in the cortisone series, 18
`out of 20 showed a steady progression of metastases. One patient of Harrison
`had definite improvement in the metastatic lesions and one in the Memorial
`Hospital series perhaps had temporary arrest.
`‘
`5. Number of patients with remission and length of remission. Twenty of the
`26 patients surviving bilateral adrenalectomy (omitting 4 additional patients
`dying postoperatively) were felt to have clinical remissions.
`The period of improvement in the Memorial Hospital series varied from 14
`to 220 days, averaging 83 days. This is almost identical to the average length
`of remission in our cortisone series (82 days). However, the average length of
`remission in the other adrenalectomy series appears to be considerably longer.
`
`EFFECTS OF BILATERAL ADRENALECTOMY AFTER CORTISONE IS NO
`LONGER EFFECTIVE
`
`We performed late bilateral adrenalectomy on 3 of our 10 patients. Two were
`operated on after exacerbation occurred following good remission from cortisone
`alone. One of these (H.M.) had beneficial symptomatic effect from cortisone for
`two months without improvement in local lesion or metastases. Adrenalectomy
`was performed 2 months after cortisone ,was discontinued. At present, 6 months
`after operation, he is back working hard on his cattle ranch and is asymptomatic,
`whereas before he was bedridden. His acid phosphatase excretion decreased from
`a preoperative level of 4 Bodansky units to 1 unit after one month and 2 units
`after eight ‘months. A large metastatic lesion in the right inguinal region which
`was extremely tender and painful immediately became no longer painful but only
`started to decrease in size during the past month, along with marked shrinking
`of his local prostatic lesion. It may be of some significance that in the last 6 weeks
`his maintenance dose of cortisone was increased’ from 37.5 mg. to 75 mg. per day.
`He has had an excellent clinical remission.
`The second patient (F.C.) was completely relieved of his severe pain for four
`weeks after operation but then began‘ having pain as severe as before. It is now
`5 months since operation. He requires 75-100 mg. of cortisone a‘ day to prevent
`adrenal insufficiency. No improvement is noted in his local lesion and there has
`been progression of the metastases. His acid phosphatase decreased from 22
`Bodansky units to 6 units after four weeks but now is 13 units. No change oc-
`curred in alkaline phosphatase excretion.
`The third patient (G.W.) was operated upon after a month of cortisone therapy
`had failed to produce any symptomatic relief or alter his progressive.downhill
`course, although it caused his local lesion to disappear by rectal palpation.
`Adrenalectomy gave him marked symptomatic improvement which, however,
`lasted less than eight weeks. During this period, his acid phosphatase excretion
`which had fallen from 45 King Armstrong,units to 26 units on cortisone, rose pro-
`gressively to 82 units. His alkaline phosphatase, which had risen from 29 units
`to 96 units, fell progressively to 50 units. He died from his malignant disease eight
`weeks after surgery.
`
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`PROSTATIC CARCINOMA
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`493
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`DISCUSSION
`
`'
`
`The basis for endocrine therapy in carcinoma of the prostate stems from
`Huggins’ initial work”-19-2° with bilateral orchiectomy and estrogen therapy.
`From this he postulated that prostatic cancer represents an overgrowth of adult
`prostatic epithelial cells and like these cells, it undergoes atrophy when the andro-
`gens are reduced. Prostatic carcinoma is therefore dependent on the presence
`of circulating androgen for its growth. Castration or testicular inhibition by
`decrease of the pituitary gonadotropin output by estrogen results in a decrease
`in androgen which in turn prodces a decrease in the size of the tumor and in the
`function of the cancer cells.
`After orchiectomy there is a fall. in 17-ketosteroid excretion, followed by an
`increase for prolonged periods [Scott and Vermeulenf‘]. The preliminary fall is
`due to removal of the gonads. Increased extragonadal production of androgens
`presumably in the adrenal glands might account for later relapse after orchi-
`ectomy. Enlargement of the adrenals has been described in patients no longer
`responding to anti-androgen therapy.-The mechanism for‘this increased adrenal
`androgen production for a long time was thought" to be by—st_imulation of the
`increased pituitary gonadotropin which results from castration. This theory has
`now been questioned and the exact mechanism is still uncertain.
`Huggins feels that cancer of the prostate eventually becomes. autonomous,
`that is independent of androgen, and is no longer repressed by anti-androgenic
`therapy. Total failure of castration and estrogen therapy in approximately 20
`per cent of the patients could then be explained on the basis of primary androgen
`independence. Support of this theory comes from Deming’s work” on intraocular
`tissue transplants in which it was found that after passage through 8 male genera-
`tions, the tissue then became independent of androgen and was able to grow in
`an estrogenized animal.
`_
`In the last few years, attempts have been made to diminish androgen secretion
`by the suppression of the pituitary gland by hormones other than estrogens.
`Trunnell et al." used progesterone in the treatment of patients with advanced
`prostatic carcinoma on the basis of Albright’s theory” that androgen production
`
`1' Huggins, C. and Hodges, C. V. : Studies on prostatic cancer; the efl'ect of castration, of
`estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the
`prostate. Cancer Research, 1: 293-297, 1941.
`1’ Huggins, C., Stevens, R. E., Jr. and Hodges, C. V.: Studies on prostatic cancer; the
`tlagelcts of castration on advanced carcinoma of the prostate gland. Arch. Surg., 43: 209-223,
`4 .
`'
`’° Huggins, C., Scott, W. W. and Hodges, C. V.: Studies on prostatic cancer; the efiects
`of fever, of desoxycorticosterone, and of estrogen on clinical patients with metastatic ca.r-
`cinoma of the prostate. J. Urol. , 48: 997-1006, 1941.
`" Scott, W. W. and Vermeulen, C.: Studies on prostatic cancer; excretion of 17-keto-
`steroids, estrogens and gonadotropins before and after castration. J. Clin. Endocrinol., 2:
`450-456, 1942.
`” Deming, C. L. and Hovenanian, M.S. : The hormonal factor in heterologous growths of
`human prostatic cancer. J. Urol., 59: 2157219, 1948.
`_
`1' Trunnell, J. B., Dufiy, B. J., Jr., Marshall, V., Whitmore, W. F. and Woodard, H:G..
`The usesff progesterone in treatment of cancer of the prostate. J. Clin. Endocrin., 11: 663-
`676, 19
`.
`“ Albright, F. and Elrick, H.: An attempt to classify hormonal disorders of the hypoph-
`ysis. 'I‘r. A. Am. Physicians, 81: 42-53, 1948.
`
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`GERALD M. MILLER AND FRANK I-EIINMAN, JR.
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`depended on the secretion of luteinizing hormone (LH). They had excellent re-
`sults in 8 of 10 patients that had had no previous therapy and in 3 of 6 patients
`who were in relapse after the usual hormonal therapy. However, some doubt
`has been cast on the LH theory as the major mechanism, since 17-ketosteroids
`increase after ACTH administration. As has been shown, the 17-ketosteroid ex-
`cretion will decrease with inhibition of ACTH by cortisone.
`Although the evidence for the importance of androgens in cancer of the
`prostate is sound, it does not extend to their exact role in the induction of the
`cancer or in the maintenance of its growth. Questions arise because of the well
`established fact that the average testis produces less androgen and more estrogen
`as age advances and yet cancer of the prostate is principally a disease of the
`elderly male. Moreover, studies on average 17-ketosteroid levels in these patients
`as coinpared with other males in the same age group showed no essential dif-
`ference. The possibility thus occurred to us that there might be basic inetabolic
`difierences in these patients so that their androgens were not primarily secreted
`as 17-ketosteroids which would explain the dilemma. However, our few experi-
`ments" with exogenous androgen would indicate that this hypothesis was wrong
`since 2 untreated patients with prostatic carcinoma had the same rise in urinary
`17~ketosteroids’ after a test dose of 100 mgm. of testosterone propionate as a
`young and an old normal patient. However, they don’t completely rule out the
`possibility of abnormal metabolism of endogenous, as opposed to exogenous,
`androgen. Brendler and Scott“ used’ large doses of testosterone on 3 patients
`with advanced disease. Two showed general improvement for a while, similar
`to the patients treated by cortisone or adrenalectomy and yet ‘their acid phos-
`phatases rose and the disease progressed——a non-specific effect of the steroid
`similar to that we have seen with cortisone.
`Bilateral adrenalectomy was undertaken by Huggins because of experimental
`evidence on the role of the adrenals in neoplasia“- 23 and in cancer of the prostate
`in particular, to remove the extra-gonadal source of androgen. This surgery has
`been successful only in carcinoma of the breast and carcinoma of the prostate,
`both of which are tumors felt to be under some endocrine control.
`That the use of rather large suppressive doses of cortisone alone (in advanced
`carcinoma of the prostate) gives results similar to surgical bilateral adrenalectomy
`is not surprising when one considers that essentially what we have done is to
`produce .a “medical adrenalectomy.” This is analogous to the use of estrogen
`alone in place of orchiectomy. Most of the symptomatic improvement seen in
`our patients on cortisone can be explained on the basis of the nonspecific effect
`of the drug and most of these effects can be seen in other diseases treated with
`cortisone. Because of this, one of our colleagues has aptly called cortisone the
`35 Miller, G. M.: (Unpublished data.)
`1“ Brendler, H., Chase, W. E. and Scott, W. W. : Prostatic cancer; further investigation of
`hormonal relationshi s. Arch. Surg., 61: 433—440, 1950.
`27 Ingle, D. J. and aker, B. L.: The effect of adrenalectomy in the rat upon the rate of
`growth of trans lantable tumors. Endocrinology, 48: 313-315, 1951.
`" Funk, C. omashefsky, P., Soukup, R. and Ehrlich, A. : The effect of hormonal factors
`and the removal of certain organs upon the growth of a transplanted rat tumor. Brit. J.
`Cancer, 5: 280-287, 1951.
`
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`PROSTATIC CARCINOMA
`
`495
`
`“magnificent aspirin.” However, this.is essentially the same symptomatic «im-
`provement as seen in patients after adrenalectomy, who of course are maintained
`on cortisone.
`
`A point of confusion and a cause for speculation is the apparent improvement
`in the local prostatic lesion in a ‘fair number of our ‘own patients, and in the
`adrenalectomy patients as well, accompanied by occasional improvement in acid
`phosphatase, and yet with progression of bony metastases in most of the patients.
`‘One possible explanation is that the local lesion may be less undifferentiated and
`thus more susceptible to hormonal influence than the metastases.
`Other mechanisms can only be mentioned here. From our findings and others”
`on the decreased thyroid function with cortisone administration, the possibility
`that the resulting decrease in general metabolism will also afl'ect the metabolism
`of the tumor cells also exists but this does not explain the difference between the
`local lesion and the metastases. The question of inhibition of thyrotropic hormone
`as well as ACTH by cortisone arises.“ Still another explanation of the shrinking
`of the prostate with cortisone arises from the known inhibiting effect of the drug
`on inflammatory tissue and thus the apparent shrinking of the tumor may be
`merely a decrease in the fibrous stroma. It must be considered that in cases no
`longer responding to one type of hormonal treatment, the residual tumor cells
`may have adapted themselves to become dependent on the new environment
`created by the treatment. This could explain the return of the local lesion in
`our two patients under these circumstances. However, Nathanson“ contends
`the ‘tumor may have acquired vulnerability to eifective therapy with other
`hormones. Hence, it appears that’ a shift in the endocrine status, as by cortisone,
`_of the host may affect the response of a given tumor to hormonal agents. Some-
`how not nowapparent cortisone changes the cellular environment or intrinsic
`cellular processes, but in a way which is peculiar to each neoplasm or group of
`neoplasms.“
`
`SUMMARY
`
`Ten patients with disseminated carcinoma of the prostate in severe exacerba-
`tion following previous remission from orchiectomy and estrogen therapy were
`treated with cortisone, starting with 50 mg. per day by mouth in divided doses.
`Eight out of the *10 patients had m