Management of Reactivated Prostatic Cancer * G. P. MURPHY Roswell Park Memorial Institute, New York State Department of Health, State University of New York at Buffalo, Buffalo, New York I. Scope of the Problem. . . . . . . . . . . . . . . . 11. The Basis for Hormonal Therapy . . . . . . . . . . . . 111. Further Hormonal Manipulations in Relapsing Metastatic Prostatic Cancer IV. Newer Agents . . . . . . . . . . . . . . . . . . V. Summary and Conclusions . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . .
I. SCOPEOF
THE
399 400 401 410 412 413 415
PROBLEM
Adenocarcinoma of the prostate as we know it in the United States and elsewhere is a generalized disease in which most patients have metastases a t the time of presentation (Murphy, 1974; Williams e t al., 1974). It is not infrequent that patients exhibit anemia associated with this metastatic disease, although some of the anemias can be corrected (Williams e t d., 1974). The probability of developing clinical carcinoma of the prostate increases with age, and death rates appear to be higher in the United States in white married men, ages 54 to 74 years, than in single men (Murphy, 1974). There is also some suggestion in Western culture that in certain population groups, mortality rates are rising faster in nonwhite males than in white males (Murphy, 1974). Because of the situation of advanced stage D or advanced classification of disease by T N M or any other system, many patients are treated with hormonal palliation therapy involving estrogen, orchiectomy, or estrogens plus orchiectomy. Regardless of the clinical stage of the disease, even if it is limited or localized to the prostate, patient survival is not long and remissions are of short duration (Schoonees et al., 1972a). Clinical survival in stage C carcinoma using the classification of Whitmore (Schoonees e t al., 1972a) a t our own institution has an average of slightly under four years. State D patients survive for an average of 1.7 years. It is important to note that, despite primary treatment such as orchiectomy or castration and orchiectomy in stage C or D cases, the cause of death is generally prostatic carcinoma in 50-65% of instances (Scho-
* This paper was supported in part by United
States Public Health Service grant
Nos. 55-05648-08 and RR-00262-09, of The National Institutes of Health. 399
400
G . P. MURPHY
onees et crl., 1972a). Postmortem studies a t our own Institution corroborate the findings of others that the actual survival of patients with metastatic disease with palliative therapy is not signifirantly altered from those who receive no treatment (Schoonees et nl., 1972a). Thus one is faced with an important clinical dilemma in the management of patients who haye been given hormonal treatment whether in a developing stage of metastases or in a presenting stage of metastases. These patients, when they progress further have had, until now, little to afford them clinical relief and present a clinical dilemma. The purpose of this presentation is to review possible objective criteria associated with additional techniques for beneficial management of patients in these situations.
11. THEBASISFOR HORMOR'AL THERAPY The basis for manipulation of the hormonal milieu of patients with prostatic cancer is based upon sound experimental evidence from the laboratories of Dr. Huggins (1947) and others (Schoonees et al., 197213). For example, marked differences in the composition of resting and pilocarpine-stimulated canine prostatic fluid have bcen described (Huggins, 1947). The volume and acid phosphatase concentration of pilocarpinestimulated canine prostatic fluid have been proved to be rcliable indices of androgenic stimulation of the prostate in experimental situations (Schoonees et al., 197213). The role of zinc concentration in the prostate and in its secretions has also been suggested to have an associated hormonal relationship (Schoonees et al., 1972b). Surprisingly, certain alterations in the mature prostatic tissue of the dog can be effected by castration (Varkarakis ef al., 1973). For example, depleting such animals of testosterone increases the avidity of the prostate equally for dihydrotestosterone and for estriol (Varkarakis et al., 1973). I n experimental situations such studies emphasize again that there may well be species differences. The fact that the dog apparently can concentrate administered radiolabeled estriol and possibly diethylstilbestrol to an equal degree as dihydrotestosterone, suggests that following castration other basic hormonal relationships of the prostate gland may be altered. T o what degree this is applicable in a clinical situation, is unknown. Wc suspect that it is important, when considering further hormonal manipulation in a patient who has relapsed following orchiectomy and/or estrogens. Vnderstandably, in ongoing work further studies are necessary before the nature of the conjugated steroids present in prostatic fluid can be further established in experimental situations (Varkarakis et al., 1972a).
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
40 1
However, a detectable relationship in aging males with benign prostatic hyperplasia was not demonstrable in carefully conducted studies (Schoonees e t al., 1971a). By no means, however, may the same situation be present in adenocarcinoma of the prostate in man. Antiandrogens are also known to have demonstrable effects on various species, including the canine, in terms of various criteria of prostatic function (Schoonees e t al., 1973). Similar results have been found when antiandrogens have been employed to treat prostatic carcinoma in man (Schoonees e t al., 1971b). However, in our hands, such agents have not been of marked benefit when used following relapse after conventional hormonal palliative therapy for advanced clinical carcinoma of the prostate in man (Murphy, 1973a). For this reason a t the present time, as well as in the past, other surgical steps have been undertaken in an effort, in selected instances, to produce a remission in a patient following castration and estrogen treatment who is in a state of relapse in the presence of advanced clinical disease. 111. FURTHER HORMONAL MANIPULATIONS IN RELAPSING METASTATIC PROSTATIC CANCER Hypophysectomy for advanced prostatic carcinoma as described by
W. W. Scott and associates has been utilized in selected instances since 1952 (Scott, 1953). I n review of such series, although significant palliation has been achieved for periods of 1-2 years on the average, the open hypophysectomy has proved to be a hazardous procedure with a considerable morbidity and operative mortality (Murphy et aZ., 1969, 1971). Ablation of the anterior pituitary and its subsequent control over other hormonal factors associated with widespread prostatic cancer has been the basis for the utilization of hypophysectomy. However, open procedures have been generally found not to be associated with entire ablation of all pituitary cells (Scott and Schirmer, 1962). I n 1969 in our own clinic, we approached the possibility of using a functional assessment of a degree of ablation of the anterior pituitary (Murphy e t al., 1969, 1971). These studies were conducted in order to assess whether by transsphenoidal cryosurgical hypophysectomy significant destruction of the anterior pituitary could be achieved, in comparison to the open conventional procedure (Murphy e t al., 1969). As an end point in measurement, growth hormone levels were assayed in various patients before and after surgery. The levels were provoked by insulininduced hypoglycemia. This technique has now been utilized in a series of well over 50 such patients who have had repeat measurements in fol-
402
G . P. MURPHY
low-up periods extending as long as three years. The measurement of the growth hormone levels in the presence of insulin-induced hypoglycemia has been achieved without any untoward episode but always with a physician in attendance. Pre- and postoperative measurements of growth hormones exhibit a typical flat curve following open hypophysectomy (Fig. 1). Such flat curves are maintained for an indefinite period. West and Murphy (1973) studied a n additional group of patients who had undergone adenohypophysectomy by either open craniotomy in 8 instances or by stereotaxic cryohypophysectomy in 19 patients. All these patients had multiple growth hormone assays performed during insulin-induced hypoglycemia in the preoperative control period and a t least twice during the postoperative experimental period, which lasted up to and including an average of one year. Figure 2 shows the close correlation, before and after surgery with open hypophysectomy, between the levels of growth hormone and the depression of blood glucose. To our surprise, we also learned that such similar levels of depressions were observed following cryosurgical hypophysectomy (Fig. 3 ) . Such studies performed in a careful and chronological fashion have established that the anterior pituitary can be destroyed to an equal de-
I
O -0
O
30
60
90
TIME (minutes)
FIG.1. Typical flat curve for human growth hormone (HGH) seen after open hypophysectomy (0-0) in advanced metastatic prostatic cancer in man. 0-0, preoperative.
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
=f
403
30 2826-
.120
42-
t---F-c----.
FIG. 2. Concentrations of plasma growth hormone associated with blood glucose depression plotted as a function of time following the intravenous infusion of insulin. Each point represents a mean value with a standard error for 8 to 16 determinations on eight patients. @, After open hypophysectomy ; 0, before surgery; -, growth hormone; ---,blood sugar.
EFFECTIVENESS OF POSTOPERATIVE GROWTH HORMONE
LEAST
4
2
INTERMEDIAT
9
*= -MAXM I AL
0
30
60
90
Time (minutes)
FIG. 3. Concentrations of plasma growth hormone plotted as a function of time after start of insulin infusin. Each plotted point represents mean values with standard error of mean (vertical half bars) for ten or more determinations from five or more patients in each group designated. 0, After cryohypophysectomy; 0, before surgery.
404
G . P. MURPHY
gree by either cryosurgical or open procedure (Murphy et al., 1969, 1971; Rest and Murphy, 1973). These observations have similarly established that growth hormone levels under insulin-induced provocation are suitable criteria for the degree of ablation of the anterior pituitary (Murphy et aE.. 1971; Wcst and Murphy, 1973). The criteria for response to hypophysectomy regardless of the technique, involved both objective and subjective signs (Murphy et al., 1969). The common criteria that have been found of benefit both by ourselves and others are the subjective responses as follows: (1) pain relief; (2) sense of well being; (3) improved appetite. The criteria for objective response similarly have been as fol1o.cvs: (1) decrease in serum acid phosphatase level ; (2) sustained decrease in serum alkaline phosphatase level ; (31 m i g h t gain ; (4) improved radiological and radioisotopic appearance of osseous metastases; ( 5 ) improvement of anemia defined as an increase in relative hematocrit or by stability of hematocrit readings a t 30 volumes percent or greater. Naturally the sixth criterion is survival. This may bc difficult to measure in such patients who are under prior Rsngrssiox
TABLE I SURVIV.\L PERIODSO
AND
Operative Procedures Stereotaxic crgosurgiral adenohypophysectomy (effectiveness of GI3 suppression*) Criterion
Least
Intermediate
hlaximal
Craniotomy with adenohypophysectomy
~~
Numbcr of patients Age (gears) Duration of remission (months) Subjective Objective Survival following adcnohypophyscctomy (months)
7 70.40 ( 1.76) 0.87 (*O.:52) 0.12 ( + O .05) 4.80
(21.3)
5 65.0 (k1.78) 10.2.3 ( f3.84)
7.60
( t 3.04)
13..38
(t3.0)
7 67.14 (k2.40) 7.54 (k2.22) 6.25 (t2.55) 13.57 (k2.83)
8 58.09 ( 2 1.30)
5.11
(k1.48) 6.78 ( 42.62)
10.88 ( 42.36)
a Following adenohypophysectomy for disseminated prostatic carcinoma; values tabulated represent means (2SEhf). Categories of least, intermediate, and maximal effectiveness of GH suppression refer to similar categories designated in the tent; GH indicates growth hormone.
405
MANAGEMENT O F REACTIVATED PROSTATIC CANCER
paIliative therapy and, of course, have a dire prognosis. Such responses have been found in our hands to be reproducible with cryohypophysectomy to an equal degree as with an open procedure. To this date in 1975, we have not had any morbidity or mortality using this procedure (Table I). The degree of benefit to the patient with cryosurgical hypophysectomy can be measured in terms of the depression of growth hormone. A quantitative separation is possible. Based on such results, we have repeated the cryosurgical procedure in selected cases until a suitable level of depression of growth hormone is seen. I n such instances, both objective and subjective signs of improvement have been uniformly observed. As shown in Table 11, the degree of depression of the anterior pituitary can be expressed in terms of the index of ablation. Over 90% of the tissue is destroyed by the open procedure (Table 11).However, with cryosurgical hypophysectomy, when maximal reduction is achieved as measured by growth hormone levels, a similar degree of ablation is noted. Patients with intermediate reduction have clinical remissions. Thus the fact that TABLE I1 HUMANGROWTHHORMONE (GH) RESPONSES TO INSULIN-INDUCED HYPOGLYCEMIA~ Integrated average G H level, over SO-minute period (mg/ml of plasma) Procedure Craniotomy with h ypoph ysectomy
Preoperative
Postoperative
8/8 15.6 ( 5 0 . 9 )
0.94 ( 5 0 . 0 3 )
8/16
7/14
1 . 3 (+0.12)"*' Stereotaxic cryohypophysectomy
19/19
13.5 ( f 1 . 8 )
6/10
3 . 6 (+0.6)d9'
7/14
10.5 (+0.8)e*f
Index of adenohypophyseal ablation (%)b
93.9
90.3 73.3
22.2
Data tabulated represent mean values ( + S E M ) for the number of determinat.ions indicated in boldface (number of patients/number of determinations). All patients underwent GH assay once preoperatively and twice in the postoperative period. Based on GH suppression; mean differences between respective preoperative and postoperative values are significant at the level of P < 0.001 and are expressed as percent decrease from preoperative values. Maximal reduction. Intermediate reduction. Least reduction. f Significance of mean difference between adjacent postoperative values at the level of P < 0.001.
406
G. P. MURPHY
70% reduction in growth hormone levels can be associated with objective clinical responses proves that destruction of the entire anterior pituitary is not necessary in this group of patients. This knowledge should be further applied to other individuals, as the technique can be performed under local anesthesia in less than an hour. Immediate relief is characteristically evident (Murphy et al., 1969, 1971; West and Murphy, 1973). The initial reduction of androgenic hormone by bilateral orchiectomy and/or estrogen therapy has been noted to produce a regression of advanced prostatic carcinoma (Huggins and Hodges, 1941). Measurement of the 24-hour excretion of urinary 17-ketosteroids correlates well with the relapse of the disease and can be decreased following bilateral adrenalectomy (Bhanalaph et al., 1974). Since cortisone has become available, adrenalectomy has been used to a limited extent following relapse of advanced carcinoma of the prostate. Previous investigators have agreed that bilateral adrenalectomy produced a remarkable degree of subjective improvement (Table 111).It has been unclear in the minds and opinion of some, however, whether increased survival with objective response could be obtained to a satisfactory degree. I n our own studies, which have now exceeded 50 patients, we have found this t o be true (Bhanalaph e t al., 1974; Reynoso and Murphy, 1972; Schoonees et al., 1972c; Merrin et al., 1974) (Fig. 4). As shown in Table IV, in a series of 26 patients with proven disseminated reactivated prostatic carcinoma, subjective improvement was achieved in most instances. I n the presence of prior castration and hypophysectomy, however, a significant degree of improvement was not noted (Table IV) . Following bilateral adrenalectomy, serum acid phosphatase levels are usually decreased within 1 month. They are increased again, however, in association with a demonstrable clinical relapse (Bhanalaph et al., 1974). Mean plasma testosterone levels after adrenalectomy generally exhibit no significant change (Bhanalaph et al., 1974). This is not unremarkable, as such levels, although generally low, have not been found to be helpful in following patients who have been hypophysectomized (Murphy et al., 1971). The 24-hour urinary excretion of total 17-ketosteroids in previously castrated or hypophysectomized patients is sometimes slightly higher before adrenalectomy (Bhanalaph et al., 1974). However, a marked decrease of the ll-deoxy-17-ketosteroids is consistently noted in previously castrated patients (Bhanalaph et al., 1974). This has been noted in follow-up periods extending up t o 1 year and beyond (Merrin et al., 1974) and is associated with clinically evident and suitable signs of subjective and objective response. The major cause of death following adrenalectomy is disseminated disease (Bhanalaph et al., 1974). Such studies demonstrate the 24-hour urinary ketosteroid ex-
TABLE I11 RESULTSOF BILATERAL ADRENALECTOMY FOR ADVANCED PROSTATIC CARCINOMA FROM
Author
Number of patients
Subjective improvementa Good
Fair
A
REVIEWFROM
THE
LITERATURE
FZ
* Ei 3 G,
Immediate Objective postoperative death improvementb
M
Longest survival
0
Huggins and Scott (1945) Huggins et al. (1952) Baker (1953) Scardino et al. (1953) Taylor et al. (1953) Whitmore et al. (1954) Fergusson (1954) Pyrah (1954) Morales et al. (1955) MacFarlane et al. (1960)
a
4 7 10 3 6 17 17 3 20" 13
1 3 7 1 5 6 9 2 4/10 9
Judged according to pain and sense of well-being. Judged according to growth regression (no bone improvement). Only ten patients had pain before adrenalect,omy.
5 3 5/10
1 1 2 1 1
3 1
1 2 2
115 Days 7
6 Months 9 Months
7 Months 330 Days 10 Months 24 Months 46 Months (mean 13 months)
w M, b
2 tiM -4
W
w m
0 u1
3 Q
5
:
8
M,
Period of subject,ivc improvcment”
iL’b
Pat.ient.s still alive
16
>
No relapsed
10 Cases (62.5,%)
5
4
-
1 Case
Previous castration and hypophysectomy with relapse
5
-
2 Cases (40%)
1 Case
Conditions of patient, a t the timc of bilateral adrcnalcctomy Previous castration with relapsc
a
Up to 3 months
Period of subjective improvement after adrenalectomy in months. = Number of patients who had bilateral adrenalectomy. Mean survival time in months after adrenalectomy. Castration 2-4 months after adrenalectomy.
*N
>3-12
Months 1 Case
>12 Mont,hs
Mean period of subjective improvement
Mean survival t imec
0
4 . 8 Months
8 . 2 Months
4 Cases
5
18.0 hZont>hs
2 0 . 8 Months
1 . 6 Months
6 . S Months
2
-
4 Cases (2.5 %) (80%)
409
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
X
AGE
I
2
63 64
3 4 5 6
74 68 60 71
7
7-4
.
8
7n
70 70
70 73
21 22 23 24 25 26
60 53,
0
9
c*
3
1
O D
*
"c-0
P.or-
0
D
*
9
I
*
l - Ec n
A
C
9
I.
Dm
C ? D
,o
1*
* *
0
71 62 65 56 54 6% 55
]
. I 1
O U m
68 61 68
17 18 19 20
9 0
m
=
O D .
54
16
D
ObC C
.-
.,
I3 14 15
0
66
a
-
+ c O
c*:o
.-
10
II 12
o-
.
* *
*
1
I
I
Dm D
. . I 7 , , , , ,,, , , , , 0
C D
0
160 140 120100 80 60 40 20 10 0
3
6
9
12
15
18
21
24 27
30
MONTHS
FIG.4. The survival and remission rates for a Roswell Park Memorial Institute prostatic cancer adrenalectomy series. Time course of 26 patients with advanced prostatic carcinoma after bilateral adrenalectomy. m, Period of subjective improvement; 0, period of nonresponse or relapse after treatment.. 0, Orchiectomy ; A, D, C , clinical stage of prostatic carcinoma; v, hypophysectomy; *, alive.
cretion, particularly that associated with the androgenic fraction (11deoxy) is also a good index and prognostic indicator in the presence of hypophysectomy (Bhanalaph et al., 1974) or after hypophysectomy. Those patients who respond to hypophysectomy or adrenalectomy show a persistent and significant decrease in 11-deoxy-17-ketosteroid 24-hour excretion rates (Murphy et al., 1969; West and Murphy, 1973; Bhanalaph et al., 1974) (Table V ) . Widespread use of adrenalectomy remains limited, as patients who are candidates for adrenalectomy are generally younger and must have the ability to withstand a more formidable operative procedure. We have found that such patients who have previously shown a response to endocrine therapy, whether it be orchiectomy or exogenous es-
410
G . P. MURPHY
TABLE V TNTNTY-FOGR H O U IURINARY ~ KETOSTEKOID EXCRETION AFTER BILATERAL ADRIIN.\LF:CTOYY I N ADVANCED P R O S ~ A TCI A C R C I N OPATIENTS X.~ WITH P R I O R C.ISTR.ITION
Ketosteroid
(11E.\N
Before adrenalectomy
VALUE
&SEhI)
After adrenalectomy 3 Weeks
1 Month
2-3 Months
1.30 (0.17)" 1.59 (0.34)* 1.32 (0.54)b
Total 11-deoxy-17-Ketosteroids
2.56 (0.60) 15
17
7
8
Total 11-0~y-17-Kcto-
1.48 (0.30)
4.39 (0.95).
4.97 (1.66)
4.27 (1.22)
15
17
7
8
4 . 0 4 (0.71) 15
5.66 (0.97) 17
6.61 (1.8) 7
5 . 6 0 (1.72)
w
A-
steroids
Total 17-ketost eroids A: a
P
bP
8
< 0.01. < 0.05.
rV = n'umber of observations.
trogens, generally will do well following adrenalectomy (Bhanalaph et al., 1974; Merrin et al., 1974). A similar situation has been generally but not uniformly true in the case of hypophysectomy by either route (Murphy et al., 1971; N'est and Murphy, 1973). We do not recognize that adrenal suppression and androgen excretion can be achieved to a significant degree by present chemical or nonoperative means despite claims to the contrary (Robinson et al., 1974). Such studies have failed to show the essential urinary depression in androgenic excretions as described in this Presentation. In advanced prostatic cancer paticnts, following relapse, radiotherapy similarly has not proved t o be of superior advantage (Varkarakis et al., 1972b). However, there has been some suggestion, in the hands of others, that hormonal therapy combined with megavoltage radiation therapy may provide some increased palliation and improved survival (Tsuya et al., 1974). We have not found this in our own experience (Varkarakis et al., 1972b).
IV. XEWERAGENTS Est,racyt, a chemical ester of a nitrogen mustard with estradiol-17/3, has been tested for its effects on the prostate in various species (Kirdani et al., 1974) and is further discussed in this symposium. Oral or parenteral estracyt was shown to have clinical activity in the early studies
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
411
or Jonsson and Hogberg (1971). Swedish and other investigators in Europe as well as in the United States (Muntzing et al., 1974) have used the compound in the presence of advanced carcinoma of the prostate resistant to conventional therapy. The oral agent has been given with minimal toxicity a t a generally effective therapeutic dose of 15 mg/kg daily in three divided doses (Muntzing e t al., 1974). Any toxicity when noted is mild and exclusively gastrointestinal. We have not seen any objective evidence of estrogen effects following the administration of this agent for prolonged periods (Miintzing et a$., 1974). There is good evidence that Estracyt is specific for human prostatic carcinoma (Tritsch et al., 1974). I n a recent series of 32 patients with stage D carcinoma of the prostate treated a t a therapeutically effective dose (Mittelman et al., 1975a,b), objective remission, which included decreases in soft tissue masses, lymph nodes, and prostatic masses, were noted in 25%, that is, 8 of 32 patients. Subjective responses, which included relief of pain, weight gain, sense of well-being, and improved performance status occurred in all the objective responders and 7 other patients with stable disease for a rate of 4776, or 15 out of 32 patients. Nonhematologic or hepatic or renal toxicity was observed. Transient nausea occurred early in half the patients, and in only 2 patients in this particular series was nausea and vomiting dose-limiting. Oral Estracyt is thus well tolerated and worthy of further clinical use (Mittelman et al., 1975a,b). We feel that this agent, on the basis of both phase I and I1 trails (Muntzing et al., 1974; Mittelman et al., 1975a,b) in the United States may be a preferable alternative to hypophysectomy or adrenalectomy. I n fact, a recent review evaluated the survival rates in such relapsed patients following the various forms of palliation including bilateral adrenalectomy, hypophysectomy, combination hypophysectomy and adrenalectomy, or chemotherapy with Estracyt (Welvaart e t al., 1974). Good long-term palliative responses were achieved with bilateral adrenalectomy, hypophysectomy, or Estracyt. However, because of ease of administration, effectiveness, and lack of toxicity, oral Estracyt may be considered the method of choice in such cases for failures following conventional hormonal therapy (Welvaart et al., 1974). Such observations must necessarily be repeated by others, but if valid will provide an easier means of initial management of a relapsed patient with advanced disease. Hypophysectomy and adrenalectomy still have their roles but may be utilized in more selective instances. Thus far, other more conventional chemotherapy has also not been fully evaluated (Murphy, 197313). The National Prostatic Cancer Project in the United States is currently demonstrating that 5-fluorouracil or cytoxan may provide both objective and subjective responses in patients
412
G . P. MURPHY
with advanced metastatic disease who have relapsed following conventional therapy (Murphy, 197311).At the present time, a variety of cooperative groups in the United States are evaluating the effectiveness of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, actinomycin, adriamycin, and procarbazine. That single agent chemotherapy can be given to patients in this age group with dose adjustments with minimal toxicity is indeed important to note (Murphy, 197313). Single agent or multiple agent chemotherapy may well, in the future, have a role in the management of reactivated prostatic carcinoma following conventional therapy. At the present time, it appears in the Kational Prostatic Cancer Project that 5-fluorouracil and cytoxan are superior to conventional chemotherapeutic agents used in such circumstances (Murphy, 1973b). Although initial pilot studies altering the immune status of the advanced prostatic cancer patient are underway, there is no immediate projection that such therapy will become routine in an adjuvant manner (hlerrin et al., 1973). However, results have been noted and cannot be dismissed lightly. With the development of other means of measuring progression of disease, including biological markers and so forth, further exploration of other therapies will doubtless be fruitfully pursued. At the present time the management of the patient with advanced prostatic carcinoma following relapse from conventional therapy is thus hardly in a state of hopelessness nor necessarily one of confusion. Multiple agents and operative procedures are available and can be safely used with a reasonable hope for palliation, subjective improvements, and, to a surprising degree, increased survival.
V. SUMMARY A N D CONCLUSIOKS The management of a patient v i t h metastatic relapsing prostatic carcinoma following conventional therapy has been a clinical dilemma. Earlier endeavors in this limited field have been devoted toward hormonal manipulation. I n view of the fact that the majority of the patients in the United States present with metastatic disease, and th a t their palliation may be limited for a short period, other forms of management have been sought by various clinical investigators over the years. Hypophysectomy through the open route has been somewhat hazardous with a significant operative mortality rate. It has been found in recent times that cryosurgical transsphenoidal hypophysectomy can achieve both objective and subjective response rates equal on occasion to tha t of open hypophysectomy. Moreover, with the cryosurgical technique, it has also been determined that growth hormone levels under insulin-induced hypoglycemia are an
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
413
accurate index of the degree of pituitary ablation necessary for a subjective and objective clinical response. Such responses can be achieved by either route of hypophysectomy with a minimal ablation of 70% of the anterior pituitary. In view of this and in view of the absence of morbidity and mortality in our hands, transsphenoidal cryosurgical hypophysectomy appears to be the route of choice for such patients in whom hypophysectomy is selected. Bilateral adrenalectomy, similarly, for younger patients has provided a suitable means of subjective and objective improvement following relapse after conventional therapy. I n both types of patients, the daily 24-hour measurement of 11-deoxy-17-ketosteroidsin the urine has provided a better assay of the degree of androgenic ablation following either endocrine procedure or their combination. When such objective measurements are made for long periods following the initial procedure, a persistent decrease is associated with a good clinical course. Estracyt, a new oral, nonsteroidal agent has been found to be of superior benefit compared to radiation therapy or antiandrogens. Moreover, in ongoing studies reported in this presentation, it is of equal benefit to patients after adrenalectomy or hypophysectomy. The agent has been found to have minimal toxicity in phase I and I1 studies with response rates of a significant degree that have lasted for over one year in our own hands. The evaluation of chemotherapy with such agents as 5fluorouracil and cytoxan is currently underway. However, such agents a t the present time can be administered to such patients with minimal toxicity and offer significant hope for improvement in objective remission. Immune manipulation with BCG injection is in its earliest clinical trails. I n the face of these variations, it is thus possible to provide additional modes of management to the patient who has reactivated prostatic cancer. REFERENCES Baker, W. J. (1953). J. Urol. 70, 275. Bhanalaph, T., Varkarakis, M. J., and Murphy, G. P. (1974). Ann. Surg. 179, 17. Fergusson, J. D. (1954). Proc. R o y . Sac. Med. 47, 1007. Huggins, C. (1947). Harvey Lect. 42, 148. Huggins, C., and Bergenstal, D. M. (1952). PTOC.Nnt. Acad. Sci. U S . 38, 73. Huggins, C., and Hodges, C. V. (1941). Cancer Res. 1,293. Huggins, C., and Scott, W. W. (1915). Ann. S w g . 122, 1031. Jonsson, G., and Hijgberg, B. (1971). Scand. J. Urol. Nephrol. 5, 103. Kirdani, R. Y., Miintzing, J., Varkarakis, M. J., Murphy, G. P., and Sandberg, A . (1974). Cancer Res. 34, 1031. MacFarlane, D. A., Thomas, L. P., and Harrison, J. H. (1960). Amer. J. Surg. 99, 562. Merrin, C., Han, T., Klein, C.. and Murphy, G. P. (1973). Urology 2, 651. Merrin, C., Murphy, G. P., Chu, T. M., and Mittelman, A. (1974). Urology 3,223. Mittelman, A., Shukla, S. K., and Murphy, G. P. (1975a). J . Urol. (in press).
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G . P. MURPHY
Mittelman. A., Shukla, S. K., Welvaart, K., and Murphy, G. P. (1975b). Cancer Chemother. Rep. 59, 219. Morales, P. A.. Brendler. H., and Hotchkiss, R. S. (1955). J. Urol. 73, 399. Muntzing, J., Shukln, S. K., Chu, T. M., Mittelman, A., and Murphy, G. P. (1974). Invest. Urol. 12, 65. Murphy, G. P. (1973a). In “Perspectives in Cancer Researc.h and Treat,ment” (G. P. Murphy, D. Pressman, and E. A. Mirand, eds.), pp. 1-24. Alan R. Liss, Inc., Xew Yolk. Murphy, G. P. (1973h). Cancer 32, 1089. Murphy, G. P. (1974). Cancer 24, 282. Murphy, G. P., Boctor, 2. N., Gailani, S., and Belmusto, L. (1969). J . Surg. Oncol. 1, 81. Murphy, G. P., Reynoso. G., Schoonees. R., Gailani, S., Bourke, ti., Kenny, G., Mirnnd, E. A., and Schalach, D. S. (1971). J. Urol. 105,817. Pyrah, L. N. (1954). Proc. Roy Soc. Med. 47, 1002. Reynoso. G., and Murphy, G. P. (1972). Cnncer 29,941. Robinson, M. R . G., Shearer, R. J., and Fergusson, J. D. (1974). Bn’t. J . Urol. 46, 555.
Scardino, P. L., Prince, C. L., and McGoldrick, T. A. (1953). J . Urol. 70, 100. Schoonees. R., Bender, M. A., Schalch, D. S., and Murphy, G. P. (1971a). Cur. Top. Surg. Res. 3, 233. Schoonees, R.., Schalach, D. S., and Murphy, G. P. (1971b).Znvest. Urol. 8,635. Srhoonees, R., Palmn, 1,. D., Gaeta, J. F., Moore, R. H., and Murphy, G. P. (1972a). N . Y . State J. M e d . 72, 1021. Schoonees, R., Reynoso, G., and Murphy, G. P. (1972b). J . S w g . Oncol. 4, 169. Schoonees, R., Schalch, D. S., Reynoso, G., and Murphy, G. P. (1972~).J . Ur01. 108, 123. Schoonees, R., Reynoso, G., DeKlerk, J. ?IT., and Murphy, G. P. (1973). Invest. L‘rol. 10, 434. Scott, W. W. (1953). Trans. Amer. ASS. Genitourin. S U T ~44, . 101. Scott, W. W., and Schirmer, H. K. A. (1962). I n ‘‘On Cancer and Hormones: Essays in Experimental Biology,” pp. 175-204. Vniv. of Chicago Press, Chicago, Illinois. Taylor, S. G., 111, Li, M. C., Eckles. X., Slaughter, D. P., and McDonald, J. H (1953). Cnncer 6, 997. Tritsch, G. L.. Shukla, S. K., Mittelman, A., and Murphy, G. P. (1974). Invest. Urol. 12, 38. Tsuya, A , , Kaaai, T., Fukushima, S., Shida, K., Shimazaki, J., Matsumoto, K., and Seto, T. (1974). Strnhlenfhernpie 148, 24. Varkarakis, M. J., Iiirdani, R. Y., Murphy, G. P., and Sandberg, A . A. (1972a). J . Szo‘g. Res. 13, 39. Varkarakis, M. J,, Rcbster, J., Bhanalaph, T., and Murphy, G. P. (1972b). J. Surg. Oncol. 4, 520. Varkarakis, M. J., Kirdani, R . Y., Abramczyk, J., Murphy, G. P., and Sandberg, A. A. (1973). Invest. [‘rol. 11, 106. Welvaart. I
I. SCOPEOF
THE
399 400 401 410 412 413 415
PROBLEM
Adenocarcinoma of the prostate as we know it in the United States and elsewhere is a generalized disease in which most patients have metastases a t the time of presentation (Murphy, 1974; Williams e t al., 1974). It is not infrequent that patients exhibit anemia associated with this metastatic disease, although some of the anemias can be corrected (Williams e t d., 1974). The probability of developing clinical carcinoma of the prostate increases with age, and death rates appear to be higher in the United States in white married men, ages 54 to 74 years, than in single men (Murphy, 1974). There is also some suggestion in Western culture that in certain population groups, mortality rates are rising faster in nonwhite males than in white males (Murphy, 1974). Because of the situation of advanced stage D or advanced classification of disease by T N M or any other system, many patients are treated with hormonal palliation therapy involving estrogen, orchiectomy, or estrogens plus orchiectomy. Regardless of the clinical stage of the disease, even if it is limited or localized to the prostate, patient survival is not long and remissions are of short duration (Schoonees et al., 1972a). Clinical survival in stage C carcinoma using the classification of Whitmore (Schoonees e t al., 1972a) a t our own institution has an average of slightly under four years. State D patients survive for an average of 1.7 years. It is important to note that, despite primary treatment such as orchiectomy or castration and orchiectomy in stage C or D cases, the cause of death is generally prostatic carcinoma in 50-65% of instances (Scho-
* This paper was supported in part by United
States Public Health Service grant
Nos. 55-05648-08 and RR-00262-09, of The National Institutes of Health. 399
400
G . P. MURPHY
onees et crl., 1972a). Postmortem studies a t our own Institution corroborate the findings of others that the actual survival of patients with metastatic disease with palliative therapy is not signifirantly altered from those who receive no treatment (Schoonees et nl., 1972a). Thus one is faced with an important clinical dilemma in the management of patients who haye been given hormonal treatment whether in a developing stage of metastases or in a presenting stage of metastases. These patients, when they progress further have had, until now, little to afford them clinical relief and present a clinical dilemma. The purpose of this presentation is to review possible objective criteria associated with additional techniques for beneficial management of patients in these situations.
11. THEBASISFOR HORMOR'AL THERAPY The basis for manipulation of the hormonal milieu of patients with prostatic cancer is based upon sound experimental evidence from the laboratories of Dr. Huggins (1947) and others (Schoonees et al., 197213). For example, marked differences in the composition of resting and pilocarpine-stimulated canine prostatic fluid have bcen described (Huggins, 1947). The volume and acid phosphatase concentration of pilocarpinestimulated canine prostatic fluid have been proved to be rcliable indices of androgenic stimulation of the prostate in experimental situations (Schoonees et al., 197213). The role of zinc concentration in the prostate and in its secretions has also been suggested to have an associated hormonal relationship (Schoonees et al., 1972b). Surprisingly, certain alterations in the mature prostatic tissue of the dog can be effected by castration (Varkarakis ef al., 1973). For example, depleting such animals of testosterone increases the avidity of the prostate equally for dihydrotestosterone and for estriol (Varkarakis et al., 1973). I n experimental situations such studies emphasize again that there may well be species differences. The fact that the dog apparently can concentrate administered radiolabeled estriol and possibly diethylstilbestrol to an equal degree as dihydrotestosterone, suggests that following castration other basic hormonal relationships of the prostate gland may be altered. T o what degree this is applicable in a clinical situation, is unknown. Wc suspect that it is important, when considering further hormonal manipulation in a patient who has relapsed following orchiectomy and/or estrogens. Vnderstandably, in ongoing work further studies are necessary before the nature of the conjugated steroids present in prostatic fluid can be further established in experimental situations (Varkarakis et al., 1972a).
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
40 1
However, a detectable relationship in aging males with benign prostatic hyperplasia was not demonstrable in carefully conducted studies (Schoonees e t al., 1971a). By no means, however, may the same situation be present in adenocarcinoma of the prostate in man. Antiandrogens are also known to have demonstrable effects on various species, including the canine, in terms of various criteria of prostatic function (Schoonees e t al., 1973). Similar results have been found when antiandrogens have been employed to treat prostatic carcinoma in man (Schoonees e t al., 1971b). However, in our hands, such agents have not been of marked benefit when used following relapse after conventional hormonal palliative therapy for advanced clinical carcinoma of the prostate in man (Murphy, 1973a). For this reason a t the present time, as well as in the past, other surgical steps have been undertaken in an effort, in selected instances, to produce a remission in a patient following castration and estrogen treatment who is in a state of relapse in the presence of advanced clinical disease. 111. FURTHER HORMONAL MANIPULATIONS IN RELAPSING METASTATIC PROSTATIC CANCER Hypophysectomy for advanced prostatic carcinoma as described by
W. W. Scott and associates has been utilized in selected instances since 1952 (Scott, 1953). I n review of such series, although significant palliation has been achieved for periods of 1-2 years on the average, the open hypophysectomy has proved to be a hazardous procedure with a considerable morbidity and operative mortality (Murphy et aZ., 1969, 1971). Ablation of the anterior pituitary and its subsequent control over other hormonal factors associated with widespread prostatic cancer has been the basis for the utilization of hypophysectomy. However, open procedures have been generally found not to be associated with entire ablation of all pituitary cells (Scott and Schirmer, 1962). I n 1969 in our own clinic, we approached the possibility of using a functional assessment of a degree of ablation of the anterior pituitary (Murphy e t al., 1969, 1971). These studies were conducted in order to assess whether by transsphenoidal cryosurgical hypophysectomy significant destruction of the anterior pituitary could be achieved, in comparison to the open conventional procedure (Murphy e t al., 1969). As an end point in measurement, growth hormone levels were assayed in various patients before and after surgery. The levels were provoked by insulininduced hypoglycemia. This technique has now been utilized in a series of well over 50 such patients who have had repeat measurements in fol-
402
G . P. MURPHY
low-up periods extending as long as three years. The measurement of the growth hormone levels in the presence of insulin-induced hypoglycemia has been achieved without any untoward episode but always with a physician in attendance. Pre- and postoperative measurements of growth hormones exhibit a typical flat curve following open hypophysectomy (Fig. 1). Such flat curves are maintained for an indefinite period. West and Murphy (1973) studied a n additional group of patients who had undergone adenohypophysectomy by either open craniotomy in 8 instances or by stereotaxic cryohypophysectomy in 19 patients. All these patients had multiple growth hormone assays performed during insulin-induced hypoglycemia in the preoperative control period and a t least twice during the postoperative experimental period, which lasted up to and including an average of one year. Figure 2 shows the close correlation, before and after surgery with open hypophysectomy, between the levels of growth hormone and the depression of blood glucose. To our surprise, we also learned that such similar levels of depressions were observed following cryosurgical hypophysectomy (Fig. 3 ) . Such studies performed in a careful and chronological fashion have established that the anterior pituitary can be destroyed to an equal de-
I
O -0
O
30
60
90
TIME (minutes)
FIG.1. Typical flat curve for human growth hormone (HGH) seen after open hypophysectomy (0-0) in advanced metastatic prostatic cancer in man. 0-0, preoperative.
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
=f
403
30 2826-
.120
42-
t---F-c----.
FIG. 2. Concentrations of plasma growth hormone associated with blood glucose depression plotted as a function of time following the intravenous infusion of insulin. Each point represents a mean value with a standard error for 8 to 16 determinations on eight patients. @, After open hypophysectomy ; 0, before surgery; -, growth hormone; ---,blood sugar.
EFFECTIVENESS OF POSTOPERATIVE GROWTH HORMONE
LEAST
4
2
INTERMEDIAT
9
*= -MAXM I AL
0
30
60
90
Time (minutes)
FIG. 3. Concentrations of plasma growth hormone plotted as a function of time after start of insulin infusin. Each plotted point represents mean values with standard error of mean (vertical half bars) for ten or more determinations from five or more patients in each group designated. 0, After cryohypophysectomy; 0, before surgery.
404
G . P. MURPHY
gree by either cryosurgical or open procedure (Murphy et al., 1969, 1971; Rest and Murphy, 1973). These observations have similarly established that growth hormone levels under insulin-induced provocation are suitable criteria for the degree of ablation of the anterior pituitary (Murphy et aE.. 1971; Wcst and Murphy, 1973). The criteria for response to hypophysectomy regardless of the technique, involved both objective and subjective signs (Murphy et al., 1969). The common criteria that have been found of benefit both by ourselves and others are the subjective responses as follows: (1) pain relief; (2) sense of well being; (3) improved appetite. The criteria for objective response similarly have been as fol1o.cvs: (1) decrease in serum acid phosphatase level ; (2) sustained decrease in serum alkaline phosphatase level ; (31 m i g h t gain ; (4) improved radiological and radioisotopic appearance of osseous metastases; ( 5 ) improvement of anemia defined as an increase in relative hematocrit or by stability of hematocrit readings a t 30 volumes percent or greater. Naturally the sixth criterion is survival. This may bc difficult to measure in such patients who are under prior Rsngrssiox
TABLE I SURVIV.\L PERIODSO
AND
Operative Procedures Stereotaxic crgosurgiral adenohypophysectomy (effectiveness of GI3 suppression*) Criterion
Least
Intermediate
hlaximal
Craniotomy with adenohypophysectomy
~~
Numbcr of patients Age (gears) Duration of remission (months) Subjective Objective Survival following adcnohypophyscctomy (months)
7 70.40 ( 1.76) 0.87 (*O.:52) 0.12 ( + O .05) 4.80
(21.3)
5 65.0 (k1.78) 10.2.3 ( f3.84)
7.60
( t 3.04)
13..38
(t3.0)
7 67.14 (k2.40) 7.54 (k2.22) 6.25 (t2.55) 13.57 (k2.83)
8 58.09 ( 2 1.30)
5.11
(k1.48) 6.78 ( 42.62)
10.88 ( 42.36)
a Following adenohypophysectomy for disseminated prostatic carcinoma; values tabulated represent means (2SEhf). Categories of least, intermediate, and maximal effectiveness of GH suppression refer to similar categories designated in the tent; GH indicates growth hormone.
405
MANAGEMENT O F REACTIVATED PROSTATIC CANCER
paIliative therapy and, of course, have a dire prognosis. Such responses have been found in our hands to be reproducible with cryohypophysectomy to an equal degree as with an open procedure. To this date in 1975, we have not had any morbidity or mortality using this procedure (Table I). The degree of benefit to the patient with cryosurgical hypophysectomy can be measured in terms of the depression of growth hormone. A quantitative separation is possible. Based on such results, we have repeated the cryosurgical procedure in selected cases until a suitable level of depression of growth hormone is seen. I n such instances, both objective and subjective signs of improvement have been uniformly observed. As shown in Table 11, the degree of depression of the anterior pituitary can be expressed in terms of the index of ablation. Over 90% of the tissue is destroyed by the open procedure (Table 11).However, with cryosurgical hypophysectomy, when maximal reduction is achieved as measured by growth hormone levels, a similar degree of ablation is noted. Patients with intermediate reduction have clinical remissions. Thus the fact that TABLE I1 HUMANGROWTHHORMONE (GH) RESPONSES TO INSULIN-INDUCED HYPOGLYCEMIA~ Integrated average G H level, over SO-minute period (mg/ml of plasma) Procedure Craniotomy with h ypoph ysectomy
Preoperative
Postoperative
8/8 15.6 ( 5 0 . 9 )
0.94 ( 5 0 . 0 3 )
8/16
7/14
1 . 3 (+0.12)"*' Stereotaxic cryohypophysectomy
19/19
13.5 ( f 1 . 8 )
6/10
3 . 6 (+0.6)d9'
7/14
10.5 (+0.8)e*f
Index of adenohypophyseal ablation (%)b
93.9
90.3 73.3
22.2
Data tabulated represent mean values ( + S E M ) for the number of determinat.ions indicated in boldface (number of patients/number of determinations). All patients underwent GH assay once preoperatively and twice in the postoperative period. Based on GH suppression; mean differences between respective preoperative and postoperative values are significant at the level of P < 0.001 and are expressed as percent decrease from preoperative values. Maximal reduction. Intermediate reduction. Least reduction. f Significance of mean difference between adjacent postoperative values at the level of P < 0.001.
406
G. P. MURPHY
70% reduction in growth hormone levels can be associated with objective clinical responses proves that destruction of the entire anterior pituitary is not necessary in this group of patients. This knowledge should be further applied to other individuals, as the technique can be performed under local anesthesia in less than an hour. Immediate relief is characteristically evident (Murphy et al., 1969, 1971; West and Murphy, 1973). The initial reduction of androgenic hormone by bilateral orchiectomy and/or estrogen therapy has been noted to produce a regression of advanced prostatic carcinoma (Huggins and Hodges, 1941). Measurement of the 24-hour excretion of urinary 17-ketosteroids correlates well with the relapse of the disease and can be decreased following bilateral adrenalectomy (Bhanalaph et al., 1974). Since cortisone has become available, adrenalectomy has been used to a limited extent following relapse of advanced carcinoma of the prostate. Previous investigators have agreed that bilateral adrenalectomy produced a remarkable degree of subjective improvement (Table 111).It has been unclear in the minds and opinion of some, however, whether increased survival with objective response could be obtained to a satisfactory degree. I n our own studies, which have now exceeded 50 patients, we have found this t o be true (Bhanalaph e t al., 1974; Reynoso and Murphy, 1972; Schoonees et al., 1972c; Merrin et al., 1974) (Fig. 4). As shown in Table IV, in a series of 26 patients with proven disseminated reactivated prostatic carcinoma, subjective improvement was achieved in most instances. I n the presence of prior castration and hypophysectomy, however, a significant degree of improvement was not noted (Table IV) . Following bilateral adrenalectomy, serum acid phosphatase levels are usually decreased within 1 month. They are increased again, however, in association with a demonstrable clinical relapse (Bhanalaph et al., 1974). Mean plasma testosterone levels after adrenalectomy generally exhibit no significant change (Bhanalaph et al., 1974). This is not unremarkable, as such levels, although generally low, have not been found to be helpful in following patients who have been hypophysectomized (Murphy et al., 1971). The 24-hour urinary excretion of total 17-ketosteroids in previously castrated or hypophysectomized patients is sometimes slightly higher before adrenalectomy (Bhanalaph et al., 1974). However, a marked decrease of the ll-deoxy-17-ketosteroids is consistently noted in previously castrated patients (Bhanalaph et al., 1974). This has been noted in follow-up periods extending up t o 1 year and beyond (Merrin et al., 1974) and is associated with clinically evident and suitable signs of subjective and objective response. The major cause of death following adrenalectomy is disseminated disease (Bhanalaph et al., 1974). Such studies demonstrate the 24-hour urinary ketosteroid ex-
TABLE I11 RESULTSOF BILATERAL ADRENALECTOMY FOR ADVANCED PROSTATIC CARCINOMA FROM
Author
Number of patients
Subjective improvementa Good
Fair
A
REVIEWFROM
THE
LITERATURE
FZ
* Ei 3 G,
Immediate Objective postoperative death improvementb
M
Longest survival
0
Huggins and Scott (1945) Huggins et al. (1952) Baker (1953) Scardino et al. (1953) Taylor et al. (1953) Whitmore et al. (1954) Fergusson (1954) Pyrah (1954) Morales et al. (1955) MacFarlane et al. (1960)
a
4 7 10 3 6 17 17 3 20" 13
1 3 7 1 5 6 9 2 4/10 9
Judged according to pain and sense of well-being. Judged according to growth regression (no bone improvement). Only ten patients had pain before adrenalect,omy.
5 3 5/10
1 1 2 1 1
3 1
1 2 2
115 Days 7
6 Months 9 Months
7 Months 330 Days 10 Months 24 Months 46 Months (mean 13 months)
w M, b
2 tiM -4
W
w m
0 u1
3 Q
5
:
8
M,
Period of subject,ivc improvcment”
iL’b
Pat.ient.s still alive
16
>
No relapsed
10 Cases (62.5,%)
5
4
-
1 Case
Previous castration and hypophysectomy with relapse
5
-
2 Cases (40%)
1 Case
Conditions of patient, a t the timc of bilateral adrcnalcctomy Previous castration with relapsc
a
Up to 3 months
Period of subjective improvement after adrenalectomy in months. = Number of patients who had bilateral adrenalectomy. Mean survival time in months after adrenalectomy. Castration 2-4 months after adrenalectomy.
*N
>3-12
Months 1 Case
>12 Mont,hs
Mean period of subjective improvement
Mean survival t imec
0
4 . 8 Months
8 . 2 Months
4 Cases
5
18.0 hZont>hs
2 0 . 8 Months
1 . 6 Months
6 . S Months
2
-
4 Cases (2.5 %) (80%)
409
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
X
AGE
I
2
63 64
3 4 5 6
74 68 60 71
7
7-4
.
8
7n
70 70
70 73
21 22 23 24 25 26
60 53,
0
9
c*
3
1
O D
*
"c-0
P.or-
0
D
*
9
I
*
l - Ec n
A
C
9
I.
Dm
C ? D
,o
1*
* *
0
71 62 65 56 54 6% 55
]
. I 1
O U m
68 61 68
17 18 19 20
9 0
m
=
O D .
54
16
D
ObC C
.-
.,
I3 14 15
0
66
a
-
+ c O
c*:o
.-
10
II 12
o-
.
* *
*
1
I
I
Dm D
. . I 7 , , , , ,,, , , , , 0
C D
0
160 140 120100 80 60 40 20 10 0
3
6
9
12
15
18
21
24 27
30
MONTHS
FIG.4. The survival and remission rates for a Roswell Park Memorial Institute prostatic cancer adrenalectomy series. Time course of 26 patients with advanced prostatic carcinoma after bilateral adrenalectomy. m, Period of subjective improvement; 0, period of nonresponse or relapse after treatment.. 0, Orchiectomy ; A, D, C , clinical stage of prostatic carcinoma; v, hypophysectomy; *, alive.
cretion, particularly that associated with the androgenic fraction (11deoxy) is also a good index and prognostic indicator in the presence of hypophysectomy (Bhanalaph et al., 1974) or after hypophysectomy. Those patients who respond to hypophysectomy or adrenalectomy show a persistent and significant decrease in 11-deoxy-17-ketosteroid 24-hour excretion rates (Murphy et al., 1969; West and Murphy, 1973; Bhanalaph et al., 1974) (Table V ) . Widespread use of adrenalectomy remains limited, as patients who are candidates for adrenalectomy are generally younger and must have the ability to withstand a more formidable operative procedure. We have found that such patients who have previously shown a response to endocrine therapy, whether it be orchiectomy or exogenous es-
410
G . P. MURPHY
TABLE V TNTNTY-FOGR H O U IURINARY ~ KETOSTEKOID EXCRETION AFTER BILATERAL ADRIIN.\LF:CTOYY I N ADVANCED P R O S ~ A TCI A C R C I N OPATIENTS X.~ WITH P R I O R C.ISTR.ITION
Ketosteroid
(11E.\N
Before adrenalectomy
VALUE
&SEhI)
After adrenalectomy 3 Weeks
1 Month
2-3 Months
1.30 (0.17)" 1.59 (0.34)* 1.32 (0.54)b
Total 11-deoxy-17-Ketosteroids
2.56 (0.60) 15
17
7
8
Total 11-0~y-17-Kcto-
1.48 (0.30)
4.39 (0.95).
4.97 (1.66)
4.27 (1.22)
15
17
7
8
4 . 0 4 (0.71) 15
5.66 (0.97) 17
6.61 (1.8) 7
5 . 6 0 (1.72)
w
A-
steroids
Total 17-ketost eroids A: a
P
bP
8
< 0.01. < 0.05.
rV = n'umber of observations.
trogens, generally will do well following adrenalectomy (Bhanalaph et al., 1974; Merrin et al., 1974). A similar situation has been generally but not uniformly true in the case of hypophysectomy by either route (Murphy et al., 1971; N'est and Murphy, 1973). We do not recognize that adrenal suppression and androgen excretion can be achieved to a significant degree by present chemical or nonoperative means despite claims to the contrary (Robinson et al., 1974). Such studies have failed to show the essential urinary depression in androgenic excretions as described in this Presentation. In advanced prostatic cancer paticnts, following relapse, radiotherapy similarly has not proved t o be of superior advantage (Varkarakis et al., 1972b). However, there has been some suggestion, in the hands of others, that hormonal therapy combined with megavoltage radiation therapy may provide some increased palliation and improved survival (Tsuya et al., 1974). We have not found this in our own experience (Varkarakis et al., 1972b).
IV. XEWERAGENTS Est,racyt, a chemical ester of a nitrogen mustard with estradiol-17/3, has been tested for its effects on the prostate in various species (Kirdani et al., 1974) and is further discussed in this symposium. Oral or parenteral estracyt was shown to have clinical activity in the early studies
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
411
or Jonsson and Hogberg (1971). Swedish and other investigators in Europe as well as in the United States (Muntzing et al., 1974) have used the compound in the presence of advanced carcinoma of the prostate resistant to conventional therapy. The oral agent has been given with minimal toxicity a t a generally effective therapeutic dose of 15 mg/kg daily in three divided doses (Muntzing e t al., 1974). Any toxicity when noted is mild and exclusively gastrointestinal. We have not seen any objective evidence of estrogen effects following the administration of this agent for prolonged periods (Miintzing et a$., 1974). There is good evidence that Estracyt is specific for human prostatic carcinoma (Tritsch et al., 1974). I n a recent series of 32 patients with stage D carcinoma of the prostate treated a t a therapeutically effective dose (Mittelman et al., 1975a,b), objective remission, which included decreases in soft tissue masses, lymph nodes, and prostatic masses, were noted in 25%, that is, 8 of 32 patients. Subjective responses, which included relief of pain, weight gain, sense of well-being, and improved performance status occurred in all the objective responders and 7 other patients with stable disease for a rate of 4776, or 15 out of 32 patients. Nonhematologic or hepatic or renal toxicity was observed. Transient nausea occurred early in half the patients, and in only 2 patients in this particular series was nausea and vomiting dose-limiting. Oral Estracyt is thus well tolerated and worthy of further clinical use (Mittelman et al., 1975a,b). We feel that this agent, on the basis of both phase I and I1 trails (Muntzing et al., 1974; Mittelman et al., 1975a,b) in the United States may be a preferable alternative to hypophysectomy or adrenalectomy. I n fact, a recent review evaluated the survival rates in such relapsed patients following the various forms of palliation including bilateral adrenalectomy, hypophysectomy, combination hypophysectomy and adrenalectomy, or chemotherapy with Estracyt (Welvaart e t al., 1974). Good long-term palliative responses were achieved with bilateral adrenalectomy, hypophysectomy, or Estracyt. However, because of ease of administration, effectiveness, and lack of toxicity, oral Estracyt may be considered the method of choice in such cases for failures following conventional hormonal therapy (Welvaart et al., 1974). Such observations must necessarily be repeated by others, but if valid will provide an easier means of initial management of a relapsed patient with advanced disease. Hypophysectomy and adrenalectomy still have their roles but may be utilized in more selective instances. Thus far, other more conventional chemotherapy has also not been fully evaluated (Murphy, 197313). The National Prostatic Cancer Project in the United States is currently demonstrating that 5-fluorouracil or cytoxan may provide both objective and subjective responses in patients
412
G . P. MURPHY
with advanced metastatic disease who have relapsed following conventional therapy (Murphy, 197311).At the present time, a variety of cooperative groups in the United States are evaluating the effectiveness of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, actinomycin, adriamycin, and procarbazine. That single agent chemotherapy can be given to patients in this age group with dose adjustments with minimal toxicity is indeed important to note (Murphy, 197313). Single agent or multiple agent chemotherapy may well, in the future, have a role in the management of reactivated prostatic carcinoma following conventional therapy. At the present time, it appears in the Kational Prostatic Cancer Project that 5-fluorouracil and cytoxan are superior to conventional chemotherapeutic agents used in such circumstances (Murphy, 1973b). Although initial pilot studies altering the immune status of the advanced prostatic cancer patient are underway, there is no immediate projection that such therapy will become routine in an adjuvant manner (hlerrin et al., 1973). However, results have been noted and cannot be dismissed lightly. With the development of other means of measuring progression of disease, including biological markers and so forth, further exploration of other therapies will doubtless be fruitfully pursued. At the present time the management of the patient with advanced prostatic carcinoma following relapse from conventional therapy is thus hardly in a state of hopelessness nor necessarily one of confusion. Multiple agents and operative procedures are available and can be safely used with a reasonable hope for palliation, subjective improvements, and, to a surprising degree, increased survival.
V. SUMMARY A N D CONCLUSIOKS The management of a patient v i t h metastatic relapsing prostatic carcinoma following conventional therapy has been a clinical dilemma. Earlier endeavors in this limited field have been devoted toward hormonal manipulation. I n view of the fact that the majority of the patients in the United States present with metastatic disease, and th a t their palliation may be limited for a short period, other forms of management have been sought by various clinical investigators over the years. Hypophysectomy through the open route has been somewhat hazardous with a significant operative mortality rate. It has been found in recent times that cryosurgical transsphenoidal hypophysectomy can achieve both objective and subjective response rates equal on occasion to tha t of open hypophysectomy. Moreover, with the cryosurgical technique, it has also been determined that growth hormone levels under insulin-induced hypoglycemia are an
MANAGEMENT OF REACTIVATED PROSTATIC CANCER
413
accurate index of the degree of pituitary ablation necessary for a subjective and objective clinical response. Such responses can be achieved by either route of hypophysectomy with a minimal ablation of 70% of the anterior pituitary. In view of this and in view of the absence of morbidity and mortality in our hands, transsphenoidal cryosurgical hypophysectomy appears to be the route of choice for such patients in whom hypophysectomy is selected. Bilateral adrenalectomy, similarly, for younger patients has provided a suitable means of subjective and objective improvement following relapse after conventional therapy. I n both types of patients, the daily 24-hour measurement of 11-deoxy-17-ketosteroidsin the urine has provided a better assay of the degree of androgenic ablation following either endocrine procedure or their combination. When such objective measurements are made for long periods following the initial procedure, a persistent decrease is associated with a good clinical course. Estracyt, a new oral, nonsteroidal agent has been found to be of superior benefit compared to radiation therapy or antiandrogens. Moreover, in ongoing studies reported in this presentation, it is of equal benefit to patients after adrenalectomy or hypophysectomy. The agent has been found to have minimal toxicity in phase I and I1 studies with response rates of a significant degree that have lasted for over one year in our own hands. The evaluation of chemotherapy with such agents as 5fluorouracil and cytoxan is currently underway. However, such agents a t the present time can be administered to such patients with minimal toxicity and offer significant hope for improvement in objective remission. Immune manipulation with BCG injection is in its earliest clinical trails. I n the face of these variations, it is thus possible to provide additional modes of management to the patient who has reactivated prostatic cancer. REFERENCES Baker, W. J. (1953). J. Urol. 70, 275. Bhanalaph, T., Varkarakis, M. J., and Murphy, G. P. (1974). Ann. Surg. 179, 17. Fergusson, J. D. (1954). Proc. R o y . Sac. Med. 47, 1007. Huggins, C. (1947). Harvey Lect. 42, 148. Huggins, C., and Bergenstal, D. M. (1952). PTOC.Nnt. Acad. Sci. U S . 38, 73. Huggins, C., and Hodges, C. V. (1941). Cancer Res. 1,293. Huggins, C., and Scott, W. W. (1915). Ann. S w g . 122, 1031. Jonsson, G., and Hijgberg, B. (1971). Scand. J. Urol. Nephrol. 5, 103. Kirdani, R. Y., Miintzing, J., Varkarakis, M. J., Murphy, G. P., and Sandberg, A . (1974). Cancer Res. 34, 1031. MacFarlane, D. A., Thomas, L. P., and Harrison, J. H. (1960). Amer. J. Surg. 99, 562. Merrin, C., Han, T., Klein, C.. and Murphy, G. P. (1973). Urology 2, 651. Merrin, C., Murphy, G. P., Chu, T. M., and Mittelman, A. (1974). Urology 3,223. Mittelman, A., Shukla, S. K., and Murphy, G. P. (1975a). J . Urol. (in press).
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