0022-534 7/89/1424-092l$02.
00/0
THE JOURNAL OF UROLOGY
Copyright© 1989 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Review Article
MANIFESTATIONS OF ADVANCED PROSTATE CANCER: PROGNOSIS
AND TREATMENT
BABU V. SURYA* AND
From the Urology Service, Veterans Administration Medical Center, and Department of Urology, New York University School of Medicine,
New York, New York
Carcinoma of the prostate is the most common cancer in
men. 1 A significant number of these patients will present with
advanced disease.'· 2 Advanced prostate cancer can manifest in
several forms by involving the contiguous and distant organs.
The urologist has a major role in their management. An under-
standing of the pathogenesis, treatment options and prognosis
of these secondary manifestations will be helpful in providing
better care to these patients. Despite extensive data on the
subject, there is no comprehensive and systematic review of the
available literature. In this article we collate and review the
available information.
URETERAL OBSTRUCTION
Ureteral obstruction is one of the more common secondary
manifestations of advanced prnstate cancer. The exact inci-
dence varies from 2 to 51 % depending upon the study popula-
tion.3-5 The incidence ofureteral obstruction is similar between
patients with and without bony metastases. 6 The mechanism
of ureteral obstruction in prostate cancer can be varied. The
tumor can invade and lift the trigone, and cause a relative
obstruction to the egress of urine. In about 80% of the cases
the tumor tissue compresses the ureterovesical junction. The
rest involve the lower third of the ureter. Compression of the
ureter from enlarged metastatic lymph nodes has been re-
ported. 7 Occasionally, intraluminal metastatic deposits causing
ureteral obstruction also have been described. 7• 8 Bladder outlet
obstruction from the carcinomatous gland also can impede
ureteral flow. More than two-thirds of the patients with ureteral
obstruction present with bilateral hydronephrosis. The proba-
bility of a patient with advanced prostate cancer having ureteral
obstruction is unknown. Even though it commonly is believed
that ureteral obstruction is seen only in advanced disease
Michigan and Catalona found that tumor stage and grade had
no influence on the incidence.4 Ureteral obstruction can be
present for several months without overt signs or symptoms.
Patients with advanced prostate cancer should have periodic
monitoring of renal function. Annual sonograms of the kidney
together with serum blood urea nitrogen and creatinine levels
should be sufficient to detect silent alterations in renal func-
tion.
In the past, active therapeutic intervention was discouraged
in these patients because of the poor prognosis associated with
ureteral obstruction from pelvic malignancy. 9 However, pa-
tients with carcinoma of the prostate fare better than those
with other primaries. Khan and Utz reported a 1-year survival
rate of 50% and a 5-year survival rate of 30% in 25 patients
treated by a variety of methods. 10 Good survival also was
reported by Brin and associates in patients with prostate cancer
and ureteral obstruction. 11 In a series of patients treated by
androgen deprivation, Michigan and Catalona reported a 1-
year survival rate of 83% and a 2-year survival rate of 61 %.4 In
another series of patients treated by surgical diversion the mean
survival was less than 10.6 months. 5 Patients known to have
* Present address: Department of Urology, SUNY Health Science
Center, 750 E. Adams St., Syracuse, New York 13210.
Vol. 142, October
Printed in U.S. A.
JOHN A. PRO VET
carcinoma of the prostate before the onset of ureteral obstruc-
tion fare better than those who present with ureteral obstruc-
tion. Similarly, patients who do not have bone lesions with
hydronephrosis survive longer than those who do. Patients in
whom bone lesions develop during treatment fare worse than
those who do not have such lesions. Acid phosphatase, if
elevated, serves as a useful marker to monitor therapy.
Traditional treatment of ureteral obstruction consists of
hormonal manipulation and radiation therapy. Before any ther-
apy, blad~er neck obstruction must be ruled out by passing a
catheter mto the bladder. If bladder neck obstruction is the
cause the hydronephrosis will decrease with a few days of
catheter drainage. In these circumstances transurethral resec-
tion is performed to relieve obstruction, although androgen
deprivation alone will alleviate bladder outlet obstruction in a
significant number of patients. In patients with no prior ther-
apy androgen deprivation has yielded better results than any
other form of therapy. A 74 % response was noted in 25 patients
treated by endocrine therapy. Response to orchiectomy was
better than to estrogen alone.4 In an earlier series Ganem
reported a 40% response to hormonal manipulation. 6 Response
to orchiectomy can be seen within 2 days to 2 months. The role
of the newer anti-androgen drugs, such as ketoconazole has
not been evaluated in the treatment of ureteral obstructidn.
Radiation therapy has been used to treat ureteral obstruction
with mixed results. Usually, 5,000 to 6,000 rad are delivered to
the affe_cted side. Michigan and Catalona reported that only 2
of 8 patien~s responded favorably to radiation therapy.4 Megulli
and associates reported that 9 of 10 patients responded to
radiation therapy. 12 However, several of their patients had
concomitant hormonal manipulation. Kraus and associates
documented that 4 of 5 patients responded to 4,000 to 5,000
rad. 13 Carlton and associates noted favorable results in 8 of 11
patients treated with 6,000 to 7,500 rads. 14 Even though initial
response to radiation therapy is favorable, the long-term re-
sponse and survival status in these patients is not well docu-
mented.
Surgical relief of obstruction in these patients includes ure-
teral reimplantation, ileal loop diversion and cutaneous ureter-
ostomy. Kihl and Bratt treated these patients with ureteral
reimplantation and cutaneous ureterostomy: 19 of 21 in the
reirnpl~ntation ~oup and all 6 in the cutaneous ureterostomy
group improved m terms of renal function. 5 Average survival
was 10.6 months. Blackard and associates reported a mean
survival of 2 months with loop diversion in these patients. 15
The advent of endourology has significantly altered the ap-
proach to these patients. Percutaneous nephrostomy with ure-
teral stenting not only offers prompt relief but also provides
long-term diversion with minimal inconvenience to the patient.
Whenever there is a choice, an internal stent is preferred to an
externally communicating nephrostomy tube. 16 If a stent can-
not be placed retrograde it can be inserted in an antegrade
fashion. The Universalt stent of Smith combines the advan-
t Cook Urological, Inc., Spencer, Indiana.
922 SURYA AND PROVET
tages of a nephrostomy tube and a ureteral stent. 17 Increased
familarity and relatively few complications associated with
endourological techniques have fostered an aggressive approach
in these patients. A decision to divert or not must be based on
the disease status, availability of further therapy and the wishes
of the patient and family. No useful purpose is served by
diverting a patient with hormonally resistant, widely metastatic
cancer and bilateral ureteral obstruction. 18• 19
Based on the available literature an algorithm for manage-
ment of a patient with bilateral ureteral obstruction can be
developed. In those who present with uremia and in whom a
decision to divert has been made, the better kidney is decom-
pressed with either a retrograde catheter or, more commonly,
with percutaneous nephrostomy. Renograms with split creati-
nine clearance values are helpful to predict the relative func-
tions of the 2 kidneys. In patients who have not had hormonal
manipulation orchiectomy is performed, since response to or-
chiectomy is faster than to estrogens. In patients with prior
orchiectomy local radiation therapy can be attempted. Endou-
rological techniques have made surgical diversion obsolete in
these patients. Often, patients with carcinoma of the prostate
present with unilateral obstruction only. Most of these patients
are treated conservatively, with close monitoring to detect
contralateral obstruction at an early stage. Chiou and associates
noted that percutaneous nephrostomy in unilateral obstruction
did not prolong survival. 20 In a series of 12 patients with
unilateral obstruction treated by hormonal manipulation
Michigan and Catalona noted only 1 patient who subsequently
had contralateral obstruction.
SPINAL CORD COMPRESSION
Spinal cord compression from carcinoma of the prostate
constitutes a neurological emergency. Early recognition and
treatment are essential for salvage of neurological function.
The incidence of spinal cord compression in carcinoma of the
prostate varies from 1 to 10%. 21 - 23 Prostate cancer is the second
most common cause of metastatic cord compression among
men. 24- 26 The incidence is related directly to the grade and stage
of the tumor.
The mechanism of spinal cord compression in prostate cancer
and other primaries is well described. 24• 27 Most of the respon-
sible lesions are epidural in location, although an occasional
intradural lesion has been reported. The epidural space is
defined by the bony vertebrae and dura. There are no lym-
phatics in the epidural space. The lesion begins as a hemato-
genous spread to the body of the vertebra. Batson first proposed
that there were several valveless communications between the
inferior vena cava and the vertebral venous system. 28 These
branches diverted the venous return from the pelvis to the
vertebral veins during periods of increased intra-abdominal
pressure. The vertebral veins constituted a large reservoir in
which cancer cells seed and grow. This theory of preferential
prostatic drainage to the vertebral column has been questioned
recently. Dodds and associates reviewed bone metastasis pat-
terns in several primaries, including the prostate, lung, bladder,
head, neck and esophagus. 29 The distribution of metastases was
virtually identical in patients with prostatic and nonprostatic
primaries. The majority of these lesions occur in the thoracic
vertebrae followed by the lumbar and cervical vertebrae. 30- 32
Occasionally, these lesions can be multiple. The majority of
spinal cord compressing lesions from carcinoma of the prostate
are accompanied by roentgenographic changes, although rare
cases of compression without x-ray changes have been reported.
Kuban and associates noted a median interval of 15.5 months
between the appearance of vertebral metastases and the devel-
opment of spinal cord compression. 22
Pain radiating to the lower extremities usually is the first
symptom. Pain may precede the actual compression by several
months. Localized tenderness usually is present. Although mo-
tor dysfunction usually precedes sensory loss, both may develop
simultaneously. Sphincter damage usually occurs late and has
an ominous prognostic sign. 24 ' 27 Findings on neurological ex -
amination in these patients may range from isolated sensory
loss to frank paraplegia. Roentgenographic studies of the spine
reveal abnormalities in up to 90% of these patients. 33 Comput-
erized tomography (CT) of the spine also is helpful to delineate
the extent of the lesion. Myelography usually is required to
establish the level of compression. Contrast medium is used to
visualize the epidural space; it can be left in the epidural space
to monitor the response to therapy. The extent of the obstruc-
tion must be defined and this might require a separate puncture
at the cisterna magna or at the C2 level.
Once the diagnosis of spinal cord compression is made the
treatment must be expeditious, since in these patients "the out-
look is less bleak than for many others in similar advanced
malignant states". 34 Immediate treatment consists of steroid
administration. Dexamethasone (10 mg.) is given intravenously
followed by 6 mg. orally every 4 months. After this therapy one
may elect to treat spinal cord compression by hormonal ther-
apy, laminectomy or radiotherapy.
In patients not previously treated by hormones orchiectomy
offers the best and the fastest response. 34 - 36 Recovery of neu-
rological function has been noted within 48 hours of instituting
hormonal therapy. In cases of impending compression intra-
venous diethylstilbestrol might be equally effective. 37 Ketocon-
azole in high doses (400 mg. every 8 hours orally) also can
be used. Laminectomy usually is offered to patients with rapid
onset complete spinal cord compression. Before laminectomy
the exact level and the extent of the compression must be
defined. A limitation of laminectomy is the inability to remove
the anterior lying lesions completely, although recent innova-
tions in spinal surgery have produced better results. 38 Radiation
therapy has been shown to be as effective as laminectomy alone
in relieving the compression. Several studies have documented
that radiation therapy alone is equal to or better than laminec-
tomy with or without postoperative radiation therapy. 24- 27 , 39
Usually, 2,000 to 4,000 rad are delivered to the involved verte-
brae. The limiting factor in radiation therapy of vertebral
metastases is the radiation tolerance of the spinal cord.
Prognosis of patients with spinal cord compression depends
on several factors. Generally, previously undiagnosed and,
therefore, untreated patients do well. Those with paraparesis
fare better than those with paraplegia. Sphincter involvement
and rapid onset of symptoms are bad prognostic signs. Even
though various investigators proclaim the superiority of differ-
ent modes of therapy, generally the over-all success rate for
various modes of therapy is approximately 30% (see table).
Success is defined as ambulation and sphincter control. Lack
of prospective randomized control studies makes comparison
of different treatment modalities difficult. However, in a pre-
viously untreated patient hormonal treatment is effective con-
sistently and must be part of the treatment plan. In patients
with impending compression radiation therapy can be at-
tempted. In patients with rapid onset compression and in those
who respond poorly to radiation therapy and/or hormonal
therapy, laminectomy is the treatment of choice. Patients who
respond to treatment must be monitored for future develop-
ment of spinal cord compression, since 15% of these patients
may have recurrent compression. 22
BLADDER OUTLET OBSTRUCTION
Bladder outlet obstruction is a common secondary manifes-
tation of advanced prostatic carcinoma. The exact incidence is
hard to define, since in patients with prostate cancer concom-
itant benign hyperplasia can cause outlet obstruction. The
reported incidence ranges from 17 to 72%. 40- 42 Significant
among these data is the report by Forman and associates , who
in 240 patients with mostly advanced disease noted a 72%
incidence of bladder outlet obstruction. 42
 923
Treatme,1,t results in patients with spinal cord compression from underwent radical prostatectomy. 51 In these patients
prostate cancer transurethral resection of the prostate had no adverse effect on
Median interval to failure. Babaian and Archer found that in 208
Mode of Success*
Reference No. Pts.
Therapy No.(%)
Survival patients with stage C carcinoma of the prostate treated by
(mos.) external beam radiation, tumor volume and not the mode of
Liskow and 13 Surgery, 1 (7.6) 23 biopsy influenced the interval to progression. 52 In view of these
associates23 radiation data, the effect of transurethral resection of the prostate in a
Barron and 6 Surgery 4 (66)
associates 24
patient with bladder outlet obstruction and in a carefully staged
Bruckman and 35 Surgery, 11 (11) Not available C lesion is not clear. Randomized prospective studies would be
B1oomer25 (pooled radiation necessary to establish the role of transurethral resection of the
data) prostate in these patients.
Gilbert and 5 Surgery, 1 (20) Not available
associates 26 radiation
Androgen deprivation has been a standard mode of therapy
Rubin and 9 Hormonal 2 (22) Not available to relieve bladder outlet obstruction in patients with advanced
associates30 3 Surgery 1 (33) Not available prostate cancer. 53 Chute and associates reported on 13 patients
4 Radiation 1 (25) Not available treated by subcapsular orchiectomy and diethylstilbestrol and
Iacovou and 34 Surgery 20 (58) Not available
associates 33
found that 9 were able to void freely. 54 They believed that if
Marshall and 13 Surgery 9 (69) 17 voiding does not occur within 2 weeks the patient should
associates 31 undergo transurethral resection. Shrinkage of prostate volume
Gaches and 6 Surgery, 2 (33) 10.5 after orchiectomy is a well known phenomenon. Spirnak and
Roberts 34 8 radiation 2 (25) Not available
Jameson 35 24 Surgery, 20 (83) 60
Resnick noted by transrectal sonography that a significant
hormonal decrease in prostate volume occurred up to 6 months after
* Defined as ambulation and sphincter control.
orchiectomy but subsequent changes were minimal. 55
Fleischmann and Catalona treated 35 patients with bladder
outlet obstruction secondary to carcinoma of the prostate with
hormonal therapy and achieved successful results in 68.5% of
The optimal management of these patients currently is being
the patients. 56 Tumor volume and stage did not influence the
debated. Traditionally, these patients were managed by trans-
result. Varenhorst and Alund reported on 122 patients treated
urethral resection of the prostate. 40 • 43 • 44 A channel transure-
by hormonal manipulation and found that 80 (65.6%) became
thral resection followed by radiation or hormonal therapy is
free of a catheter by hormonal manipulation (87% of those who
the usual mode of therapy in these patients. Recently, several
became free of a catheter did so within 4 months). 41 They also
investigators have suggested that transurethral resection of the
noted that orchiectomy produced tumor regression faster than
prostate may be involved in disseminating prostate cancer.4 5 - 48
estrogens.
In 1965 Jonasson and associates demonstrated that transme-
Thus, it seems preferable to try androgen deprivation in
thral resection of the prostate releases cancer cells into the
these patients as the initial mode of therapy, except in those
general circulation.4 9 McGowan first drew attention to the
who wish to retain potency. If they fail to void within 3 months
adverse influence of prior transurethral resection of the pro-
transurethral resection can be performed. In patients with
state on patients undergoing radiation therapy.4 5 Among pa-
clearly localized cancer causing bladder outlet obstruction, es-
tients with stage B2/C disease, survival and intervals free of
pecially those in whom a radical operation or radiation therapy
disease were significantly lower for those whose diagnosis was
is being contemplated, androgen deprivation can be attempted.
established transurethral resection of the prostate compared
Temporary estrogen therapy might be more appropriate in
to those whose diagnosis was made by needle biopsy. Hanks
these settings.
and associates reported on a pattern of care study in 24 7
patients. 46 Transurethral resection had an adverse influence on
BONE PAIN
the distant recurrence and death rate. This difference was noted
only in stages T3 and T4 tumors. Most of the tumors in the Bone pain is one of the more disabling manifestations of
transurethral resection group were poorly differentiated, while advanced prostate cancer. Most of the affected patients have
those in the needle biopsy group were mostly well differentiated. significant with severe limitations in activity. The exact
Despite this bias the adjusted data showed the adverse influence etiology of pain in these patients i.s not clear. It is presumed to
of prior transurethral resection of the prostate. Forman and be related to prostaglandin synthesis and other related mech-
associates studied the effect of transurethral resection of the anisms. The nature of can be varied. Pain can be contin-
prostate on tumor dissemination in 240 n"·t,,.,·m'.~ with localized uous or intermittent, diurnal variations and can be mi-
carcinoma.4 2 Half of these patients had stage C disease, with a gratory in nature. The most common sites affected dre the low
significant percentage of patients with signs of bladder outlet back and hip, followed the legs, neck, shoulders and ribs.
obstruction. Again, transurnthral resection adversely influ- Even in the presence of extensive skeletal metastases headache
enced the development of metastases. With a multivariate seldom is noted. 57
analysis these investigators found that elevated acid phospha- The treatment of choice for metastatic bone pain is androgen
tase is the most important predictor of failure, followed by deprivation. 53 A significant number of patients will respond to
tumor grade and mode of biopsy. Elder and associates also hormonal manipulation, which should be attempted first in
noted that in stage C cancer patients transurethral resection of previously untreated patients. Orchiectomy produces rapid re-
the prostate had a negative impact on survival. 47 Kuban and sults with relief beginning within 24 hours. Intravenous dieth-
associates, while analyzing the appearance of bone metastases ylstilbestrol can be tried in patients who will not undergo
in patients undergoing radiation therapy, found no adverse orchiectomy to achieve prompt symptomatic relief. Ketocona-
effect of prior transurethral resection of the prostate on the zole has produced comparable results. In a series of 17 patients
development of metastatic disease. 48 The validity of the conclu- being treated with 400 mg. every 8 hours orally Vanuytsel and
sions in these studies has been questioned. 50 Lack of proper associates noted an 88% over-all response. 58 Pain relief when
pre-therapy staging with pelvic lymphadenectomy and bone present, was seen within 2 weeks.
scans, unequal distribution of patient groups, retrospective Bone pain in patients who are resistant to androgen depri-
nature of the studies and failure to define indications for vation is an extremely distressing problem. Various analgesics
transurethral resection for several of these patients were some usually are tried as the first resort. Aspirin-related compounds
of the problems in interpreting the data. Paulson and Cox are effective because of the ability to inhibit prostaglandin
reviewed the outcome in stage Tl/2NOMO cancer patients who synthesis. Response to meperidine and morphine sulfate can
924 SURYA AND PROVET
be varied and unpredictable. 57 Localized external beam radia-
tion therapy usually is the most common method of palliation.
Benson and associates reviewed their experience with external
beam radiation for relief of pain. 59 In a series of 62 patients
they noted complete relief in 42% and partial relief in 35%.
Better results were seen in patients in whom only 1 site was
irradiated compared to those in whom multiple sites were
irradiated. The average duration of pain relief was 6 months.
Pain from metastases to the lumbosacral spine was extremely
resistant to radiation. For palliation, usually 2,000 to 3,000 rad
are delivered in divided doses. Concomitant or sequential treat-
ments can be given to multiple sites.
Diffuse skeletal pain is a frustrating problem faced by many
patients. Most have failed on androgen deprivation therapy
and require large amounts of narcotics to alleviate the symp-
toms. Experience with other cancers, such as myeloproliferative
disorders and certain solid neoplasms, has led to the application
of total body irradiation in these patients. This can be achieved
with either an external beam source or an internal source, such
as radioactive phosphorous (32P). 60 • 61 Total body irradiation
usually is given in 2 half body treatments with the umbilicus
as the arbitrary dividing point. The more symptomatic half is
treated first followed by the other half after an interval of 4 to
6 weeks. During this period the marrow cells from the nonra-
diated half will repopulate the radiated marrow. Usually, 800
to 1,000 rad are given to the lower half and about 600 to 750
rad to the upper half. The doses are delivered in a single session
to avoid discomfort and prolonged hospitalization to these
already sick and debilitated individuals. Relief of pain usually
is seen within 24 to 48 hours. The response rate is about 70 to
80% and the mean duration of response is about 4 to 5
months. 61 - 63 Complications with total body radiation include
bone marrow suppression, radiation pneumonitis, gastrointes-
tinal disturbances and alopecia. Bone marrow suppression usu-
ally manifests in the form of pancytopenia. Complete blood
count must be monitored closely in these patients, especially
between the treatment of 2 body halves. Adequate levels of
marrow activity must be demonstrated before treatment is
begun to the second half. Radiation pneumonitis can be pre-
vented by delivering the lower dose to the upper half of the
body. Gastrointestinal symptoms, such as nausea and vomiting,
are transient and can be treated with conventional methods.
Alopecia is almost universal. The scalp hair usually regrows.
Total body radiation with 32 P has been attempted in these
patients. 32P emits fJ rays and concentrates selectively in new
bone. 64 The uptake of 32P in new bone can be increased signif-
icantly by hormones, such as testosterone and parathor-
mone. 65· 66 32P usually is given intravenously at 1 mCi. per day.
Various dose regimens have been described ranging from a
single dose to a total dose of 7 mCi. The most significant
limiting factor is the bone marrow suppression. Patients can
be primed with testosterone or parathormone before adminis-
tration of the radioactive material to enhance the uptake. Relief
of pain is seen within 24 to 48 hours. Corwin and associates
described a 50% response without testosterone priming and an
87.5% response with priming. 67 Morales and associates reported
that 10 of 14 patients with testosterone priming became com-
pletely free of pain for a mean duration of 6.3 months. 65
Significant exacerbation of prostate cancer can occur during
testosterone administration. 68 Spinal cord compression and
pathological fracture can occur, and this has deterred many
from using testosterone as a priming agent. Tong alternatively
has used parathormone as a priming agent with excellent
results. 69 Since there appears to be no difference between
testosterone and parathormone, the latter is preferable to use
as the priming agent. 70
Hypophysectomy is another mode of palliation in patients
with diffuse pain. The pituitary gland is presumed to act on
the prostate gland through prolactin. The significant surgical
risks of pituitary surgery in the past have deterred many from
pursuing this option. Nonetheless, recent techniques, such as
trans-sphenoidal and ethanol ablation, have made the opera-
tion considerably simpler. 71- 73 However, the need for replace-
ment therapy has made this a less attractive choice. Bone
resorption inhibitors also have been used effectively in the
management of these patients. Adami and associates described
the use of dichloromethylene-diphosphonate in 17 patients with
severe bone pain due to metastases. 74 A positive response was
noted in 16 patients. Further studies are required to evaluate
the efficacy of this drug in this setting.
RECTAL OBSTRUCTION
Advanced prostate cancer can produce rectal obstruction
mimicking primary rectal carcinoma. Distinction between the
2 is essential because of the different primary treatment strat-
egies used for each. A rectal primary is treated by surgical
resection, whereas a prostatic tumor invading the rectum usu-
ally is managed by hormonal therapy. Normally, the 2-layered
Denonvillier fascia provides a tough barrier to the posterior
growth of the prostate cancer. However, locally aggressive
prostate cancer can invade through the fascia to cause severe
rectal symptoms. The incidence of rectal obstruction in ad-
vanced prostate cancer is approximately 10%.15- 77 Rectal in-
volvement by prostate cancer manifests in 3 different forms: 1)
an anterior rectal mass compressing or occluding the lumen of
the rectum, 2) rectal stricture and 3) a mass with mucosal
ulceration. 75 • 78 Rectal obstruction secondary to metastatic
.lymph nodes and rectovesicourethral fistulas also have been
described. 76• 77 ' 79 ' 80
Rectal obstruction is the initial mode of presentation in more
than 50% of the patients with rectal involvement. The other
half will have rectal obstruction during the course of the disease.
Most of these patients will present with significant rectal
symptoms, such as diarrhea, rectal bleeding, constipation and
tenesmus. Urinary tract symptoms may be mild to absent.
Physical examination may reveal a hard mass in the anterior
wall of the rectum. An intact rectal mucosa on proctoscopy has
been identified as characteristic of secondary involvement,
usually from a prostate primary. 76 Barium studies of the lower
gastrointestinal tract usually are not helpful to distinguish the
primary rectal carcinoma from prostatic cancer. The combi-
nation of rectal symptoms and relative paucity of urinary
symptoms might delay the diagnosis. 81 • 82 A high index of sus-
picion is essential in these patients to arrive at the correct
diagnosis. Excretory urography usually will show significant
changes in up to 90% of the patients. 76• 83 Serum acid phospha-
tase usually is elevated and up to 60% of the patients will have
evidence of skeletal metastases. Cystoscopy will reveal eleva-
tion and distortion of the trigone. A CT scan of the pelvis is
useful to delineate the rectal origin of these lesions. 84
Tissue diagnosis is essential to start appropriate therapy in
these patients. In the past there was considerable difficulty in
determining the origin of these tumors because of their poorly
differentiated nature and the occasional mucous formation.
Diagnosis was primarily established by the clinical pattern.
Short course therapy with estrogens and repeat biopsy have
been suggested in doubtful cases to identify the origin of these
tumors. Degenerative changes in the tumor cells would indicate
a prostatic primary. The recent introduction of staining for
acid phosphatase and prostate specific antigen should signifi-
cantly improve the accuracy of tissue diagnosis in these difficult
situations. 85' 86
Treatment depends upon the degree of bowel obstruction and
the hormonal sensitivity of the primary lesion. Patients with
impending or frank bowel obstruction will require diverting
colostomy. In hormonally sensitive tumors androgen depriva-
tion offers excellent palliation. Even though the radical extir-
pation has been tried in localized disease without evidence of
distant metastases, 87 it generally is not advocated as the treat-
ment of choice. In general, prognosis for these patients is poor,

with mean survivals of less than 1 year. 78 Transurethral resec-
tion, if necessary, must be performed with caution in these
patients, since the likelihood of a perineal fistula is high.
HEMATOLOGICAL DYSFUNCTION
Coagulation defects in the presence of metastatic prostate
cancer have been recognized for a long time. In 1930 Jurgens
and Trautwein described a patient with severe hypofibrinoge-
nemia and bleeding. 88 They, and subsequently Seale and asso-
ciates,89 postulated that low fibrinogen levels were due to the
destruction of the reticuloendothelial system by prostate can-
cer. Tagnon and associates postulated that bleeding in prostate
cancer patients was secondary to fibrinolysis from proteolytic
enzymes produced by the carcinomatous gland. 90 The prostate
gland is known to be the source of plasminogen activator-like
enzymes and thromboplastins. 91 -93 These enzymes have several
important biological regulatory functions. 94 Their release into
the blood stream and subsequent fibrinolysis were considered
to be the cause of bleeding in advanced prostate cancer patients.
This theory of fibrinolysis later was questioned by several
investigators who could not demonstrate clot lysis in these
patients. 95 -93 Hypofibrinogenemia secondary to depletion of the
factors by intravascular clotting was proposed as the primary
or main event with secondary fibrinolysis. 99 Prostate tissue
releases thromboplastin into the circulation, which activates
the intravascular clotting cascade. Release of plasminogen ac-
tivator substance from the prostate and injured tissues will
secondarily produce fibrinolysis. Disseminated intravascular
coagulation with secondary fibrinolysis currently is the pre-
ferred theory to explain the severe bleeding diathesis associated
with advanced prostate cancer. 92 -94 Normally, a triggering
event, such as an operation or instrumentation, would precipi-
tate bleeding. However, patients with carcinoma of the prostate
have a latent tendency to bleed. Tagnon and associates reported
a 12% incidence of fibrinolytic activity in 48 patients with
prostatic cancer. 100 Andersson compared fibrinolytic activity in
men with prostate cancer and age-matched controls. 101 Patients
with prostate cancer had significantly elevated levels of fibrin-
olytic activity. Fibrinolytic activity remained within the upper
range of normal values during asymptomatic periods but in-
creased during the bleeding episodes. In a prospective study of
patients undergoing transurethral resection of the prostate,
Mertens and associates found that patients with prostate can-
cer had higher levels of fibrinogen degradation products com-
pared to patients with benign disease. 102 They also correlated
increased levels with more advanced stages of the disease.
Similar results were noted by Dobbs and associates, who meas-
ured antithrombin III activity in patients with prostate cancer,
and found that those with stages C and D disease had signifi-
cantly lower levels of antithrombin III activity than those with
stages A and B disease. 103
The clinical picture usually is one of a patient with
metastases and generalized bleeding. Acid phosphatase usually
is elevated. Bleeding can be significant. The diagnosis of dis-
seminated intravascular coagulation is based on decreased
platelet cell count and elevated prothrombin time. Hepatic
dysfunction by itself can cause these abnormalities and, there-
fore, it must be excluded. When all 3 abnormalities are present
the diagnosis of disseminated intravascular coagulation can be
made. When only 2 of the tests are abnormal the diagnosis can
be confirmed by measuring the elevated levels of fibrinogen
degradation products. In patients with equivocal laboratory
results and clinical evidence of bleeding other less specific tests,
such as euglobin lysis time, the ethanol gelation test and
radioimmunoassay of serum fibrinopeptide A levels, are used
for confirmation. 91
Once a diagnosis of disseminated intravascular coagulation
and associate fibrinolysis is made, appropriate replacement
therapy with fibrinogen and platelets is initiated. 95· 97 · 103 Sepsis
is corrected and blood volume is restored. In previously un-
925
treated patients androgen deprivation usually offers dramatic
results. The traditional method of androgen deprivation in
these patients is intravenous administration of estrogens. 104
Orchiectomy usually is not recommended until the acute phase
has subsided because of wound hemorrhage. Recently, dramatic
results in the treatment of severe bleeding associated with
prostate cancer have been described with ketoconazole (400
mg. every 8 hours). The onset of effect is faster with ketocon-
azole than with intravenous estrogen therapy. 105 After cessation
of the bleeding, orchiectomy usually is performed to prevent
chronic disseminated intravascular coagulation. Spontaneous
resolution of disseminated intravascular coagulation in prostate
cancer also has been reported. 106
Intravenous heparin has been used to treat disseminated
intravascular coagulation secondary to prostate cancer. Straub
and associates reported the use of intravenous heparin in a
patient with dramatic return of laboratory values. 107 Heparin
acts by preventing intravascular coagulation. The pharmaco-
logical effects of heparin in suppressing fibrinolysis must be
remembered and the dosage must be monitored. Heparin ther-
apy may be considered when factor replacement therapy is not
effective and the primary etiology cannot be controlled effec-
tively. Usually, a loading dose of 100 units per kg. body weight
is given followed by a maintenance dose of 10 to 15 units per
kg. body weight by infusion. The best indicator of effectiveness
of heparin therapy is the cessation of bleeding. Suppression of
fibrinopeptide A levels to normal within 15 to 30 minutes of
therapy is a good prognostic sign. 108 Heparin dose must be lower
in patients with severe thrombocytopenia. Heparin always must
be administered with plasma and platelets.
Epsilon aminocaproic acid is a- potent inhibitor of plasmin
and its activators, and has been used to treat bleeding associ-
ated with prostate cancer. Epsilon aminocaproic acid should be
used only in the presence of primary fibrinolysis and in the
absence of active disseminated intravascular coagulation. Ep-
silon aminocaproic acid can either potentiate or unmask a
latent thrombotic episode. 109 Since the bleeding in prostate
cancer mainly is due to disseminated intravascular coagulation
this agent seldom is used.
Prostate carcinoma also can manifest in the form of severe
localized bleeding as hematuria. Usually, conservative measures
are sufficient. Occasionally, cystoscopic fulguration of the
bleeding points might be required. Excellent results with radia-
tion have been described in patients with chronic bleeding. 13· 14
METABOLIC ABNORMALITIES
Several metabolic abnormalities have been described in pa-
tients with advanced carcinoma of the prostate. Most of these
abnormalities are similar to the paraneoplastic syndromes as-
sociated with other advanced states of malignancy. These met-
abolic abnormalities usually imply a poor prognosis, especially
if the tumor is not androgen sensitive.
Calcium metabolism disturbances can manifest in several
forms. 110 In a survey of 75 patients Raskin and associates found
a 31% incidence of hypocalcemia in patients with advanced
prostate cancer. 110 The mean interval between the appearance
of bony metastases and the onset of hypocakemia was 12.6
months. Most of these patients had osteoblastic lesions, al-
though a few had osteolytic lesions. Active new bone formation
at the osteoblastic site acts as a reservoir to draw in calcium
from the general circulation. Infused calcium in these patients
predominantly accumulates at the osteoblastic site. Secondary
hyperparathyroidism can develop as a response to low serum
calcium levels. 111 Most of these patients are asymptomatic and
only a few will have neurological signs of hypocalcemia. Re-
sponse to androgen deprivation and calcium gluconate usually
is seen.
Hypercalcemia is relatively rare in advanced prostatic carci-
noma.112-114 Mahadevia and associates estimated the incidence
of hypercalcemia to be less than 2%. 112 Bony lesions are not a
926 SURYA AND PROVET
prerequisite for hypercalcemia. 115 Most of these patients exhibit
unusual tumor morphology. Carcinoid, oat cell and squamous
features have been associated with hypercalcemia. Most of
these patients will respond to androgen deprivation. In those
who are androgen resistant hypercalcemia usually is a poor
prognostic sign and is managed with conservative therapy.
Tumor-induced osteomalacia also has been described. 116' 117
These patients are hypophosphatemic, and show evidence of
renal phosphate wasting, gastrointestinal malabsorption of cal-
cium and phosphate, and negative calcium balance.
Patients with advanced carcinoma of the prostate can exhibit
Cushing's syndrome due to ectopic production of adrenocorti-
cotropic hormone. 11a-122 The source of adrenocorticotropic hor-
mone in cancerous prostate glands is not clear. It was presumed
that the adrenocorticotropic hormone came from the amine
precursor uptake and decarboxylation (APUD) family of cells
in the prostate gland. 123 Argentaffinity and argyrophilia, fea-
tures characteristic of APUD cells, have been demonstrated in
benign prostatic hyperplasia and prostate cancer. 124 However,
Vuitch and Mendelsohn recently questioned this assumption
and proposed that APUD cells are the result of redifferentiation
of anaplastic cells. 120 Most of these patients exhibit anaplastic
morphology. Adrenocorticotropic hormone can be localized to
these anaplastic cells. Inappropriate secretion of antidiuretic
hormone also has been described in advanced prostatic carci-
noma. 12s, 12a
PULMONARY MANIFESTATIONS
Clinical evidence of pulmonary involvement is relatively rare
in advanced prostatic cancer. Mintz and Smith noted a 24%
incidence of lung involvement in an autopsy series. 3 Bumpus
noted a 4.8% incidence of lung involvement in 246 patients. 21
All of these patients had vertebral metastases. While a discrete
pulmonary nodule is the more familiar manifestation, patients
occasionally can present with severe progressive respiratory
insufficiency. 127 The relative paucity of urinary symptoms
might delay the diagnosis. Most of these patients are resistant
to conventional medical therapy. The pathological lesion is one
oflymphangiectasis. Response to androgen deprivation therapy
usually is good. 127' 128 Pleural effusion secondary to prostatic
carcinoma also is described. 128, 129
CONCLUSION
Advanced prostate cancer, like many other primaries, can
manifest in many forms. However, compared to other primar-
ies, the prognosis in patients with prostate cancer is better,
since most of these tumors are hormone dependent at initial
presentation. Even though life expectancy cannot be extended
in many of these patients, a sense of cautious optimism is
justified. For patients with hormone resistant tumors conserv-
ative therapy will improve the quality of life.
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