Prostate Cancer and Spinal Cord Compression

Transcription

Published on Cancer Network (http://www.cancernetwork.com)
Review Article [1] | July 01, 2001 | Oncology Journal [2], Genitourinary Cancers [3], Prostate Cancer
[4]
By Thomas C. Chen, MD, PhD [5]
Prostate cancer metastasis to the spine is an extremely difficult clinical problem to treat. However,
it occurs commonly, and all clinicians—not only oncologists—should undertake to understand its
pathogenesis, diagnosis,
ABSTRACT: Prostate cancer metastasis to the spine is an extremely difficult clinical
problem to treat. However, it occurs commonly, and all clinicians—not only
oncologists—should undertake to understand its pathogenesis, diagnosis, clinical
presentation, and current treatment options. This review emphasizes the surgical
treatment of prostate cancer metastasis to the spine. The goals of this article are to (1)
present an overview of the pathophysiology of this disease, with an emphasis on the
mechanisms of metastasis and invasion, (2) provide a general overview of the clinical
presentation and diagnosis of metastatic prostate carcinoma, and (3) discuss currently
available treatment options. Such options include best medical management, nonsurgical
treatments (radiation, chemotherapy), and surgical treatment of newly diagnosed and
previously irradiated metastatic prostate carcinoma to the spine. Algorithms for the
treatment of this disease are presented. [ONCOLOGY 15(7):841-861, 2001]
Introduction
It is estimated that approximately 198,000 US men will be diagnosed with prostate cancer this
year.[1] Prostate cancer is the second leading cause of cancer death in men in the United States.
The morbidity and mortality associated with prostate cancer can often be attributed to the
consequences of bone metastases.[2] The most common site of bone metastasis in prostate cancer
patients is the spine, followed by the femur, pelvis, ribs, sternum, skull, and humerus.[3] As a result,
prostate cancer is second only to lung cancer as a cause of metastatic spinal cord compression in
men.[4] Symptomatic lumbar and cervical epidural metastases develop in 27% and 6% of prostate
patients, respectively.[5,6]
Yamashita and coworkers found that, among responders to androgen deprivation, the absence of
bone metastasis outside the pelvis and the lumbar spine was predictive of a longer survival.[7]
Because of the frequency of spinal cord compromise secondary to prostate carcinoma, the
importance of early diagnosis and treatment of patients with spinal metastasis cannot be
overemphasized.
Biology of Prostate Cancer Metastasis
FIGURE 1
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Batson's Plexus and Paravertebal Venous Connections
The most common site of metastasis is the lumbar spine.[3] Autopsy data reveal that spinal
metastases precede lung and liver metastases in many patients with prostate cancer.[8] Batson, in
1940, proposed that prostate carcinoma cells reach the lumbar vertebrae via the vertebral venous
plexus—a network of longitudinal, valveless veins running parallel to the vertebral column, which
comprises countless anastomoses to the sinusoidal structure of the vertebral marrow and epidural
venous channels (now called Batson’s plexus, Figure 1). Under transient conditions of increased
intra-abdominal pressure, the prostate cancer cells may reach the axial skeleton directly by
retrograde hematogenous spread, without passing through the lungs.[9] The cancer cells then
invade through the sinusoidal endothelial cells of Batson’s plexus into the marrow space of the
vertebral body; in the bone marrow, the prostate cancer cells are stimulated to proliferate.
Batson’s Plexus and the Metastatic Model
However, for this metastatic model to be true, several issues need to be addressed: (1) how valid is
Batson’s plexus as a model for spine metastasis? (2) how do prostate carcinoma cells "home" into
the sinusoidal endothelial cells of the vertebral body? (3) what is the invasion process that prostate
carcinoma cells employ in order to get into the host bone marrow? (4) what is special about the
vertebral body microenvironment to favor prostate cancer metastasis? (5) Why do prostate
carcinoma cells induce an osteoblastic instead of an osteolytic response?
Batson originally injected the cadaveric dorsal vein of the penis with radio-opaque material and
demonstrated the connection with the prostatic plexus and thereafter the pelvic vein, pelvic bones,
and sacral canal, leading him to hypothesize the venous route of prostate metastasis.[9]
Subsequently, other investigators, working with animal models, validated Batson’s plexus as the
preferred route of metastasis. Coman and DeLong were able to test this hypothesis directly using an
animal model. In their experiment, Walker rat 256 carcinoma cells were injected into the femoral
vein of rats while intra-abdominal pressure was exerted. The majority of animals developed vertebral
metastasis while control animals (without increased abdominal pressure) only developed tumors in
the lungs.[10]
Other Routes of Metastatic Spread
However, other investigators have questioned whether prostate metastasis occurs via Batson’s
plexus. Dodds et al in a review of various positive bone scintigrams from different cancers found
little difference in overall distribution of the various cancers and prostate carcinoma, leading them to
conclude that a systemic route of metastasis was the preferred method of spread for all cancers.[11]
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More recently, Nishijima et al reexamined the issue of bone metastasis by confining their
examination of bone scintigrams to lung and prostate carcinoma patients with "early-stage" bony
involvement (no more than two bony lesions). They concluded that there was a preponderance of
metastases to the spine and pelvis in prostate cancer patients. Patients with "late-stage" bone
involvement (more than three bony lesions) were indistinguishable in their metastatic distribution
pattern. Moreover, a number of investigators have been able to reproduce metastatic tumor growth
in the lumbar spine by injecting cancer cells into the tail vein of rats with temporary vena caval
occlusion.[12,13]
If Batson’s plexus indeed offers a conduit for prostate carcinoma cells to travel up to the vertebral
body, it does not explain how the prostate cancer cell is able to "home" into the sinusoidal
endothelial cells of the vertebral body. Haq et al recently demonstrated that bone marrow-derived
endothelial cells express adhesion ligands for prostatic cancer cells that are not expressed on either
hepatic endothelial cells or nonendothelial cells of the marrow.[14] The prostate cancer cells then
cross the leaky endothelial cell barrier into the interstices of the marrow. Here, the cancer cells are
surrounded and nurtured by the marrow.
Wu et al examined the interaction of human prostate cancer epithelial cells with bone stromal cells,
and suggested that the bone stromal cells play a protective role in the development of metastatic
cancer cells, inducing androgen independence in the prostate carcinoma cells.[15] Moreover,
Chackal-Roy et al have shown that marrow-conditioned medium is mitogenic for prostate carcinoma
cells, suggesting that mitogenic factors produced by the marrow stromal cells may also account for
the preferential growth of prostatic metastasis in bone.[16]
Growth Factors That Enhance Metastatic Potential
In addition to the favorable host microenvironment of the vertebral body stroma, prostate carcinoma
cells also secrete a variety of growth factors and proteases that enhance their metastatic potential
and growth. In order to enhance their invasiveness, urokinase plasminogen activator may be
secreted by prostate carcinoma cells. This very important protease converts the inactive zymogen
plasminogen into the active serine protease plasmin, allowing for extravasation of cancer cells and
breakdown of the skeletal matrix. Experimental evidence indicates that urokinase plasminogen
activation is found at higher levels in highly aggressive prostate cancers as opposed to more
well-differentiated lesions, and hyperplastic or normal tissues.
Urokinase plasminogen activator levels are also higher in metastatic prostate carcinoma vs the
nonmetastatic variety.[17] Chen et al have shown that rat adenocarcinoma PA III cells secrete bone
morphogenetic protein 3 (BMP3)[18]—a family of bone growth factors that have been linked to the
transforming growth factor-beta family.[19] The secretion of bone morphogenetic protein by prostate
carcinoma cells may explain the "blastic" nature of prostate metastasis. In turn, the blastic response
of prostate carcinoma may explain why new bone formation is found around the tumor cell deposits,
often without prior osteoclastic resorption.[20]
Ultimate Effects on Spinal Cord
Eventually, compression by the epidural tumor or bone fragment will result in spinal cord
compression, leading to venous obstruction and development of vasogenic edema. At this stage,
administration of dexamethasone would be extremely beneficial in decreasing cord edema and
resolving many of the patient’s initial symptoms. Continued vasogenic edema, however, will lead to
an objective decrease in the somatosensory-evoked potential, and then to a conduction block across
the area of compression. This, in turn, will result in cord demyelination, decreased blood flow, and
ischemia.
FIGURE 2
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Spinal Cord Compression
Ischemia induces a different type of edema (cytotoxic) with resultant spinal cord infarction. Figure 2
illustrates the sequence of events that occur during spinal cord compromise. There is a window of
opportunity between the development of neurologic symptoms and complete loss of neurologic
function that may range from a period of days to weeks. During this period, treatment options such
as radiation, chemotherapy, and surgery may be used to reverse this process. It is the goal of this
article to help the treating physician recognize the initial clinical presentation, order the appropriate
diagnostic tests, and then propose a treatment plan for the patient with metastatic prostate
carcinoma to the spine.
Clinical Presentation
Metastasis to the spine initially results in pain that may subsequently progress to neurologic signs
and symptoms if there is spinal cord or nerve root compromise. The initial consultation should
consist of a well-taken history with evaluation of the patient’s symptoms, followed by a careful
neurologic examination. The history is an important aspect of the evaluation. The timing of the onset
of symptoms is crucial to an accurate determination of the acuity of the situation, and the patient
will often be able to specify the exact time and location of onset of symptoms.
Osborn et al reviewed four large series of prostate metastases to the spine and concluded that
patients had four main initial presentations: pain, weakness, autonomic dysfunction, and sensory
loss.[21] In most cases, pain is the initial presentation of spinal metastasis. A cancer patient with
new onset of neck or back pain should be considered to have spinal metastasis until it is specifically
ruled out. In prostate carcinoma patients, the lumbar spine is the most common site of initial
metastasis. As a result, patients with lower back pain, but with a known history of prostate
carcinoma, must be evaluated carefully for lumbar or sacral metastases.
Pain was the initial presentation in 75% to 100% of the patients reviewed by Osborn et al.[21] The
pain tends to be localized to the site of metastasis, and is usually secondary to periosteal stretching
as the vertebral mass enlarges. However, if the tumor causes instability, it is important to determine
whether the pain is mechanical in nature. It is extremely important when taking the history to ask
the patient if the pain changes with position. For example, patients who receive high doses of
narcotics to manage their pain will say that their pain is under control when they are lying in bed;
however, if they attempt to sit up or stand, the pain becomes so intense that they feel as if they may
"pass out." In those cases, a plain x-ray will often reveal extensive bony destruction and spinal
compromise.
Obtaining information on other exacerbating factors besides position—such as laughing, coughing,
sneezing, straining, or lifting—is important. It is also important to determine whether there are
remitting factors for the pain, such as lying down or bending forward.
In addition, the patient’s motor strength needs to be determined. A patient will often notice subtle
differences in strength that are not detectable on examination. For instance, a patient with a cervical
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metastasis and root involvement may notice some weakness while holding a cup, which may not
have been apparent on initial neurologic assessment of strength. There may be changes in posture,
gait, or balance that the physician did not notice when examining the patient in a seated or prone
position.
Questions about sensory changes (ie, numbness, temperature sensitivity) should accompany those
dealing with strength. Nerve root involvement may produce sensory changes in a dermatomal
fashion and should be correlated with changes in associated motor strength noted by the patient.
Finally, because prostate metastasis often involves the lumbar and sacral region, inquiries regarding
autonomic dysfunction such as bowel and bladder compromise are extremely important. The latter is
absolutely crucial because patients often do not associate changes in bowel/bladder function with
problems noted in strength or sensation.
Physical and Neurologic Aspects
The initial examination should be divided into a physical and a neurologic exam. Much of the
patient’s physical exam can be completed at the first meeting. The overall appearance of the patient
provides clues to his general health status. The patient who is able to walk into the room without
significant pain or weakness is probably not going to need a surgical procedure. A patient who is
cachectic and appears ill may not be able to undergo a major operation. The examination must
include an evaluation of posture, stance, and gait. This may be accomplished, in part, as the patient
enters the examination room. It is important to examine the length of the spine visually, note any
abnormal curvatures, and have the patient point to the location of his discomfort.
The neurologic examination consists of an evaluation of the patient’s general mental status, cranial
nerve evaluation, motor examination, sensory examination, reflexes, and cerebellar function. In
patients with nerve root compression, the neurologic exam may be specific for the dermatomal and
myotomal distribution of the particular root involved, allowing for localization of the lesion to a
particular vertebral segment. Patients with spinal cord compression may be more nonspecific, having
complaints of bilateral weakness, sensory loss, increased deep tendon reflexes, and evidence of
autonomic compromise such as bowel and bladder dysfunction.
Diagnostic Work-up
The diagnostic work-up of a patient with spinal cord compression should consist of plain films, a
computed tomography (CT) scan, and a magnetic resonance imaging (MRI) scan. All three imaging
modalities have diagnostic virtues. Plain films are important from the standpoint of viewing the
curvature of the spine and evidence of bony destruction. A patient with a thoracic metastasis may
have a significant kyphosis with a single bony level lesion that will be well appreciated on plain
x-rays. Moreover, flexion and extension plain films are extremely useful in determining whether
there is evidence of spinal instability in a patient with significant motion pain.
The CT scan is useful from a surgical standpoint because it provides good anatomic bony detail
crucial in planning the operation. This information is obtained more easily on CT scan than on MRI
scan (which is not as good in depicting bony anatomy). I use the CT scan not only to determine the
extent of bony destruction at the level of the primary lesion, but also to evaluate bone quality above
and below the lesion, in order to determine the feasibility of stabilizing the spine after a surgical
decompression.
For example, a patient with a T9 vertebral body lesion with normal T8 and T10 vertebral bodies
would be an excellent candidate for an anterior decompression with stabilization using an anterior
plate with screw purchase at T8 and T10. On the other hand, a patient with adjacent bony
involvement at T8, in addition to the T9 vertebral body lesion causing spinal cord compression, may
be more suitably stabilized posteriorly. The axial CT scan also provides good anatomic detail on the
size of the pedicles, which helps to determine whether pedicle screws may be placed.
FIGURE 3
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Sagittal MRI Scan
The MRI scan is the gold standard for the evaluation of the spine. It is always performed with or
without gadolinium to enhance any epidural tumor masses. Because of the ease with which a sagittal
whole-spine MRI may now be obtained, patients with metastatic spinal disease should have a scout
whole-spine sagittal MRI to evaluate for other spinal lesions. The MRI scan will give excellent
anatomic detail of the spinal cord, cauda equina, and any adjacent epidural masses (Figure 3). I now
rarely obtain CT myelograms unless the MRI scan is not available, or the patient has a pacemaker
and/or metal near the area of interest. A myelogram requires a lumbar puncture, is uncomfortable,
and can precipitate neurologic deterioration in the setting of a complete block. Carmody et al have
demonstrated that the MRI scan provides as much information as a myelogram.[22]
Other diagnostic studies that may be of value include bone scans to evaluate for bony disease
elsewhere in the body and whole-body positron emission tomography (PET), which may be useful for
localizing specific areas of metastasis and for cancer staging. Rodichok et al attempted to correlate
the incidence of spinal epidural metastases on diagnostic studies with patient signs and symptoms.
They found that 78% of patients with myelopathy and 61% with radiculopathy have evidence of
epidural metastases. In patients with known malignancy and back pain, a normal neurologic exam
does not exclude the possibility of spinal cord compression. In Rodichok’s study, 36% of such
patients were diagnosed with spinal epidural metastases.[23]
Treatment Options
Initial Assessment
The initial assessment for treatment of a patient with prostate carcinoma metastastic to the spine
consists of (1) an evaluation of systemic disease, (2) optimization of medical therapy including pain
management, steroids, and bracing, (3) an evaluation for nonsurgical treatment such as
chemotherapy and/or radiation therapy, and (4) consideration of surgical options.
Evaluation of Systemic Disease
The extent of systemic disease often determines the extent and aggressiveness of medical and
surgical therapy. Unfortunately, there are no correct answers as to how individual patients should be
managed. The extremes are usually easy to handle; however, the gray areas of clinical management
are dependent on not only the expertise of the treating physician, but also his philosophy. For
example, a neurosurgeon who sees a patient with prostate carcinoma metastatic to T8 with a bad
compression fracture may advocate surgical decompression and stabilization, followed by radiation.
A radiation oncologist, on the other hand, may favor initial radiation, followed by observation, and
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surgery only in the setting of progressive neurologic deficits.
Even with the data collected from the literature, our treatment regimen is going to be biased in
many ways by our experiences and expertise. There is no absolutely correct way of handling a
certain clinical situation. The discussion below is based on the author’s experience as a
neurosurgeon, neuro-oncologist, and fellowship-trained spine surgeon.
Optimization of Medical Treatment
Pain Identification and Management: Metastatic spinal disease is painful; unfortunately, the
etiology of bone pain is still unclear. One source of pain is the presence of metastatic prostatic
carcinoma cells in the bone, resulting in osteosclerotic or "blastic" changes to the invaded vertebral
body. Approximately 90% of prostate carcinoma metastases are blastic in nature; the remaining 10%
are lytic.[21] Lytic lesions will lead to bony destruction and will induce pain.
Epidural cord and nerve root compression also induce pain. In general, the quality of that pain is
different from bony involvement alone. Pain secondary to cord compression is constant and often
worse at night, forcing the patient to get up and "walk" off the pain. Nerve root compression will
induce a sharp lancinating pain that is similar to the pain from a herniated disc.
Lastly, some patients may experience such severe vertebral body compromise that they may have a
mechanically unstable spine. It is estimated that approximately 10% of all metastases to the spine
will result in an unstable spine from a pathologic fracture.[24] In those cases, the pain is so poorly
controlled that the patient cannot sit up or move without extreme difficulty. Such patients often will
not achieve adequate pain control without a stabilization procedure.
It is beyond the scope of this article to deal with the various treatment modalities for cancer pain,
which may range from oral narcotics and epidermal patches to morphine pumps. The point that
should be stressed, however, is that the treatable causes of pain need to be differentiated from the
untreatable ones. A blanket narcotic treatment of all patients with pain is obviously not the answer.
In many ways, the oncologist and internist must distinguish initially the causes of the pain syndrome
because the pain specialist is often an anesthesiologist without formal oncologic training.
High-Dose Steroid Treatment: High-dose steroids are usually initiated if there is clinical and
radiographic evidence of cord or root compression secondary to the prostate carcinoma. The goals of
steroid administration are to decrease the inflammation and swelling of the normal spinal cord
secondary to mechanical compression, leading to venous engorgement and swelling.
Ikeda et al demonstrated in a rabbit model that cord compression leads to obstruction of the epidural
venous plexus, followed by impairment of venous drainage in the compromised spinal cord.[25]
Ushio et al demonstrated in an experimental rat model that epidural tumor was associated
with edema. Intramuscular administration of dexamethasone (10 mg/kg twice a day) resulted in a
reduction of cord edema.[26].
The dose of steroids to be administered is not clear-cut. In patients whose neurologic condition has
been stable, I commonly administer intravenous dexamethasone at a dose ranging from 4 mg every
6 hours to 10 mg every 3 hours. In patients with rapid neurologic decline, I have used spinal cord
injury dosages of methylprednisolone (30 mg/kg IV bolus, followed by 5.4 mg/kg/h for 24 to 48
hours).[27] In all patients receiving steroids, ranitidine 50 mg IV every 8 hours, is administered
concomitantly.
Clinical studies by Greenberg et al demonstrate that patients given an initial intravenous bolus of
100 mg of dexamethasone followed by 96 mg for 3 days and then a rapid taper had no significant
difference in neurologic outcome, compared with those in another study who received a more
conventional dexamethasone regimen of 10 mg IV followed by 4 mg every 6 hours. Patients
receiving the initial high-dose bolus of dexamethasone, however, did have rapid and complete relief
of pain prior to undergoing radiation.[28]
External Bracing: The use of an external brace is often beneficial for patients with spinal
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metastasis. I have found an external brace to be helpful in reducing pain and improving ambulation,
even in patients who have not shown any evidence of spinal instability on flexion-extension films.
This decrease in pain may be secondary to the fact that many of these patients have microinstability
of their spine not detected on gross studies such as flexion-extension views. Unfortunately, there is
no way of documenting microinstability in these patients because one of the tests that I commonly
use to detect microinstability is the bone scan, and it will always be positive in metastatic prostate
cancer. Braces are now available that are more lightweight and less cumbersome than the old "turtle
shell" braces, allowing for enhanced patient comfort.
Use of Bisphosphonates: Bisphosphonates have been used increasingly in the treatment of
patients with bone metastasis. They have been shown to inhibit osteoclast activity, leading to a
decrease in the formation of lytic bony lesions. Moreover, they are effective in decreasing
hypercalcemia secondary to bony destruction. The use of bisphosphonates in prostate cancer is not
well defined. As a blastic lesion, it is unclear whether bisphosphonates, which inhibit osteoclasts, will
be of any benefit. This ambivalence has been demonstrated in two clinical studies. One study
demonstrated a clear-cut benefit to the use of bisphosphonates and the other did not.[29,30]
More recently, Cheng et al demonstrated in a rat prostate skeletal metastasis that bisphosphonates
suppressed and delayed the development of hind leg metastases in a spinal prostate carcinoma
model.[31] These results, however, may be secondary to the animal model because prostate
carcinoma cells are not only notoriously difficult to establish in in vivo models, but often induce lytic
lesions instead of blastic ones.[24]
Nonsurgical Treatment
Radiation: Radiation therapy is the mainstay of treatment of patients with a metastatic prostate
carcinoma to the spine. Prostate carcinomas are considered moderately radiosensitive tumors.
Radiation should be the first mode of treatment, except in a rapidly progressive neurologic deficit
secondary to bony compression from a collapsed vertebral body and severe mechanical pain
secondary to bony destruction. In both of these situations, radiation may be ineffective because it
will not shrink a collapsed bony fragment causing cord compromise, nor will it help a patient with
severe back pain secondary to vertebral body instability.
There has been almost a "reflex response" on the part of the medical community in referring
patients with metastatic spinal disease to radiation. This has mainly been secondary to several key
papers published in the early 1980s that demonstrated no significant difference in neurologic
outcome of patients treated with radiation alone vs surgery. In 1978, Gilbert et al reported a
retrospective study of 235 cases of spinal cord compression caused by metastatic tumors.[29] In
their series, 65 patients underwent decompressive laminectomy, and 170 were treated with
radiation alone. The most common reasons for surgery in these patients were prior radiation
therapy, uncertain diagnosis, and rapid progression of symptoms. There was no statistical difference
in the functional outcome of the two groups: In fact, of the 22 patients with rapidly progressive
neurologic signs, none who underwent surgery improved, whereas 54% of the patients who received
radiation achieved an improvement in outcome.
Zelefsky et al reported similar findings in their analysis of 42 patients with spinal epidural tumor
from prostate carcinoma who had been treated with external-beam radiation.[6] At the completion of
treatment, they found that 92% of treated patients experienced pain relief, and 67% had a
significant or complete improvement on neurologic examination. Follow-up myelography (30 days
after radiation) showed that 58% of the myelograms had normalized completely, 25% had improved,
and results were unchanged in 18%. The authors also noted that the presence of a high-grade
compression fracture of the vertebral body was an indicator of poor prognosis for tumor response on
repeat myelography.[6]
Smith et al analyzed 35 patients with prostate carcinoma and spinal cord compression.[32] All
patients received high-dose steroids (100-mg intravenous bolus dexamethasone for 3 days, followed
by a 7-day taper). Radiation therapy ports were initially placed for one vertebral body above and
below the lesion, and then increased to two vertebral bodies superior and inferior to the lesion.
Patients who had not completed prior androgen deprivation underwent an orchiectomy. The authors
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concluded that in ambulatory or paraparetic patients, radiation, androgen deprivation, and steroids
are effective therapy. However, radiation and steroids alone were ineffective in patients who
presented with paraplegia or in whom paraplegia developed secondary to recurrent compression.
They recommended that surgery be performed in patients who experience a recurrence at a
previously irradiated site, who have canal stenosis secondary to osteoblastic metastases, and who
do not respond to radiation or who suffer paraplegia.[32]
Hormonal Manipulation: Androgen deprivation is the most effective therapy for metastatic
prostate cancer and has an important role in the management of spinal cord compression.
Unfortunately, the majority of patients with spinal cord compression have already completed
hormonal manipulation and have developed spinal metastasis nevertheless. These patients are, by
definition, hormonally resistant. If the patient has not undergone androgen deprivation, the most
effective and proven method of achieving it is either via bilateral orchiectomies or chemical
deprivation.
Iacovou et al compared the survival of 37 men with prostate cancer and spinal cord compression
treated by laminectomy.[33] Fifteen men also received initial hormonal manipulation at the time of
diagnosis of spinal cord compression. Of the men who received hormonal manipulation, 80% were
ambulatory following therapy; however, among patients who had already received hormonal
manipulation, only 42% became ambulatory.
Chemical androgen deprivation has also been used with some success. Diamond et al used a
combination of a long-acting gonadotropin-releasing hormonal agent and an androgen antagonist.
They were able to reduce the free testosterone concentration to < 2.2 pmol/L (normal range: 38 to
114 pmol/L) and prostate-specific antigen (PSA) levels to 6.9 ± 4.4 ng/mL from a mean of 130.8 ± 46
ng/mL.[34]
Chemotherapy: In patients with bone metastasis resistant to hormonal manipulation, Trivedi et al
showed that weekly 1-hour infusions of paclitaxel (Taxol) produced a decline in PSA of > 50%. The
major high-grade toxicity was peripheral neuropathy.[35] Other forms of chemotherapy for
hormonally resistant prostate carcinoma are available. Although it is beyond the scope of this article
to cover all the chemotherapy regimens currently available for patients for prostate carcinoma, a
recent review article by Oh summarizes recent developments.[36]
Surgery
Surgical Evaluation: Surgery is often the treatment of last resort for patients with spinal cord
compression secondary to prostate carcinoma. These patients usually have received previous
irradiation, hormonal deprivation, and chemotherapy. In spite of these treatments, they present with
multiple metastatic spinal lesions that are progressing. Most of these patients have led functional
lives until they developed a new onset of weakness or incapacitating back pain. The decision for
surgery is often easier from a technical standpoint than from an ethical one. From a surgical
standpoint, it is relatively straightforward to pinpoint the area of spinal cord compression,
decompress it, and stabilize it.
Difficulties arise, however, when that same patient presents with another lesion after his first
surgery and again has neurologic compromise. Because most of these metastatic prostate
carcinomas are unresponsive to other adjunctive therapies, there is a high probability of progression
to new lesions and new areas of cord compression. At that point, it becomes an individual decision
between the patient and the neurosurgeon as to what course of treatment should be followed.
However, the point of diminishing returns will soon be reached, and it is the responsibility of the
surgeon to inform the patient of that distinct possibility before further surgical intervention is
attempted.
Surgical Management: Although studies such as the one conducted by Greenberg et al
demonstrated no statistical difference in outcome between patients who underwent surgery and
those who received radiation alone, there have been considerable advances in our understanding of
spinal biomechanics, development of spinal instrumentation, and training for surgery of the spine
since the late 1970s.[28] It is not the goal of this article to discuss all possible surgical approaches to
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spinal cord compression, but a few major concepts are highlighted below:
FIGURE 4
Surgical Treatment Plan
1. The decompression needs to be performed at the point where the tumor is compressing the spinal
cord. Posterior decompressions for anterior vertebral body lesions will not be effective long-term.
The patient will either have continued growth of the anterior portion of their tumor with subsequent
tumor compression, or may develop spinal instability. If the compression is anterior, an anterior
decompression must be performed; if it is posterior, the decompression must be performed
posteriorly.
Understanding of the anatomy and biomechanics of the spine has improved to the point that either
an anterior or posterior approach to decompress and stabilize the spine is possible (Figures 4A- 4D).
There are several areas, however, that are more problematic than others, including the anterior high
cervical lesions (ie, Cl, C2), anterior high thoracic lesions (T2, T3), and anterior lumbosacral lesions
(L5, S1). The high anterior cervical lesions are difficult to approach because of the mandible and the
problems associated with performing anterior stabilization. These lesions may be accessed using a
transoral approach, with posterior occipital-cervical stabilization afterwards.
FIGURE 5
Posterolateral Decompression
The anterior high thoracic lesions present the same problem. A sternoclavicular or sternal approach
may be taken to decompress the spine, but because of the arch of the aorta and its branches, it is
impossible to place an adequate anterior plate for stabilization. I have used the lateral extracavitary
approach for these lesions, with a posterolateral decompression of the anterior vertebral body and
posterior stabilization (Figure 5).[37]
Finally, the lumbosacral lesions may be approached anteriorly via a transperitoneal or
retroperitoneal exposure. However, it is very difficult to place an anterior plate at L5 or S1. The
lateral extracavitary approach is also troublesome in this area secondary to the iliac crest. These
patients require an anterior decompression, graft, and posterior instrumentation.
2. The part of the spine that is uninvolved with tumor should be left alone. Rarely must part of the
patient’s normal spine be removed in order to reach the tumor. However, that is what is often done
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in laminectomies to decompress metastatic tumors. Most patients have metastatic tumors involving
the vertebral body and one or two of the pedicles; their lamina and spinous processes are often not
involved by cancer. To "decompress" them, the surgeon may remove their only remaining normal
spinal structures, temporarily decompress them with a laminectomy, and close the incision. Needless
to say, the patients initially respond well but subsequently develop numerous complications from
their surgery, including pain, instability at the surgical site, and further tumor growth.
3. The chosen approach should be dictated partially by how the reconstruction is to be performed
after the decompression. Prostate cancer often involves several contiguous vertebral bodies with one
vertebral body causing cord compression and neurologic compromise. The patient, his oncologist,
and spine surgeon must decide whether this lesion should be treated surgically, because the
possibility exists that adjacent levels will become further infiltrated with cancer and eventually cause
neurologic compromise.
However, if the decision to perform surgery is made, the lesion should be decompressed anteriorly
and stabilized posteriorly. This may be achieved via a "front-back" approach, in which the patient is
operated on from the front and his cancer decompressed. Because the contiguous bony levels are
involved with cancer, an anterior stabilization with screws through the adjacent levels would not
insure a solid fusion. These patients should then be stabilized posteriorly using a multisegmental
posterior fusion. As described previously, the lateral extracavitary approach may be used in these
situations to perform a posterolateral decompression of the anterior tumor, and posterior
stabilization.
4. Maintenance of fluid resuscitation and avoidance of intraoperative hypotension are crucial. The
most important method of optimizing surgical outcome is to maintain good blood perfusion to the
spinal cord. Surgeries for metastatic tumors in patients with many medical problems are often
bloody affairs. The Cell Saver cannot be used in these patients to recycle blood because they have
cancer. Therefore, careful recording of fluids and judicious replacement of blood and blood products
are essential.
If the spinal cord is not adequately perfused with blood, the chances of having an intraoperative
ischemic event is greatly increased in an area of the region that is already compromised in blood
flow secondary to the existing compressive mass. Moreover, the surgery may be performed in an
area that is considered a "watershed" of spinal perfusion, where the spinal cord is more vulnerable to
ischemic injury.
5. Neuromonitoring and chemical neuroprotection should be employed in order to make the surgery
as safe as possible. I always use somatosensory-evoked potentials (SSEP) during the surgery, and
monitoring is continued until the closure is being performed. Although the SSEP, which provides
monitoring of the dorsal spinal cord columns (fasciculus gracilis and fasciculus cuneatus), is often an
indirect measurement of anterior cord compromise, it is probably the easiest and safest
intraoperative monitoring system. If the SSEP remains unchanged, or improves during the case, the
outcome is usually very good. However, if the SSEP decreases, then neurologic deficits (although
often transient) may occur.
In addition, I use spinal cord injury doses of methylprednisolone during surgery.[27] The use of
methylprednisolone is a highly individualized decision, and there are no data suggesting that its use
is necessary during surgery for metastatic cancer. Nevertheless, the agent is easy to administer and
titrate, without postoperative complications. The patient is given an intravenous bolus of
methylprednisolone at 30 mg/kg initially, followed by 5.4 mg/kg for the duration of the case. I
continue use of methylprednisolone for a total of 24 hours after the surgery has been completed.
6. Infection should be prevented, since metastatic cancer patients are prone to developing a severe
infection. In many cases, these patients are debilitated by their disease, their nutritional status may
be suboptimal, their skin is often tenuous secondary to previous radiation, and their spinal surgery
may have been long (with increased chance of getting an infection). If an infection occurs, the
consequences can be devastating. The patient often has hardware that may need to be removed,
making him unstable. Therefore, I maximize the perioperative antibiotic coverage and continue it for
up to 2 days after surgery. The wound is always copiously irrigated with an antibiotic-impregnated
Page 11 of 18
saline wash, and care is taken to close it in multiple layers to prevent a skin infection. If a dural tear
occurs during surgery, it should be repaired primarily to prevent the side effects of a cerebrospinal
fluid leak.
7. The surgeon should operate under the premise of long-term survival. Patients with metastatic
spine disease were often thought of in survival terms of no more than 6 to 9 months. However, with
the development of more effective chemotherapy and radiation therapy, many of these patients are
surviving much longer. As a result, I often use a bone allograft for spine fusions because it gives
patients an opportunity to develop a bony fusion for long-term stability. I have not found the bony
fusion rate to decrease in the face of cancer. Although methylmethacrylate has often been used for
short-term stabilization, I have found bone allograft to be just as stable, while allowing the patient
the possibility of forming a bony union in the future.[38]
Published Results for Metastatic Spinal Surgery: Unfortunately, there are no large studies of
metastatic prostate carcinoma to the spine. Therefore, the results reported in this section will be
confined to metastatic spinal cancer. In general, surgical results for metastatic spinal cancer should
not be evaluated from previous laminectomy outcome data. Siegal et al compared the results of
laminectomies with surgeries performed using anterior or posterior decompressions with
stabilization.[38] They analyzed 12 series comprising a total of 806 patients who had been treated
with radiotherapy alone between 1966 and 1990. Of these patients, 41% improved and 22%
worsened after radiation. Among 1,933 patients in 20 series who underwent laminectomy followed
by radiation therapy, 44% improved after surgery and radiation, 13% became worse, and 7% died
during the procedure. These results are consistent with Greenberg’s interpretation that laminectomy
with radiation did not improve outcome.
However, if an analysis is made of more current series looking at patients who received both
decompressions (presumably at the site of compression) and stabilization, the outcome is much
better. Among 443 patients (9 series) who received a posterior decompression and stabilization,
Siegal et al reported that 66% improved. There was an objective improvement in pain control in
83%, with a 9% morbidity and a 6% operative mortality rate.[38]
Finally, among 318 patients (7 series) who received a vertebral body resection (anterior approach)
and stabilization, 73% reported improvement and 84% had improved pain control, with a morbidity
rate of 18% and an operative mortality rate of 6%.[37]
Adjunctive Therapy After Surgery: In newly diagnosed patients who underwent surgery first,
radiation therapy should be administered after surgery. In many of these patients, instrumentation
and bone will be placed for a fusion. Unfortunately, there are no good clinical data to document the
appropriate waiting period before radiation can begin. Radiation may not only retard skin healing in
these patients, but will also retard bony fusion.
The best data to address this issue were in an article published by Bouchard et al.[39] They took 27
New Zealand white rabbits and divided them into four groups. All animals underwent a posterior
lumbar spine fusion with autogenous iliac crest bone graft. Group 1 (n = 7, control) did not receive
irradiation; group 2 (n = 6) received preoperative irradiation; group 3 (n = 7) received immediate
postoperative irradiation; group 4 (n = 7) received delayed postoperative irradiation (3 weeks).
Irradiation consisted of 480 cGy/fraction for 5 consecutive days. All rabbits were sacrificed 3 months
posttreatment.
Compared with the control group, the rabbits receiving immediate postoperative irradiation had the
worst response, with consistent fibrous union of the bone graft. The preirradiated rabbits had spines
that were less stiff in extension and compression compared to the control rabbits. The rabbits who
received delayed postoperative irradiation had the best results with the highest histologic scores for
fusion.[39] Therefore, I advocate that patients who have undergone fusion should wait 3 weeks after
surgery before beginning radiation therapy. A similar time frame is suggested for patients who will
be receiving chemotherapy.
Algorithms for Management of Metastatic Prostate Carcinoma to the Spine
Page 12 of 18
FIGURE 6
Treatment Algorithm for Newly Diagnosed Spinal Metastases
FIGURE 7
Treatment Algorithm for Previously Irradiated Patients
I present these algorithms (Figure 6 and Figure 7) for the management of metastatic prostate
carcinoma to the spine with some reservation, because an algorithm implies that there is one correct
way to handle a particular situation. Unfortunately, in this field (and probably for oncology in
general), there is no one correct way of doing things. Every practitioner has developed an algorithm
with which he or she is comfortable. At the University of Southern California/Norris Cancer Center,
we have a close working relationship with our oncology, neurosurgery, and radiation oncology
departments. Therefore, our treatment plan is a multidisciplinary one.
The two algorithms that I present are based on my experience as a neurosurgeon trained in spinal
procedures and an oncologist who treats patients with metastatic spinal disease. I have divided the
treatment algorithm into newly diagnosed spinal metastases from prostate carcinoma and previously
treated spinal metastases from prostate carcinoma.
Newly Diagnosed Spinal Metastases
In patients with a known history of prostate carcinoma, persistent back pain needs to be taken
seriously. All such patients should have an MRI of their whole spine, with and without gadolinium, to
rule out spinal metastasis. In patients who do not show any evidence of cord or root compression
and who have stable spines, radiation should be the first mode of treatment. However, patients who
do not have neurologic compromise but have such debilitating pain that they require continuous
narcotic therapy should be evaluated by a spine specialist to ensure that their spine is stable. A
stabilization procedure can often improve quality of life in these patients.
Patients with evidence of cord/root compression on MRI but no neurologic deficits should be treated
in the same way as patients with no cord/root compression on MRI. Patients who have cord/root
compression with corresponding neurologic deficits or compression secondary to an epidural tumor
should have radiation first. If their neurologic condition continues to deteriorate, they should
consider surgical decompression and stabilization. Patients who have compression secondary to
bone will not respond to radiation. These patients should have surgery as their primary treatment
Page 13 of 18
modality (Figure 6).
Previously Treated Spinal Metastases
In patients who have had previous radiation to their spine and now present with new onset back
pain/neurologic deficit, a new MRI scan of the whole spine, with and without gadolinium, should be
obtained. The area of compression should be identified and correlated to the neurologic exam. If the
region of interest is in a previously irradiated portion of the spine, these patients cannot tolerate
more radiation. In such cases, if they have cord/root compression with involvement of more than one
vertebral level, it is important to decide where the decompression should be performed. Most often,
one vertebral body will be more involved than others. The typical history is a patient with metastasis
to one vertebral body causing cord compression, and MRI evidence of metastases to the levels
above and below the lesion.
In these patients, anterior decompression should be performed first, followed by a bone graft. The
patients should then be stabilized posteriorly because their adjacent bone may not be strong enough
to tolerate an anterior stabilization. In patients who predominantly have posterior compression, a
posterior decompression with posterior stabilization should be performed. Patients with only one
level of involvement and with anterior compression should be treated with anterior decompression
and stabilization. Those with posterior compression may be treated with posterior decompression
and stabilization as before. Patients who have been irradiated but have new lesions outside the
irradiated field may be treated for the newly diagnosed lesions, with radiation offered as first-line
therapy.
If the lesion itself has not been irradiated but is within the field of a previous radiation port, the
patient should be regarded as being previously irradiated (Figure 7). In all cases, the best hope the
patient has for not developing another problem down the line will be based on his response to
further adjunctive therapy such as chemotherapy. Operating on a patient who is becoming
paraparetic from a metastatic prostate carcinoma is only beneficial if effective adjunctive therapy
can be administered as follow-up, to prevent a new compressive lesion from developing later.
Otherwise, the surgeon ends up mending a very poor fence that is always in danger of collapsing.
Herein lies the challenge for both the surgeon and the oncologist: to devise a feasible treatment plan
that can be administered in concert to prevent further neurologic compromise and maintain quality
of life for the prostate carcinoma patient.
Potential Future Therapies
Potential future therapies in general should be aimed toward the biology of prostate carcinoma and
home in on reducing the number of metastases of the tumor to the bone. There are two
developments that may soon come into clinical use. These therapies, described below, are still in
preclinical stages.
Inhibition of Bony Destruction
Honore et al published a report looking at the activity of a tumor necrosis factor receptor family
molecule called osteoprotegerin ligand, secreted by osteoblasts and activated T cells. It is thought
that the osteoprotegerin ligand receptor RANK is expressed on osteoclast precursors and mature
osteoclasts. Osteoprotegerin ligand binding to RANK results in osteoclast activation with further bone
destruction. The importance of osteoprotegerin is that it acts as a decoy ligand and binds to
osteoprotegerin ligand, inhibiting its binding to RANK, preventing further osteoclast activation, and
thereby decreasing bony destruction. However, because prostate carcinoma cells involve
osteoblasts, how that will relate to osteoprotegerin remains to be determined.[40]
Radiosurgery for the Spine
The concept of radiosurgery for the spine is being pursued at several institutions. Unlike the head,
which can be immobilized by a stereotactic frame, the spine is difficult to immobilize. Patient
Page 14 of 18
breathing leads to movement of the entire spinal axis, interfering with any attempts to use highly
focused radiation. Spine radiosurgery has been pursued by different groups, including Hamilton et al,
who focused on immobilization and radiation of the spine.[40]
FIGURE 8
Reference Marker for Stereotactic Radiosurgery
Although our work is still in preclinical stages, we have been developing a spinal radiosurgery plan
that would take advantage of an internal implantable marker system, enabling the radiation
oncology team to monitor more closely the administration of radiation using a linear accelerator
(Figure 8). If radiosurgery of the spine becomes accurate enough, we should eventually be able to be
administer high-dose radiation to patients with asymptomatic spinal metastasis, thus decreasing the
treatment period to a day instead of several weeks, with treatment localized to the lesion itself only.
Conclusions
The treatment of metastatic prostate carcinoma to the spine is complex. In many situations, there is
no correct answer as to what the best management situation should be. Instead, an individual
approach based not only on an understanding of the various treatment options currently available,
but also on the patient’s unique situation and presentation, is the best approach to the problem. This
article has emphasized a global treatment plan for patients with metastatic prostate carcinoma to
the spine. I have stressed not only the best medical treatment with steroids, bracing, and pain
management, but also the virtues of nonsurgical treatment using chemotherapy and radiation
therapy. In addition, the relative virtues of surgical decompression and stabilization for certain
patients are presented.
Our treatment method is still imperfect. However, emphasis should be placed on the patient and
what modern medicine can offer him for the treatment of metastatic prostate carcinoma to the
spine.
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Source URL:
http://www.cancernetwork.com/oncology-journal/prostate-cancer-and-spinal-cord-compression
Links:
[1] http://www.cancernetwork.com/review-article
[2] http://www.cancernetwork.com/oncology-journal
[3] http://www.cancernetwork.com/genitourinary-cancers
[4] http://www.cancernetwork.com/prostate-cancer
[5] http://www.cancernetwork.com/authors/thomas-c-chen-md-phd
Page 18 of 18

Prostate Cancer and Spinal Cord Compression

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