Orthopedic Clinics of
North America
Volume 31 • Number 1 • October 2000
Copyright © 2000 W. B. Saunders Company
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ORTHOPEDIC MANAGEMENT OF METASTATIC DISEASE
MEDICAL MANAGEMENT OF METASTATIC SKELETAL DISEASE
Paul D. Savage 1 MD
William G. Ward 2 MD
1
Departments of Internal Medicine (PDS)
2
Orthopaedic Surgery (WGW), Wake Forest University Baptist Medical Center,
Winston-Salem, North Carolina
Address reprint requests to
Paul D. Savage, MD
Department of Internal Medicine
Wake Forest University Baptist Medical Center
Medical Center Boulevard
Winston-Salem, NC 27157-1082
All patients with metastatic disease involving the skeleton require thoughtful medical
management, regardless of whether or not they undergo surgical intervention.
Patients are managed optimally by a team approach; this team generally includes
an orthopedic surgeon or orthopedic oncologist, a radiation oncologist, and a
medical oncologist, although input from radiologists and pathologists
experienced in evaluating these lesions is critical. Most patients also have a
general internist or family physician, who may oversee and coordinate the
overall medical care, unless that has been delegated to the oncologists. The
medical management of patients undergoing operative intervention for metastatic disease can be quite complex. There are many factors to
consider, such as the metabolic alterations, complications, and conditions that
commonly are associated with metastatic disease. More commonly encountered factors include hypercalcemia, pulmonary or hepatic insufficiency, hypercoagulability,
depression, irritability, pain, and motivational issues. The patient that does
not require specific medical management is the exception rather than the rule.
This article outlines and discusses the three main goals in the care of the
patient with metastatic disease of the skeleton: (1) pain
relief, (2) functional preservation, and (3) quality life extension.
GOALS
The team must define clearly the goals for each individual
patient. The two main goals for the orthopedic surgeon in patients with metastatic cancers are pain relief and functional
preservation or restoration. In patients with far advanced disease, palliative
pain relief may be the primary goal, whereas in most patients, restoration or
preservation of function is the primary goal. In most patients with bony metastatic disease, cure from orthopedic
intervention is rarely the goal; there are exceptions to this generalization,
such as patients with isolated bone metastases from renal cell or thyroid
carcinomas, in whom cures with at
least 5- to 10-year disease-free survivals can be achieved by appropriate
resection of the lesions. For most patients with metastatic disease, however, the orthopedic
intervention is aimed primarily at providing pain relief and functional
restoration relating to impending or actual pathologic fractures.
Medical management often has the more difficult goal of prolonging
life, while minimizing morbidity. The medical oncologist must individualize
care to provide an extension of quality life. Palliative care alone is
appropriate in some patients, whereas a trial of cytotoxic chemotherapy is
appropriate in most. As in the case of the orthopedic surgeon, attempting to
predict which pathologic lesions will result in pathologic fractures, the
medical oncologist must decide which patients would likely benefit in terms of
quality life extension as well as palliation from chemotherapeutic intervention.
Many factors should be considered when deciding for whom chemotherapy is
appropriate; the most important factors are tumor histology, comorbid diseases,
and the toxicity profiles of the chemotherapy agents thought to be appropriate
for the particular tumor. Other factors that may be important to some patients
include but are not limited to the rate at which the tumor responds, the
likelihood of achieving enough of a response to help the particular patient,
the patient's mental status and understanding of the situation, religious
factors, and the feasibility of administering the intended chemotherapy regimen
effectively (and the handling of its side effects and toxicities); the last
factor is important so as not to infringe on the patient's quality of life and
the Hippocratic Oath itself--it would be considered inappropriate (and doing harm) to offer a regimen with the
likelihood of encountering a life-threatening toxicity under circumstances in
which appropriate treatment cannot be administered effectively is high. Nonetheless,
after careful consideration of all these factors, most patients are potential
candidates for a trial of palliative chemotherapy. An honest trial of
chemotherapy is not usually one
cycle but rather two to four cycles (which usually require about 2 to 3 months)
until an assessment of efficacy can be determined.
OVERVIEW OF MEDICAL MANAGEMENT
Medical management generally includes chemotherapy, hormonal
therapy, pain management, and metabolic or pharmacologic manipulations with medications,
such as bisphosphonates. This care usually is best coordinated by the medical
oncologist. The management of osseous metastases usually is performed by
medical and radiation oncologists, with involvement by the orthopedic surgeon
usually reserved for cases with actual or impending pathologic fractures. The
medical care of patients can be divided into several broad categories,
including preventive care, therapeutic care of medical complications, therapy
of the underlying cancer, and palliation.
NONORTHOPEDIC COMPLICATIONS IN THE PATIENT WITH METASTATIC CANCER
As a result of having advanced cancer, because of the cancer
itself or because of becoming increasingly debilitated, resulting in
deteriorating health, patients with cancer are at increased risk of many
medical complications, such as deep venous thrombosis (DVT) with or without
pulmonary emboli, hypercalcemia, and third spacing of excess fluids. The management of
these complications often requires coordination with other disciplines involved
in the care of cancer patients and can require modification of the intended
antineoplastic therapy.
Venous Thromboembolism
Most physicians believe that cancer patients are at increased risk
of developing DVT and pulmonary emboli; this is not an absolute truth, and its
belief can harm some patients by being presumed and taken into account in a
decision-making process. The tumor histology associated most frequently with a
true, hypercoagulable state is mucinous adenocarcinoma, which is typically
found arising from the genitourinary and lower gastrointestinal tracts. Other
histologies notorious for hypercoagulability are primary central nervous system
tumors (particularly during a perioperative period, when the incidence of DVT
can be 20%). Regardless of histologic subtype of tumor, compression (not
effacement but actual compressive deformity) of large vessels, such as the
superior vena cava, inferior vena cava, iliac veins, and femoral veins, can
cause formation of a DVT in that vessel; similarly, inactivity from any cause
(e.g., cachexia, dehydration and poor oral intake, postoperative state) is
associated with a higher incidence of DVT when compared with cancer patients
with normal activity levels. Because most coagulopathic events involve venous
thrombi, antiplatelet agents, such as aspirin, are ineffective at prophylaxis.
Subcutaneous heparin (5000 units subcutaneously twice a day) generally has been
used for prophylaxis; however, no good clinical trials examining cancer patients in general exist; most
trials examine a specific clinical setting (such as after total hip
replacement, laparotomy after gynecologic oncologic surgery), with general
indications being extrapolated from these. The newer, low-molecular-weight
heparin derivative, enoxaparin, also has been shown to prevent DVT in cancer
patients undergoing abdominal and orthopedic surgery. Many physicians prefer
enoxaparin over heparin because of the lower incidence of thrombocytopenia and
the lack of necessity to titrate the dose for each patient when true
anticoagulation is required. Enoxaparin is considerably more expensive than
heparin; given the truly low incidence of complications associated with
heparin, heparin remains the treatment of choice for DVT prophylaxis.
Hypercalcemia
Hypercalcemia is a complication seen commonly in
cancer patients, but similar to hypercoagulability, it is not seen uniformly among all cancer patients. Most
hypercalcemic patients are debilitated or have tumor subtypes for which hypercalcemia is known to occur; the latter group of
patients include those with multiple myeloma and metastatic cancers of the breast, lung, and kidney.
There is no direct correlation between the amount
of metastatic bone disease and the incidence or
severity of hypercalcemia--patients with little or no bone metastases with
stage IV lung or breast cancer can become hypercalcemic. There is a loose
correlation between the stage of disease and hypercalcemia, however, in that virtually no patient
with localized breast cancer, for instance, becomes hypercalcemic. Acutely,
hydration and furosemide (Lasix) diuresis lower serum calcium 1 to 3 mg/dL, but
definitive management involves administration of a bisphosphonate (discussed
later) or the gallium conjugate Ganite.
Pleural Effusion
Third spacing with the development of symptomatic effusions can be
problematic in patients with advanced cancer, particularly with tumors known to
metastasize to serosal surfaces (such as breast, gastrointestinal, and lung
cancers). Pleural effusions can be particularly problematic because many
patients with the above-mentioned cancers are older and have some component of
chronic obstructive pulmonary disease or respiratory compromise as an
underlying condition. As in cases of asymptomatic bone lesions (discussed
later), small, asymptomatic pleural effusions can be followed during an initial
trial of chemotherapy for patients with tumor types for which there is a high
likelihood of response because a response to chemotherapy can result in
resolution of the effusion. For patients who are symptomatic, a therapeutic
thoracentesis is indicated, to improve lung ventilation and to increase
oxygenation of the blood. Patients with recurrent effusions that require
repeated thoracenteses should be considered for additional intervention. Although
pleural decortication is highly effective at preventing reaccumulation, this
surgical approach is undesirable in most patients because it requires an
extensive thoracic surgical procedure and considerable postoperative time in
the hospital. Because these patients always have advanced neoplasms (they have
stage IV disease), are frequently losing weight, have a neoplasm for which
chemotherapy is often ineffective, and are often in the terminal phases of
their disease, a surgical procedure with high morbidity often is not indicated,
particularly if there are other, less morbid options. Nonetheless, surgical
approaches are often overlooked or are never considered, and this is an
injustice, too.
Today, the most common approach to recurrent pleural effusions is
placement of a sclerosing agent (such as doxycycline or bleomycin) directly
into the pleural space after complete drainage of the effusion and failure of
its reaccumulation at a rate exceeding 100 mL/24 hours. Pleurodesis often, but
not always, requires hospitalization and placement of a large-bore chest tube
for a number of days, but the procedure is less morbid, and hospitalization
times are usually less than those required for surgical decortication. The
major drawbacks of pleurodesis are the frequent development of pleuritic chest
pain and a thickened, noncompliant pleura with the sequelae of a restrictive
pneumopathy; the pleuritic pain usually is treatable with small doses of
analgesics, and the restrictive pneumopathy is a late event and often does not occur until after most
patients have expired from their advanced malignancy.
Perioperative Care
Perioperative care usually should be coordinated with or handled
by the medical oncologist, to maintain continuity in the care of the multiple
potential problems. Additional perioperative considerations are required in
patients who are currently receiving chemotherapy. Severe neutropenia (total
white blood cell count <2500 cells/mm3 or absolute neutrophil count <1000
cells/mm3 ) usually is considered a temporary contraindication to
surgery by the authors. Such patients may benefit from filgrastim (Neupogen)
administration, to facilitate their readiness for surgery. Likewise,
thrombocytopenic patients may require platelet transfusions. The likelihood and
severity of such potential of chemotherapy-associated side effects as these
must be considered in the decision making regarding surgical intervention and
its timing. The reader is referred to the article on perioperative
considerations by Bibbo for further discussion.
PAIN RELIEF
There are generally two types or sources of pain from which
patients with metastatic bone disease suffer. One is the cancer pain, which generally is related to nociceptive
stimuli, such as tissue stretching, internal tumor hemorrhage and necrosis,
compression of local structures, and local irritation. The second type of pain
is functional or mechanical pain resulting from impending or actual pathologic
fractures. This mechanical pain usually responds favorably to bony reconstruction
or stabilization and is discussed elsewhere in this article and in other
articles in this issue. True cancer pain usually responds favorably to any
medical intervention that decreases the tumor burden or tumor growth. Such
interventions include chemotherapy, radiation, and other adjuvants. These treatments are discussed later.
Pain medications can be regarded as belonging to three broad
categories--anti-inflammatory agents, narcotics, and adjuvants. In determining
a treatment program for a given patient, knowledge
of the mechanism of pain, the anticipated duration of pain, other medications,
and the end-organ status of the vital organs involved in the metabolism of most
of these agents (particularly the kidneys and liver) is essential.
Nonsteroidal Anti-Inflammatory
Drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are excellent drugs
for treating the underlying causes of much of the pain experienced by cancer
patients, particularly when the pain is caused by direct neural pressure from a
tumor mass. Although this situation often is regarded as an anatomic problem
for which anything short of correcting the anatomy is ineffective, at a
microscopic level many tumors are surrounded or infiltrated by edema, as a
result of increased vascular permeability or an immune response against either
the (viable) tumor or intratumoral necrotic material. In this setting,
reduction of inflammation can result in decreased pain. Some of the major
advantages of NSAIDs are their nonaddictive nature and overall favorable toxicity
profile.
Care must be taken in blindly
prescribing NSAIDs to cancer patients, for many reasons. Although not usually
recognized as a serious complication, NSAIDs, such as aspirin, can impair
platelet function and result in a bleeding disorder; in contrast to aspirin,
the platelet dysfunction is reversible and resolves once the NSAID is stopped
and is cleared from the circulation. This platelet dysfunction usually is not
problematic, but some patients get gastritis from the NSAID itself or from
chemotherapy; if this occurs at a time when patients are thrombocytopenic
(e.g., from chemotherapy or radiation), a potentially lethal upper
gastrointestinal hemorrhage can ensue. Renal function also can be compromised
by NSAIDs; this usually is reversible on stopping the agent, but renal function
can become compromised easily in cancer patients. This renal dysfunction can
occur as a result of prior treatments (chemotherapy, antibiotics, radiation),
intermittent volume depletion (such as in a patient who encounters severe
mucositis and becomes volume depleted because of decreased oral intake), or the
cancer itself (direct renal parenchymal involvement, obstruction, or a renal
tumor for which the patient has undergone surgical resection or radiation).
Certain chemotherapeutic drugs--particularly methotrexate--depend on renal
clearance for elimination. NSAIDs are contraindicated in patients receiving
moderate or high-dose methotrexate because persistently elevated methotrexate
levels and lethal toxicity can ensue easily despite leucovorin rescue and
urinary alkalinization.
Narcotics
Narcotic agents are used widely in oncology patients with skeletal
metastases because skeletal pain from metastases is not only some of the most
severe pain a human can experience, but also it can greatly decrease a
patient's ability to function and ambulate. As a result of many factors,
including a hypercoagulable state, the cancer patient who is bed bound or
severely limited in mobility is at great risk for severe life-threatening
complications; soft tissue breakdown with an increased risk of infection and
sepsis, DVT with or without pulmonary embolus, and atelectasis with an
increased risk of pneumonia are a few of the many complications that result
from decreased activity. Narcotics are greatly underprescribed for many
reasons, [5] [6] including patient apprehension, fear of
addiction, [4] [8] [14] and side effects; consequently, patients
who are receiving narcotics are frequently on inadequate, low doses of
(short-acting) narcotics and suffering unnecessary pain and morbidity. Numerous
studies in cancer patients have concluded that patients who are experiencing true
cancer pain do not become addicted to narcotics, regardless of the daily dose
and duration of treatment. Because the incidence and severity of side effects from
narcotics are dose related, the goal
of patient and physician is to determine the lowest dose of narcotic that
provides palliative relief. A fact that is often overlooked in the planning,
administering, and compliance with a narcotic regimen is the recognized data
that indicate that the total amount of narcotics taken over a 24-hour period in
patients with chronic pain is much less when a therapeutic dose of a
long-acting narcotic is used with as-needed doses of short-acting narcotics for
breakthrough pain when compared
with regimens using as-needed or routine doses of short-acting narcotics only.
Optimal management of chronic pain, even if it is anticipated that
the chronic pain will be present only for a few weeks, involves the use of
therapeutic doses of a long-acting analgesic (e.g., fentanyl [Duragesic] patch,
morphine [MS Contin], or oxycodone [OxyContin]) as well as as-needed dosing of
a short-acting analgesic agent. For patients who are not capable of taking oral
medications, the analogous recommendation is to use a patient-controlled analgesia-type
device with a basal rate, as opposed to as-needed bolusing of parenteral doses
only.
Adjuvants
The term adjuvant
refers to drugs that have little or no inherent analgesic activity but are
synergistic when used in combination with classic analgesics (narcotics and
NSAIDs). For example, in the appropriate setting, the addition of
antidepressant agents, such as amitriptyline, fluoxetine, or sertraline, to a
narcotic regimen might allow a lower (total) dose of narcotics to be used for
an equianalgesic effect. In this situation, the appropriate use of adjuvants
allows for lower doses of narcotics and the potential for lesser
narcotic-associated side effects; the disadvantage of adjuvants leads to the
inherent risks of polypharmacy--not only increased difficulty with compliance
(as a result of a more complicated regimen), but also the increased risk for
drug interactions and side effects that would otherwise not be encountered
(such as those from the adjuvant itself).
Surgical Decompression
Functional mechanical pain generally responds best to bone
stabilization and restoration of skeletal integrity. There is generally little
role for debulking of tumors for pain relief. Metastatic tumor debulking coupled with cementation
and internal fixation may allow a biomechanically more sound skeletal
reconstruction, but this should be done for biomechanical musculoskeletal
reconstruction, not for pain relief per se. Although the pain resulting from a
large tumor mass often is relieved to a significant degree if that tumor is
resected, many symptomatic patients respond as well or better to medical
management. A classic example is a patient with skeletal involvement of
lymphoma with a large soft tissue extension. With intravenous steroid and
chemotherapy administration or radiation therapy (or some combination), often
the soft tissue tumor extension responds dramatically with significant pain
relief and dissipation of the mass within 1 to 2 weeks. There is little role
for debulking of such responsive tumors for pain relief because the medical
management alone usually suffices. If the tumor bulk itself is causing severe
pain or progressive neurologic dysfunction because of compression of normal
structures, as is most commonly seen in spinal metastases with cord or root
compression, debulking-type decompression may be indicated, especially if
conservative management and radiation therapy fail.
MEDICAL MANAGEMENT OF SKELETAL METASTASES
When a patient is discovered to have skeletal metastases, the
first decision to be made is whether or not the lesions warrant immediate
intervention. Although not absolute, the answer when addressing lesions in
weight-bearing bones is often the answer to the question "is the lesion
symptomatic?" Other factors, such as the amount of analgesia the patient
is receiving and whether they have appropriate sensation in that region of the
body, must be considered as well. For lesions that require some immediate
intervention, the next decision is whether or not surgical intervention is
necessary; for most situations, the long bones and pelvis are bones for which
surgical stabilization is the primary intervention of choice, with this then
being followed by radiation. Radiation frequently is used in isolation for
non-weight-bearing bones and bones for which a fracture, if it occurs, is
unlikely to result in permanent functional damage. Further discussion of these
modalities in critical, weight-bearing bones occurs later in this article as
well as elsewhere in this issue.
How to primarily intervene on lesions that are asymptomatic,
particularly when non-weight-bearing bones are involved, is not as clear-cut.
These situations are not as urgent (as is the case for symptomatic lesions),
and sufficient time often is available to allow a trial of systemic
(antineoplastic) therapy to be undertaken, which if successful can result in
bone healing and avert surgical or radiotherapeutic intervention altogether.
Avoidance of surgical intervention often is preferable because these patients
usually have overt, widespread disease; there is a need to administer systemic
therapy sooner rather than later. If optimal antineoplastic treatment is palliative and not curative,
avoidance of surgery results in the patient achieving more time out of the
hospital, being with family and friends. The physician must follow the osseous
lesion and assess its response to determine the need for alternative therapies,
however, such as radiation, to avoid debilitating pathologic fractures.
Chemotherapy
In deciding whether systemic or localized (e.g., isolated limb
perfusion, intra-arterial administration, regional hyperthermia) chemotherapy
is appropriate as primary treatment of skeletal metastases, many factors
must enter into the decision. First in this decision is knowledge of the histologic
type of tumor. The second most important factor is knowledge of whether or not
the patient has previously received treatment for this tumor, because even the most
chemosensitive tumors--lymphomas--frequently are resistant on relapse. When
categorizing tumors this way, most solid tumors can be placed into four
categories: highly chemosensitive, chemosensitive or chemoresponsive, rarely
chemoresponsive, and unresponsive tumors.
Tumors that are considered highly chemosensitive are tumors for
which responses are frequent (50% of treated patients, often approaching 
75% of treated patients),
are rapid (days to a few weeks), and often result in significant tumor burden
decrements of greater than 50% of tumor size, with frequent complete or
near-complete remissions and true cures for some. Tumors that are considered
highly chemosensitive are lymphomas (Hodgkin's and nonHodgkin's) and small
round blue cell tumors (e.g., small cell carcinoma and the primitive
neuroectodermal tumors--Ewing's sarcoma, neurblastoma, rhabdomyosarcomas); many
oncologists also would place testicular carcinomas in this group. Patients with
newly diagnosed, highly chemosensitive tumors should be considered for a trial
of chemotherapy, unless the involved bone is orthopedically unstable. (See the
accompanying box
.)
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Chemotherapy Indications
First-line treatment of: Small cell lung cancer Non-Hodgkin's lymphoma Hodgkin's disease Testicular cancer (?) Other small round blue cell tumors Rhabdomyosarcoma Neuroblastoma Ewing's sarcoma
First-line treatment of: Breast cancer Testicular cancer Angiosarcoma Synovial sarcoma Ovarian cancer Osteosarcoma Myxofibrosarcoma Second-line treatment of: Small cell lung cancer Non-Hodgkin's lymphoma Rhabdomyosarcoma Neuroblastoma Hodgkin's disease Testicular cancer (?) Ewing's sarcoma
Esophageal carcinoma Non-small cell lung cancer Thyroid carcinoma Colorectal carcinoma Renal cell carcinoma Pancreatic carcinoma Prostate carcinoma Possible third-line treatment of: Small cell lung cancer Lymphoma (Hodgkin's and non-Hodgkin's)
Melanoma Adrenocortical carcinoma Mesothelioma Other neoplasms Anaplastic carcinoma |
The next group--chemosensitive or chemoresponsive tumors--are
tumors for which responses are common (on the order of 40% to 60% of patients,
possibly 70%) but are slower, occurring over weeks to months, and are less
often associated with major reductions in tumor burden; durable complete
remissions are seen in a few (10% to 15%) patients. This group of tumors
includes some chemocurable tumors; however, because of the time frame required
for a significant tumor reduction, these tumors cannot be considered in the
highly chemosensitive group. Tumors in this category include breast and ovarian
cancers, germ cell cancers, angiosarcomas, high-grade myxofibrosarcoma
(formerly malignant fibrous histiocytoma), synovial cell sarcomas, and
osteosarcomas. Most patients with asymptomatic bone lesions can be considered
for a trial of chemotherapy. Patients with a first relapse of a highly chemosensitive tumor also can be
thought of as being in this group, in which a trial of (second line)
chemotherapy is reasonable for asymptomatic bone lesions or lesions in which
progression (and possible fracture) would not result in devastating or
permanent debility (see earlier box
).
The third group--rarely chemoresponsive tumors--are tumors in
which chemotherapy is truly palliative; most patients with these tumors often
progress to front-line chemotherapy, with the responding patients frequently
achieving only partial remissions or stable disease. A rare patient with these
tumors achieves a complete remission and meaningful prolongation of life as a
result of chemotherapy. Chemotherapy should be considered as primary treatment (for skeletal metastases) only rarely
and only for asymptomatic lesions. Tumors in this category include but are not
limited to epithelial tumors of the gastrointestinal tract (primarily
esophageal, colorectal, and pancreatic cancers), non-small cell lung
carcinomas, renal cancers, prostate cancer, and thyroid carcinoma (see earlier box
).
There are some tumors for which response rates are so low that
responses are to be considered anecdotal or not meaningful and for which it is
reasonable to consider the tumor to have no
effective therapy. Patients with these tumors should never be
considered for chemotherapeutic intervention of osseous metastases, with the
possible exception of patients for whom radiotherapy or surgery is not
feasible; these patients are frequently so debilitated that chemotherapy also
could be considered inappropriate. Such tumors include mesothelioma,
adrenocortical carcinoma, melanoma, most anaplastic carcinomas, and any first
or higher relapsing histology mentioned previously with the possible exception
of second relapses of small cell carcinoma and lymphoma (which could be
considered in the rarely chemoresponsive
tumors category) (see earlier box
).
Bisphosphonates
The discussion so far has been limited to classic cytotoxic chemotherapy. A new
class of agents--the bisphosphonates--has been shown to have a significant
impact on the orthopedic aspects of cancer. Originally developed for the treatment of (malignant) hypercalcemia, these agents have been shown also to
affect the basic tumor biology of many cancers. Through mechanisms that are
just beginning to be understood, prophylactic
use of the newer bisphosphonates has been shown to decrease the actual
incidence of bone metastases, [1] [2] [3] [7] [10] orthopedic
events,[1] [2] [3] [10] and the oncologic emergency of malignant
hypercalcemia. [3] [9] Use of pamidronate and clodronate in
patients with established osseous metastases from breast cancer, prostate
cancer, and myeloma has been shown to decrease tumor burden and induce
remission or healing in these osseous lesions without concurrent chemotherapy
or radiotherapy. [3] [12] [13]
As mentioned, the mechanisms of action by which the
bisphosphonates directly affect the tumor biology of bone avid tumors is
unclear, but it appears to be different for the cases of breast cancer,
myeloma, and prostate cancer. [12] Current hypotheses and models are
derived from the soil and seed model of osseous metastatic development. Central to the models for
all three of these tumors, however, is the premise that either tumor
chemotactic factors or tumor growth factors are naturally embedded into the
osseous matrix; similarly the tumor cells themselves secrete factors that are
stimulatory to osteoclasts (and osteoclast formation) or inhibitory to
osteoblasts. The tumor cell, once implanted within the osseous matrix (such as
would be the case once a cancer cell migrates out of the vascular space in a
bone) would find itself in a medium enriched with tumor cell growth factors;
these would stimulate tumor cell proliferation, which would result in increased
levels of factors that are stimulatory or attracting to osteoclasts.
Locoregional osseous matrix breakdown would result in release of more tumor
cell growth factors as well as additional room for tumor cell proliferation. In
the case of breast cancer, the breast cancer cells secrete parathyroid
hormone-related protein (PTHrP), which induces an osteoblastic intermediary to
stimulate osteoclast activity; the increased bone resorption would release an
inactive transforming growth factor (TGF)-beta from the osseous matrix, which
is converted to active TGF-beta and interacts with TGF-beta receptors on the
breast cancer cells, resulting in the breast cancer cells producing PTHrP. In
myeloma, interleukin-6 (which is known to be incorporated
within the bone matrix) is released locally as a consequence of bone
resorption, stimulating myeloma cell proliferation; in turn, the myeloma cell
excretes a factor that stimulates osteoclasts, resulting in further bone
resorption and release of interleukin-6. It is not yet know whether or not
osteoclast-activating factor is the intermediary that stimulates the
locoregional osteoclasts.
The bisphosphonates inhibit bone resorption by a number of
mechanisms. The predominant mechanism of action for a given bisphosphonate
differs between the various bisphosphonates that currently are available but
include interaction with molecules on the osteoclast surface, prevention of
osteoclast attachment to the bone matrix, and incorporation into the inorganic
bone matrix itself, forming an analog to calcium hydroxyapatite that is more
resistant to osteoclast degradation than native matrix.
Currently the most active bisphosphonate in clinical oncologic use
in the United States is pamidronate (Aredia), although newer bisphosphonates
that are more potent or more readily available by the oral route are under
development and early phase testing. The older bisphosphonate etidronate
(Didronel) is rarely used given its short duration of activity (it must be
taken daily) and long-term complication of causing osteomalacia. The promise of
the newer bisphosphonates is more effective prophylaxis of bone metastases and
fractures and the prevention of hypercalcemia.
The currently approved use of pamidronate in the United States is
for treatment of hypercalcemia (of malignancy) and prevention of
orthopedic complications in myeloma and breast cancer. Pamidronate is given as
a once-monthly infusion over 1 to 2 hours, although its formal approval is as a
24-hour infusion for hypercalcemia, as a 2-hour infusion in breast cancer, and as a 4-hour
infusion in myeloma. The risk of hypocalcemia is low, as are the risks of
hypophosphatemia and hypomagnesemia.
NONOPERATIVE TREATMENT
Nonoperative management of metastatic bone lesions is indicated whenever the
goals of pain relief and functional preservation or restoration are
unattainable or unreasonable with surgical management or when these goals can
be met satisfactorily with medical management alone. Most lesions in this
category are managed by the medical oncologist, in conjunction with the
radiation oncologist, without ever coming to the attention of the orthopedic
surgeon. For example, a skeletal metastatic lesion that is detected on a screening
study but that is causing no symptoms or functional impairment and does not
place the skeleton at risk for fracture usually should be managed
conservatively. The lesion should be periodically reevaluated by the physician
and the patient to prevent unrestricted progression of the lesion, however.
Radiation treatment
of a small bone lesion may prevent a future fracture that would result if the
lesion progressed. Patients must be counseled to report any future change in
symptoms, especially the onset of any new weight-bearing pain.
Operative and
Nonoperative Indications
The medical oncologist often is in the midst of a course of
chemotherapy when a bone lesion with a potential impending pathologic fracture
is discovered, and the decision of whether to operate or to treat
conservatively must be made. The reader is referred to the article by Rougraff
on operative indications for a full discussion of these decisions, but a brief
synopsis follows.
The goal of restoration and preservation of function implies that
the patient is otherwise functional to begin with. Points to consider when
evaluating a patient for medical versus combined medical and surgical
management are the overall health of the patient, the expected response of the
tumor and the patient to adjuvant interventions such as radiation, the treating
surgeon's experience and capability at bone reconstruction, the reconstructability of the bone in question
if a fracture does occur, whether or not the bone is a weight-bearing bone, the
extent of functional disruption that would occur if a fracture does occur (and
whether this is an upper or lower extremity because this affects the
weight-bearing status and the function of the patient), and the options that
are available to the patient within their locale because some patients may be
forced to travel long distances for some therapies. As a general overriding
rule, however, if a patient has an impending pathologic fracture, it is usually
easier to prevent a fracture than it is to heal one.
In general, the major surgical options are internal fixation, with
or without cementation, versus arthroplasty, or bone replacement, with
artificial materials. The selection of the preferred technique for any specific
patient and disease must be individualized. The objective scoring system
described by Mirels [11] (Table 1) (Table Not Available) was
based on a retrospective study of 78 radiated long bone lesions and allows some
prediction of the likelihood of fracture. The risk of fracture by score is
shown in Table 2 (Table Not Available) . The general guideline the authors
follow is nonoperative management of patients whose score is less than or equal
to 7 and internal stabilization of lesions that rate a score of 9 or greater.
For patients with a score of 8, internal fixation should be considered, and
care is individualized. Computed tomography scan of metastatic bone lesions is of great benefit in
defining the extent of bone destruction. It allows optimal surgical planning
and provides an excellent baseline study for future comparison if there is any
question regarding disease progression. It has proved helpful to the authors,
allowing more informed decisions to be made, especially in patients with
borderline surgical indications.
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TABLE 1 -- MIRELS OBJECTIVE SCORING SYSTEM *
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(Not Available) |
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From Mirels H: Metastatic disease in long bones: A proposed
scoring system for diagnosing impending pathologic fractures. Clin Orthop
249:256-264, 1989; with permission. |
*Based on radiographs, not computed
tomography scans; 78 radiated metastatic long bone
lesions.
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TABLE 2 -- RISK OF FRACTURE BY MIRELS OBJECTIVE SCORING SYSTEM *
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(Not Available) |
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From Mirels H: Metastatic disease in long bones: A proposed
scoring system for diagnosing impending pathologic fractures. Clin Orthop
249:256-264, 1989; with permission. |
*Based on radiographs, not computed
tomography (CT) scans; 78 radiated metastatic long bone
lesions. General guidelines for scoes:
Score 
7--no internal fixation
Score >9--internal fixation
Score = 8--Consider internal fixation, individualized care, and possibly CT
scan.
The relative contraindications to surgery are shown in the
accompanying box
. A classic example requiring only medical management is the patient with
widespread metastatic
disease who is bed ridden on the basis of general debility. Such patients are
typically too ill and would not benefit from surgery sufficiently to warrant
the risk of surgery. Medical management alone is appropriate in these patients.
In patients with severely limited life expectancy who have insufficient time to
heal surgical wounds and to enjoy the benefits of restored or preserved
function, surgery is inappropriate. Each patient must be individually assessed
in terms of the time required for recovery from the intervention being
considered to determine if surgery is indicated at all. If surgery is possibly
indicated, selection of the type of surgery is critical. Although it is
generally inappropriate to perform a massive allograft reconstruction that
would require months to heal in a patient with extensive bone disease, the use
of an intramedullary nail to prevent an impending fracture is often indicated
because of the quick recovery and functional restoration. Patients with disease
that is so extensive that their anatomic destruction is unrestorable are
generally not surgical candidates.
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RELATIVE CONTRAINDICATIONS TO SURGERY Moribund patient Distorted mental status Disoriented agitated, flailing patient Multiple risks Fixation failure Infections Poor rehabilitation cooperation Fluid overload (brain metastasis,
increased intracranial pressure) Severely limited life expectancy Insufficient time to heal and enjoy the
benefits of restored or preserved function Unrestorable function Disease too extensive--no good surgical
reconstruction Venous thromboembolic disease of the
extremity Significant neurovascular compromise
(can be surgical indication in some patients) Deep or wound infection |
Splinting
For patients managed conservatively, treatment often includes splinting. When a splint
is applied to a moribund patient, it should be well padded. It must be removed
and changed frequently to check the patient for sores. Removable splints with
daily skin checks often are appropriate. The end-stage cachectic cancer victim
is at high risk for skin breakdown. Similar concerns arise in patients with a
distorted mental status. Such patients also must be checked frequently for skin
and soft tissue breakdown because of their inability to verbalize to the
physician complaints referable to pressure sores and other mechanical cast and
splint problems. Appropriate splints may provide significant comfort, however.
Wheelchair and Other
Mobility Aids
One nonoperative intervention that can be appropriately offered to
debilitated patients is the use of a wheelchair. The wheelchair can restore a patient
to the community. Likewise, the use of assistive devices, such as walkers,
crutches, and canes, should be liberal. Because of coexisting bone disease at
multiple locations, platform and rolling walkers and other special adjustments
may be required. Traction or bed rest are indicated rarely unless the patient
is quite debilitated or moribund. Restoration and preservation of mobility
allows the patient to continue social activities, an area of great personal
importance to the cancer patient.
Postoperative Treatment and Follow-up
Medical management and adjunctive treatment generally is required to assist with
local control of a skeletal lesion once it has been managed surgically. Unless
the metastasis was widely or radically excised, the area must be treated to
prevent disease progression. Otherwise the skeletal reconstruction will
probably fail, often within months. [15] The chosen adjuvants depend on the
expected responsiveness of the underlying tumor. In many patients with metastatic carcinoma, the primary therapeutic
option is radiation therapy. Chemotherapy, immunotherapy, or other therapy may
well be appropriate, however. Radiofrequency tumor ablation, an evolving
technique, may become useful in the future. The principle that should be
followed is to assess the lesion clinically over time to ensure that there has
been an appropriate response to the intervention employed and specifically to
document that there is no progression of the local lesion, which would make the
surgical intervention and skeletal reconstruction fail. The team must decide
who will be the one following and assessing the patient's metastatic bone disease and the need for additional
therapy.
Radiation
Radiation often relieves the pain of metastatic bone disease. A standard dose of 3000
cGy given in 10 fractions generally gives about 80% lasting pain relief from metastatic disease. Patients with severe pain,
especially those near death, often receive excellent short-term palliation from
one or two fractional treatments to a total of 1000 cGy. For patients with extensive
metastases, 600 to 800 cGy in a single fraction can give 80% pain relief within
8 hours. The bone metastatic lesions that are most likely to undergo radiographic
healing or reconstruction are sclerotic lesions or lesions that have a mixed
lytic and blastic appearance on plain radiograph, especially breast cancer
lesions. It has been the authors' experience that patients with purely lytic
bone lesions of metastatic lung cancer, myeloma, and renal cell cancer rarely
reconstitute when treated with radiation. These patients usually need some form
of skeletal stabilization or reconstruction, often coupled with tumor excision
or curettage. For a more complete presentation on radiation therapy, the reader
is referred to the article by Frassica et al.
SUMMARY
The medical management of metastatic disease generally includes chemotherapy,
hormonal therapy, and metabolic pharmacologic manipulations with medications,
such as bisphosphonates as well as nonoperative physical measures, such as
orthoses and ambulatory or mobility aids. This comprehensive complex care is
best coordinated with the medical oncologist. If well planned and coordinated,
such care can improve the life of the cancer patient greatly.
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Abstract
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.