Orthopedic Clinics of North America
Volume 31 • Number 1 • October 2000
Copyright © 2000 W. B. Saunders Company
ORTHOPEDIC MANAGEMENT OF METASTATIC DISEASE
_____
MEDICAL MANAGEMENT OF METASTATIC SKELETAL DISEASE
Paul D. Savage 1
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#O054501> MD
William G. Ward 2
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#O054502> 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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545005> ] [ 6
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545006> ] including patient apprehension, fear of
addiction, [ 4
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545004> ] [ 8
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545008> ] [ 14
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545014> ] 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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#B054501> .)
Chemotherapy Indications
Tumors for which chemotherapy should definitely be considered as primary
treatment for bone metastases
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
Tumors for which chemotherapy should possibly be considered as primary
treatment for bone metastases (nonemergent situations)
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
Tumors for which chemotherapy should rarely be considered as primary
treatment for bone metastases
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)
Tumors for which chemotherapy should never be considered as primary
treatment for bone metastases
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 <http://home.mdconsult.com/das/article/body/jorg=j
ournal&source=&sp=11501616&sid=52257413/N/189623/#B054501> ).
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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#B054501> ).
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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#B054501> ).
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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545001> ] [ 2
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545002> ] [ 3
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545003> ] [ 7
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545007> ] [ 10
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545010> ] orthopedic events,[ 1
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545001> ] [ 2
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545002> ] [ 3
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545003> ] [ 10
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545010> ] and the oncologic emergency of malignant
hypercalcemia. [ 3
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545003> ] [ 9
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545009> ] 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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545003> ] [ 12
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545012> ] [ 13
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545013> ]
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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545012> ] 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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545011> ] (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.
TABLE 1 -- MIRELS OBJECTIVE SCORING SYSTEM *
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#T054501.01>
(Not Available)
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.
_____
TABLE 2 -- RISK OF FRACTURE BY MIRELS OBJECTIVE SCORING SYSTEM *
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#T054502.01>
(Not Available)
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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#B054502> . 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.
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
<http://home.mdconsult.com/das/article/body/jorg=journal&source=&sp=11501616
&sid=52257413/N/189623/#R0545015> ] 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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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.
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