Dennis A. Casciato, James R. Berenson, and Howard A. Chansky
I. METASTASES TO CORTICAL BONE. Metastases to bone marrow are discussed in Chapter 34, Section I.A in “Cytopenia.”
A. Pathogenesis. The bones most frequently involved with metastases are the femur, pelvis, spine, and ribs. Tumor cells may metastasize to vertebral bodies or the skull without entering the systemic circulation by seeding through Batson vertebral venous plexus (a valveless system of veins along the entire vertebral column that communicates with other venous systems, from the pelvis to the brain).
1. Mechanisms. Osteoclast-mediated destruction and direct tumor cell–mediated destruction are the two mechanisms by which skeletal metastases destroy bone. Stimulation or inhibition of osteoblastic activity also occurs. The relative balance of osteoclastic and osteoblastic activity determines whether a lesion is osteolytic or osteoblastic. Malignant cells secrete many factors known to both stimulate the proliferation and activity of osteoclasts and produce osteolysis, possibly indirectly through the osteoblasts. These factors include the following:
a. Transforming and fibroblastic growth factors; tumor necrosis factors
b. Prostaglandins; interleukin-1 (IL-1), IL-6, and IL-11
c. Parathyroid hormone–related protein
d. Bone morphogenic proteins
e. Matrix-degrading proteins, such as specific metalloproteinases
f. Receptor activator of nuclear factor kappa B ligand (RANKL), the essential osteoclast differentiation factor (discussed in Chapter 22, Section II.D.3.a)
g. Chemokines and chemokine receptors
h. Osteoblast inhibitory proteins: Dickkopf-1 and secreted frizzled protein 2
2. Frequency. A relatively small number of different malignancies account for most tumors that spread to bone.
a. Tumors that commonly metastasize to bone. Carcinomas of unknown primary site, lung, breast, kidney, prostate, and thyroid; plasmacytoma; melanoma; and occasionally Ewing sarcoma
b. Tumors that rarely metastasize to bone. Ovarian carcinoma and most soft tissue sarcomas
c. Certain carcinomas have a predilection for metastasizing to particular skeletal sites. For example, skeletal metastases to the hands are unusual, but about 50% of these metastases arise from a lung primary. Renal cell carcinomas often metastasize to the bones of the shoulder girdle.
3. Types of bone metastases and their occurrence in various tumors are shown in Table 33.1.
a. Osteolytic lesions are characterized by specific radiolucent areas: myeloma and commonly in renal cell and breast carcinomas.
b. Osteoblastic lesions are characterized by radiopaque areas: commonly in prostate cancer.
c. Mixed lesions: commonly in breast carcinoma and most tumors
Table 33.1 Radiologic Characteristics of Bone Metastases
B. Natural history. Bone metastases are usually confined within the bony substance and generally do not cross joint spaces. They lead to pain, pathologic fracture, neurologic compromise, and progressive immobility. Crippling bone disease can make bedridden patients susceptible to decubitus ulcers, hypercalcemia, and infections.
1. Cervical spine metastases compressing the cord may result in myelopathy and weakness of the muscles of respiration, resulting in paralysis, pneumonia, and possibly death. Thoracic spine metastases compressing the cord can result in paraplegia.
2. Dense osteoblastic metastases (e.g., with prostate cancer) or extensive involvement of bone marrow spaces can result in refractory pancytopenia. Pathologic fracture is less likely in the osteoblastic variant of metastatic prostate cancer.
C. Prognosis. The expected survival of patients with skeletal metastasis varies. Patients with lung cancer may only survive a few months. The median survival of patients with breast cancer and only skeletal metastases, however, is 2 years. The median survival time of patients with stage IV renal cancer is 11 months, but 20% to 30% of those with a solitary metastasis survive 5 years after the lesion is surgically resected. About 20% of patients with skeletal metastases from prostate cancer survive 5 years.
D. Diagnosis
1. Symptoms and signs
a. Dull, aching, or boring pain that is worse at night than with physical activity is characteristic of pain from bone metastases. This pain pattern also occurs with malignant invasion of retroperitoneal structures without bony involvement. As disease progresses, weight-bearing pain becomes more prominent. These characteristics are directly opposite to the typical pain of degenerative diseases, in which pain related to activity is present earlier and worse than pain at rest.
b. Bone pain intensified by activity is often the first symptom of imminent fracture. On the other hand, pathologic fractures, particularly in non–weight-bearing bones, can also be painless. Patients often report falling down, but it is often not clear whether the fracture was the cause or the effect of the fall.
c. Spinal instability secondary to bone loss can cause excruciating pain, which is mechanical in origin. The patient is comfortable only when lying absolutely still.
d. C-7 to T-1 vertebral pain is usually referred to the interscapular region; radiography of both cervical and thoracic spines is essential in these patients.
e. T-12 to L-1 vertebral pain is usually referred to the iliac crest or sacroiliac joint.
f. Sacral pain is usually referred to the buttocks, perineum, and posterior thighs. The pain typically is exacerbated by sitting or lying down and relieved by standing.
2. Serum alkaline phosphatase levels are usually elevated in patients with bone metastases. Elevations appear to reflect an osteoblastic (or healing) response to tumor destruction. In pure osteolytic tumors, such as plasma cell myeloma, the serum alkaline phosphatase level is normal.
a. Nonneoplastic causes of increased bone alkaline phosphatase include primary hyperparathyroidism, thyrotoxicosis, acromegaly, renal disease, Paget disease, osteomalacia, and healing fractures.
b. Physiologic increases occur in the pediatric age group (before bony epiphyseal closure) and pregnancy (placental source).
3. Radionuclide bone scan, using 99mTc-methylene bisphosphonate, is the most effective screening test for skeletal metastases. The scan often detects metastases several months before radiologic changes are evident. Radionuclide bone scans reflect osteoblastic activity; thus, purely osteolytic lesions with a preponderance of osteoclastic activity, such as in patients with myeloma, may not be apparent on a bone scan.
a. Specificity. Patients with a known cancer and bone pain have positive bone scans in 60% to 70% of cases; patients without bone pain have positive scans in 10% to 15% of cases. Multiple “hot spots” are more specific than one or two.
(1) Retroperitoneal tumors often cause a bony response, characterized by diffuse isotope uptake over the anterior aspect of the spine.
(2) Patients with metastases from breast or prostate cancer, when clinically responding to endocrine therapy, may develop new abnormal areas on scans because of bone healing and increased osteoblastic activity.
(3) Multiple myeloma, a predominantly osteolytic process except in the presence of pathologic fracture, is the most frequent cause of false-negative bone scans. These patients often have negative bone scans except in areas with fractures.
(4) Decreased uptake of radioisotope is seen in irradiated bone that never did contain metastases and thus cannot be interpreted as a sign of absence of metastases or of reduced tumor burden.
b. Benign conditions that can cause a positive bone scan
(1) Bone healing after fracture
(2) Radiation osteitis
(3) Arthritis and spondylitis
(4) Osteomyelitis
(5) Osteonecrosis
(6) Regional osteoporosis
(7) Paget disease of bone
(8) Hyperostosis frontalis interna
(9) Osteopetrosis (Albers-Schönberg disease)
(10) Osteogenesis imperfecta
4. Plain radiographs remain essential for the diagnosis and characterization of bone metastases. Metastatic lesions must involve 30% to 50% of bone matrix to be visualized on plain radiographs. Diffuse osteoporosismay be the only radiologic abnormality in some patients with extensive bony involvement (e.g., multiple myeloma). Skeletal infections with pyogenic bacteria are frequently associated with sclerotic reactions; chronic granulomatous infections, however, may result in purely osteolytic lesions. Other causes of osteoblastic reactions are shown in Table 33.1.
a. Indications. Radiographs should be obtained and compared with previous films of the involved areas in patients with bone pain, abnormalities on physical examination suggestive of fracture, or asymptomatic abnormalities in bone scans.
b. Routine complete skeletal surveys are not indicated except in patients with plasma cell myeloma, which may be associated with painless osteolytic lesions in crucial bone sites, such as the femora or cervical spine.
c. Vertebral involvement from metastatic cancer is manifested by loss of the pedicles or lateral spinous processes and vertebral collapse with sparing of the intervertebral space. Infections that involve the intervertebral disk space destroy it. Some chronic infections (e.g., tuberculosis or bru cellosis), however, may involve the vertebrae and not the intervertebral spaces, result in vertebral collapse, and thereby mimic malignancy.
d. Postirradiation osteitis produces irregular, diffuse (rather than localized) osteolytic or mixed lesions confined to the radiation portal.
5. Positron Emission Tomography (PET) using 18F-deoxyglucose has become a standard tool in treatment planning for many cancers. PET scans cannot provide as detailed anatomic information as standard radionuclide bone scans, but this limitation can be overcome by performing a combined PET/CT scan. PET scans have greater specificity for detecting skeletal metastases, but radionuclide bone scans retain improved sensitivity and are much less expensive than PET scans. Thus, while useful information about skeletal metastases can be obtained from PET scans used to follow the course of a primary tumor, their use to diagnose skeletal metastases remains experimental.
6. CT scans are useful to diagnose early metastases of bone, particularly the spine, when hot spots are detected on the radionuclide scan but corresponding plain radiographs are normal. CT scans elucidate cortical erosion, subtle fractures, and matrix calcification or ossification. In addition, they are useful to evaluate epidural compression, the extent of metastases (e.g., in the femur), and areas difficult to image by conventional radiographs (e.g., costovertebral junction, sternum, and sacrum).
7. MRI scanning is best at delineating the extraosseous extension of a soft tissue mass through the bone cortex (e.g., epidural compression). This technique is also ideal for demonstrating the intraosseous extension of tumor into the cancellous bone. MRI may also be used to reveal subtle insufficiency or pathologic fractures about the hip and pelvis or to evaluate specific sites associated with pain.
8. Biopsy. If a fracture has already occurred, care must be taken to sample the tumorous area adequately rather than the healing area of fibrous tissue and osteoid formation. Specific expertise in bone histopathology must be available. If only a single bone is involved, the biopsy must be approached as if the lesion were resectable for cure. Potentially curable lesions include a solitary renal cell metastasis and sarcoma.
a. Indications. If other sites associated with a lower risk for morbidity are not available, bone biopsy for the differential diagnosis of cancer is indicated in patients with the following conditions:
(1) An isolated bone lesion that the radiologist interprets as being compatible with a primary bone tumor
(2) An osteolytic bone lesion in a crucial area (e.g., cervical spine or femoral neck) and no history of cancer
(3) A history of a cancer that metastasizes to bone, localized bone pain, normal radiographs of the area, equivocal bone scan and alkaline phosphatase results, and no evidence of disease elsewhere
(4) Isolated bone pain in a region that was previously irradiated and radiographic findings that are not typical of postirradiation osteitis
b. Contraindications. Bone biopsy should not be done in asymptomatic patients known to have cancer but with isolated, osteolytic lesions in non-crucial areas that are suspected to be benign lesions or metastatic disease. Biopsy in these patients often results in chronic pain at the biopsy site. If a cancer is discovered, it is a metastasis for which treatment could have awaited the development of symptomatic disease.
E. Medical management is necessary in patients with multiple painful metastatic sites.
1. Chemotherapy and endocrine therapy are useful for treating metastatic tumors known to respond to these modalities. Chemotherapy doses may need to be attenuated because of compromised marrow function from neoplastic invasion or irradiation.
2. Bisphosphonates. Pyrophosphonates are natural compounds that are potent inhibitors of osteoclast-mediated bone resorption and contain two phosphonate groups bound to a common oxygen. Bisphosphonates (such as pamidronate or clodronate) are analogs of the endogenous pyrophosphonate with a carbon replacing the oxygen atom. The wide variety of alternative carbon substitutions results in marked differences in antiresorptive properties and side effects. Bisphosphonates have become the standard treatment for tumor-induced hypercalcemia (see Chapter 27, Section I), have been successfully used in the treatment of conditions characterized by increased osteoclast-mediated bone resorption (such as Paget disease of bone or osteoporosis), and are a valuable form of therapy for bone metastases.
These drugs are poorly absorbed and often poorly tolerated when administered orally. They are highly concentrated in bone and become biologically inactive once the drug becomes a part of bone that is not remodeling. As a result, continued administration of bisphosphonates is required to achieve the desired lasting inhibition of bone resorption.
a. Intravenous bisphosphonates. Zoledronic acid (Zometa, 4 mg IV over 15 minutes) or pamidronate (Aredia, 90 mg IV over 2 hours) every 3 to 4 weeks as a supplement to antitumor therapy substantially reduces morbidity and subsequent skeletal events for patients with myeloma and metastatic bone disease. Although both pamidronate and zoledronic acid have shown efficacy for patients with osteolytic bone disease caused by breast cancer or myeloma, only zoledronic acid has reduced skeletal events among patients with other cancers, regardless of whether the disease results from osteolytic, osteoblastic, or mixed metastatic bone lesions. Pain is improved in about half of the patients given pamidronate even without anticancer treatments. Oral clodronate is also helpful but is less effective than the intravenous forms.
It has become increasingly recognized that many different cancer treatments may induce bone loss and increase the risk of fracture. Glucocorticosteroids lead to enhanced loss of bone and induce fractures. Gonadal ablation with drugs such as GnRH agonists or aromatase inhibitors also has been shown to increase bone loss and heighten the risk of fracture. Several studies have shown the ability of IV bisphosphonates administered less frequently to prevent bone loss and actually increase bone density and, in some cases, reduce fracture risk among cancer patients receiving therapies that induce bone loss. However, more studies are needed to establish the long-term safety and efficacy of this approach for this at-risk cancer population.
Bisphosphonates may also have an antitumor effect. Some randomized trials have shown a reduction in both skeletal and visceral metastases in patients with myeloma or breast cancer. Recent studies show an overall survival advantage among previously untreated myeloma patients receiving zoledronic acid compared to oral clodronate.
b. Adverse effects of bisphosphonates. It is important to recognize that these agents occasionally are associated with side effects, including renal dysfunction and osteonecrosis of the jaw (ONJ).
(1) Renal dysfunction. The type of renal lesion is different between the two bisphosphonates. Pamidronate more often will cause a glomerular lesion initially associated with proteinuria, which may be at nephrotic syndrome levels. By contrast, zoledronic acid more often causes tubular dysfunction and thus is not often associated with albuminuria. Most reports of renal insufficiency during bisphosphonate therapy have involved patients with multiple myeloma.
The nephrotoxicity is both dose- and infusion time dependent. After the bisphosphonate is temporarily discontinued and renal function returns to baseline, the drug may be cautiously reinstituted using longer infusion times (e.g., 30 to 60 minutes for zoledronic acid).
(2) Hypocalcemia. Most patients receiving high-potency bisphosphonates do not become hypocalcemic because of compensatory mechanisms, most importantly, increased secretion of parathyroid hormone. Hypomagnesemia and/or reduced creatinine clearance frequently are simultaneous factors. Thus, serum creatinine, magnesium, calcium, and phosphate should be monitored during bisphosphonate therapy.
(3) Osteonecrosis of the jaw (ONJ) is defined as the presence of exposed bone in the maxillofacial region that does not heal within 8 weeks of treatment. IV bisphosphonates are associated with an increased risk of ONJ (3% to 8% of patients). The concomitant use of angiogenesis inhibitors (e.g., bevacizumab, sunitinib) may be additive risk factors for the development of ONJ in patients receiving bisphosphonates.
This complication occurs more frequently among patients who have had recent dental surgery (especially dental extraction or implant) or trauma or who abuse alcohol, use tobacco, or have poor dental hygiene. Before initiating bisphosphonate treatment, patients should have a complete dental exam, and any dental extractions or removal of jawbone(s) should be completed several months before initiating these drugs to reduce the risk of ONJ. Conservative management of ONJ with limited debridement, antibiotic therapy, and topical mouth rinses may result in healing.
The course of ONJ is quite variable, and many patients do not show worsening of the condition, although this can occur. Whether or not to discontinue bisphosphonate therapy at the time of the diagnosis of ONJ or to reinitiate therapy after treatment of ONJ are subjects of debate. It is clear that surgical intervention to treat this problem should be minimized and only undertaken by dental professionals experienced with this problem.
(4) Other adverse effects of IV bisphosphonates
(a) In about 15% to 30% of patients, the intravenous agents cause transient fever and an influenza-like syndrome in patients naive to these drugs.
(b) Severe and rarely incapacitating bone, joint, or muscle pain can occur within days, months, or years after starting a bisphosphonate and does not always resolve completely with discontinuation of therapy.
(c) Ocular toxicities such as conjunctivitis, uveitis, scleritis, and orbital inflammation may rarely occur, but these manifestations require a prompt ophthalmologic evaluation; further treatment with the offending bisphosphonate is not recommended.
(d) A modest association between the use of oral and intravenous bisphosphonates and atrial fibrillation and stroke has been suggested.
3. Denosumab (Prolia, Xgeva) is a monoclonal antibody with affinity for nuclear factor kappa ligand (RANKL).
a. Mechanisms. Osteoblasts secrete RANKL; RANKL activates osteoclast precursors and subsequent osteolysis. Denosumab binds to RANKL, blocks the interaction between RANKL and RANK (a receptor located on osteoclast surfaces), and prevents osteoclast formation.
b. Use. Denosumab is approved by the FDA for the treatment of osteoporosis in postmenopausal women (60 mg SQ every 6 months) and for reduction of skeletal-related events in patients with bone metastases from solid tumors (120 mg SQ every 4 weeks). The drug is not approved for myeloma. Dosage adjustment is not needed for renal impairment.
c. Adverse reactions include limb pain, rash, and ONJ. At 120 mg monthly dosing, hypocalcemia, hypophosphatemia, fatigue, headache, nausea, diarrhea, and dyspnea can also occur.
4. Criteria for response of bone metastases to therapy. The appearance of new osteoblastic lesions on radiographs or bone scans or increasing size of sclerotic lesions does not necessarily indicate progression of metastases. Indeed, these findings may represent clinical improvement. Although the response of bone metastases to treatment is difficult to quantitate, it may be evaluated by assessing the following:
a. Pain relief and quality of life
b. Serum tumor markers
c. Biochemical markers of bone resorption (e.g., urinary hydroxyproline excretion)
d. CT scans
e. PET is a promising but not yet validated technique to assess response of metastases to therapy.
5. Bracing of the vertebral column may help relieve pain and protect neurovascular structures while the lesions are resolving with radiation therapy (RT) or chemotherapy. Bony strength to resist gravitational forces must be adequate. Bracing of the lower extremities is seldom helpful.
F. Management with radiation
1. External beam RT ameliorates pain and may produce bone union and prevent fracture. The optimal dose of RT has not been defined. Smaller doses (e.g., 800 cGy given once) may be as effective as 2,500 to 4,000 cGy given over 2 to 4 weeks. This undoubtedly convenient, single or very short dose schedule, however, may not be adequate for patients with a relatively good prognosis.
a. Pathologic fractures. The administration of RT after orthopedic fixation of pathologic fractures is considered standard therapy. However, recent advances have indicated that this dictum may no longer be necessary in all cancer cases. After orthopedic fixation, the bone encompassing the entire prosthesis is typically included in the radiation portal. RT may begin as soon as the patient can be moved if the incision can be spared; otherwise, treatment is delayed until the skin has healed.
b. Isolated sites of bone pain. RT controls local pain from bony metastases in more than 80% of patients within 2 weeks to 3 months. Irradiating a few severely painful sites may reduce the analgesic dose needed to manage patients with multiple sites of pain.
c. Asymptomatic osteolytic lesions of the cervical spine and long bones are irradiated to prevent complications.
d. Hemibody irradiation is used by some centers for control of pain caused by bone metastases. The treatment is effective in about 60% of patients, but it is associated with gastrointestinal upset and hematosuppression, particularly transfusion-dependent anemia.
2. Radiopharmaceuticals, especially 89Sr (Metastron), can decrease pain for several months in about 75% of patients with skeletal metastases from breast or prostate cancer. Such agents are useful when endocrine therapy fails to control the disease (see Chapter 2, Section IV.B).
a. 89Sr is preferentially taken up and retained at sites of increased bone mineral turnover; uptake in bone adjacent to metastases is up to five times greater than for normal bone. This agent appears to provide effective adjuvant therapy to local-field RT with decreased new sites of pain, decreased need for further RT, decreased analgesic requirement, and improved quality of life.
b. Hematologic toxicity is the major precaution but is usually transient. Other agents (including 32P, 153Sm, and 186Re) generally are associated with more hematologic toxicity or have undergone fewer clinical trials than 89Sr.
c. Unfortunately, substantial numbers of patients achieve incomplete pain resolution, and some patients get no pain relief at all. None of the radiopharmaceuticals affects survival. Relatively few patients exhibit antitumor activity when treated with radiopharmaceuticals.
G. Surgical management. Surgery plays a crucial role in managing bony metastases that endanger neurologic function or ambulation. Surgery can usually be avoided when RT or chemotherapy is effective and adequate stability of the bone permits natural repair.
Orthopedic consultation should be obtained in all patients with metastatic lesions of the femoral neck or shaft or deemed to be at risk for impending or actual pathologic limb fracture. When considering operative treatment, the major factors include the patient’s general medical condition, functional goals, and comfort and quality of life; the anticipated responsiveness of the tumor to RT alone; the ease of delivering nursing care; and the morbidity of the contemplated procedure.
1. Methyl methacrylate, an acrylic bone cement, replaces deficient bone and greatly enhances the ability to use metal implants. It increases compressive strength and torque capacity, promotes hemostasis, and should be used with fixation devices whenever bone stock is inadequate to permit rigid fixation or implantation. The use of methyl methacrylate entails considerable potential for local complications, and the circulating monomer may be associated with intraoperative cardiac complications.
2. Complications. Surgical treatment for pathologic fractures is associated with an operative mortality rate of about 8% and an infection rate of about 4%. The risk for infection increases in previously irradiated sites and in immunocompromised patients. Common reasons for failure of internal fixation include poor initial fixation, improper implant selection, and progression of disease within the operative field.
3. Embolization. Blood loss during surgical stabilization or biopsy of a metastatic lesion may be life-threatening. Metastatic breast cancer, myeloma, and particularly renal cell cancers are notoriously hypervascular. Preoperative angiography and occlusion of feeding vessels, particularly for lesions of the acetabulum or spine, may be indicated. The embolization of vertebral lesions, however, is associated with a risk for spinal cord injury.
4. Rehabilitation. Patients treated surgically for pathologic fractures caused by metastases are good candidates for intensive rehabilitation programs unless they have hypercalcemia or require parenteral narcotics, which are associated with very short survival times.
5. Prognosis. In general, median survival is <1 year after surgical treatment of an impending or actual pathologic fracture. In one study of 299 patients treated with arthroplasty for metastatic disease of the hip, median duration of survival was 9 months, and only 40% of patients were alive 1 year after surgery. (see Schneiderbauer MM, et al. in Selected Reading)
H. Surgical management of the appendicular skeleton. The threshold to treat lower extremity lesions is lower than that for upper extremity disease due to the weight-bearing function of the legs and the increased mechanical load on the involved bone. However, lifting and pulling with the arms generate high distractive forces. In addition, patients with metastases to the lower extremities often require crutches or a walker, which generate high compressive loads in the bones of the arms. These issues must be factored into the decision of how to best treat an upper extremity (usually humeral) lesion.
1. Surgical methods for metastases to long bones of the limbs include the following:
a. Reinforcement of the involved bone with internal splints (bone plates, compression hip screws and side plates, intramedullary rods). Whenever possible, intramedullary fixation (nails or endoprostheses) is preferred over extramedullary fixation (plates) because the former results in smaller dissections, more durable fixation, and more rapid return to weight bearing. Newer less-invasive plating techniques can be used if plating is a viable option.
b. Removal of the metastatic tumor from the bone (either by surgical resection or by curettage), insertion of an internal fixation device or prosthesis, and supplemental fixation with bone cement
c. Reconstruction of the articular surfaces of the proximal humerus, hip, or knee after en bloc excision of involved segments of periarticular bone with either total joint arthroplasty or hemiarthroplasty. Arthroplasty is the best option if it is suspected that the patient’s life expectancy exceeds the longevity of the construct with intramedullary nailing or plating. Prosthetic arthroplasty is useful in the following circumstances:
(1) Reconstruction of large destructive areas that are not amenable to internal fixation
(2) Salvage of failed internal fixation devices
(3) Salvage of lesions in which there are no RT options to prevent disease progression
d. Amputation of dysfunctional extremities riddled with tumor in patients with intractable pain, reasonable life expectancy, and an absence of limb-sparing treatment options
2. Upper extremities. Small lesions involving the humerus that are unlikely to fracture and that are sensitive to RT may be treated successfully with nonoperative measures, including RT. Lesions that are larger and in patients using walkers or crutches may be best treated with prophylactic fixation or endoprosthetic replacement followed by RT.
Pathologic fracture of the humerus usually occurs at the junction of its proximal and middle thirds and in the past was often treated by stabilizing the extremity in a cast or sling. Internal fixation or prosthetic replacement is now the treatment of choice for these patients because the risk for nonunion and infection increases when surgery is performed on an irradiated limb, and pain relief is predictable with modern orthopedic techniques and radiotherapy.
3. Lower extremities: prophylactic orthopedic surgery. Prophylactic internal fixation, followed by RT to inhibit further tumor growth, is always considered in patients with osteolytic lesions in the femoral neck or shaft that are at risk for pathologic fracture. Prophylactic surgery should be considered in the following circumstances:
a. The patient is in good general medical condition.
b. The osteolytic lesion of the femur or tibia is >2.5 cm in diameter or involves more than half of the total cortical width (implies a 50% likelihood of fracture if untreated).
c. Spontaneous avulsion of the lesser trochanter has occurred.
d. Pain from osteolytic lesions persists despite RT.
4. Lower extremities: pathologic fractures. Untreated pathologic fractures rarely heal, and although RT may achieve local control, bony union remains unlikely. Internal fixation is indicated for pathologic fractures of the femur or tibia to decrease pain and to permit early ambulation.
a. Femoral head and neck fractures. Internal fixation may be considered but is usually inadequate. A long-stem cemented femoral hemiarthroplasty is safe, provides long-lasting relief from pain, permits early ambulation without the need for postoperative RT, and is preferred. Prosthetic replacement is particularly required if extensive cortical destruction would not allow a stable construction even with bone cement augmentation. If the articular cartilage and subchondral bone of the acetabulum are intact, an endoprosthesis is used. The complication rate is 20%. Insertion of long femoral stems with bone cement can create dangerous embolic loads, and some surgeons routinely vent the distal femur to minimize pressure within the medullary canal. Biologic porous ingrowth fixation is usually not indicated as protected weight bearing is difficult in debilitated patients and life expectancy may be short. In addition, RT interferes with ingrowth.
b. Intertrochanteric fractures. Modern intramedullary devices or sliding hip screws are usually preferred so that the entire femur is reinforced with a load-sharing device. Prosthetic replacement is considered if there is extensive bony loss; if pathologic fracture has developed slowly, resulting in extensive destruction; or if there is no possibility of obtaining structural stability. The complication rate, however, is substantial.
c. Subtrochanteric fractures are more difficult to repair because the fracture often extends into the intertrochanteric area or femoral shaft. The fractures are usually stabilized with a reconstruction nail with cementation as needed. Sliding hip screws are associated with a high frequency of implant failure. Extensive destruction may require the use of a modular oncologic or calcar-replacing prosthesis, but local morbidity is significant, and the ideal device to attach the abductor muscles to the prosthesis has yet to be devised.
d. Femoral shaft fractures require intramedullary fixation supplemented with interlocking screws and bone cement if there has been extensive cortical loss.
e. Lesions of the acetabulum may respond to chemotherapy, but they still leave the patient with a painful hip if subchondral collapse and deformity have already begun. Reconstructive surgery with total hip replacement is often beneficial in patients with reasonable life expectancy (e.g., those with breast cancer). This procedure is demanding because acetabular support and fixation may require the use of flexible Steinmann pins and bone cement in the superior ilium and across the sacroiliac joints to transmit the weight-bearing stresses to intact bone. A protrusio acetabulum ring is often needed to provide additional structural support.
I. Surgical management of the axial skeleton. The majority of patients that die of cancer have spinal metastases at autopsy. The majority of these lesions were asymptomatic. Thus, as cancer care evolves and life expectancy improves, symptomatic spinal metastases will become more common. Most cancer patients with mild mechanical instability of the spine and neck or back pain can be successfully treated with supportive medical care (e.g., chemotherapy, corticosteroids), bracing, and RT. Surgery is associated with a significant rate of complications (about 20%) but can be very important when the spine becomes unstable. Segmental spinal fixation systems use pedicle screws to attach rods to the posterior spine at multiple vertebral levels. Newer techniques use combinations of bone cement, allograft bone, and metallic implants (cages) to replace or supplement diseased vertebral bodies. Patients may get out of bed on the first postoperative day and typically require a custom-fitted, low-profile plastic orthosis.
Patients in whom spinal instability is likely to develop should undergo surgical stabilization before RT. Whenever possible, adjuvant RT should be delayed 3 to 6 weeks after surgery to minimize wound complications. As a generalization in the appropriate patient, surgical decompression and stabilization combined with RT are more efficacious than RT alone (see Patchell RA, et al. in Selected Reading).
1. Surgery for spinal metastases may be indicated in the following circumstances:
a. The diagnosis of metastatic cancer has escaped diagnosis at other sites. Percutaneous trocar biopsy may be necessary when needle biopsy fails to provide a diagnosis.
b. Mechanical instability from fracture causes pain and progressive deformity.
c. Pathologic fracture or tumor extension causes compression of the spinal cord or nerve roots.
d. A symptomatic tumor is known to be resistant to RT (e.g., renal cell carcinoma).
e. A spinal tumor continues to progress despite adequate RT.
2. Stabilization of the spine may not be indicated in the following circumstances:
a. Multiple osseous and soft tissue metastases exist.
b. More than two or three vertebrae are destroyed and need replacement.
c. The patient has poor nutritional, immunologic, or pulmonary status or severe disease not related to the malignancy.
d. Life expectancy is very limited (typically <3 months).
3. Cervical spinal metastases often require radiation therapy regardless of symptoms and immobilization of the head and neck. A soft cervical collar is the least uncomfortable method but should be used only in patients with minimal disease. A rigid collar-like brace is adequate support if there is some intrinsic stability.
As in the thoracic and lumbar spine, metal implants to replace vertebral bodies anteriorly, and screws into the pedicles or lateral masses posteriorly, can restore spine and spinal cord integrity. In patients with severely limited life expectancy, in lieu of major surgery, the head can be immobilized with a special halo device and placement of screws into the skull. These prosthetic devices are often used until the patient succumbs.
4. Thoracolumbar spinal metastases
a. Painful lesions may require RT. MRI should be done first to search for potential sites of epidural compression and to map out radiation fields. Many patients have a soft tissue mass extending around the involved vertebrae. These masses compress nerves, contribute to pain, and should be included in the radiation port. Fiberglass braces and corsets may reduce back pain and help stabilize the spine.
b. Rapidly progressive metastases that are refractory to RT may manifest by increasing pain, worsening destruction on radiographs, or the development of neurologic deficits. Open decompression of the spinal cord and internal fixation to permit early mobility (1 to 3 weeks) should be considered, but the outlook for these patients is poor.
5. Spinal decompression
a. Laminectomy provides direct access to posterior and posterolateral tumors but compromises the stability of the spine. Spinal cord compression is usually a result of tumors of the vertebral body (i.e., anterior to the spinal cord); thus, laminectomy does not reliably relieve symptoms. Below the level of the third cervical vertebra, laminectomy should only be used for lesions in the dorsal elements, laminae, and pedicles.
b. Anterior surgical decompression of the spinal cord is performed using thoracotomy or laparotomy, especially for RT-resistant tumors (e.g., renal cell carcinoma). Anterior decompression involves the removal of the vertebral body and all tumors anterior to the spinal cord (vertebrectomy). The spinal column is reconstructed with a graft or cage, and posterior stabilization with rods and pedicle screws is also usually needed. Custom-shaped methyl methacrylate in combination with plates can be used to supplement fixation; bone grafts are preferred in patients when life expectancy exceeds 6 months because any purely mechanical construct will eventually fail if there is no bony healing. The anterior route provides immediate mechanical stability and the best chance for neurologic improvement. The associated success rate is reported to be 75% to 90%, with less blood loss and fewer complications than with laminectomy.
c. Posterolateral surgical decompression is an alternative for the technically difficult lesions above the sixth thoracic vertebra and is useful in more debilitated patients. Patients are able to sit in a chair on the night of surgery and to begin walking the next day.
(1) Posterolateral decompression removes a part of the rib and lamina to gain access to the vertebral body and decompress the anterior aspect of the spinal cord from the side. After completing vertebrectomy and removing the disks, the surgeon inserts a vertical strut (graft or cage) between the end plates of the healthy vertebrae above and below the tumor site. Posterior fixation rods, which can be placed through the same incisions, provide immediate stability.
(2) The advantage of this approach is that it does not require thoracotomy. Posterior spinal instrumentation can be carried out at the same time as tumor removal, often with video-assisted endoscopic techniques. This procedure may reduce patient morbidity, days in intensive care, and days of hospitalization while providing the same quality of neurologic recovery and maintenance of function as anterior resection. Access to the tumor, however, is usually limited because the surgeon is working around the spinal cord. Neurologic recovery has been less reliable than with a formal anterior approach.
6. Percutaneous vertebroplasty and balloon kyphoplasty are minimally invasive procedures consisting of the percutaneous injection, under fluoroscopic guidance, of methyl methacrylate into a diseased vertebral body. These procedures have been most commonly used to treat osteoporotic compression fractures, but experience in treating myeloma and metastatic carcinoma has been accumulating. Unlike vertebroplasty, the kyphoplasty procedure uses a balloon to restore vertebral height and compress both cancellous bone and tumor before injecting the cement. Both procedures can be done quickly, have been shown to lead to very rapid and sustained reduction in back pain for patients with vertebral compression fractures or metastases, and are associated with low surgical risk and minimal morbidity.
a. Contraindications. Vertebroplasty and kyphoplasty are contraindicated in presence of epidural compression or severe involvement of the posterior vertebral body adjacent to the spinal canal.
b. Cement extrusion is the most frequent complication, generally asymptomatic, and usually harmless. The leakages range from asymptomatic damage of the surrounding tissue to nerve irritation through compression of nerve roots. Significant complications of these procedures are few as long as they are used in patients without contraindications.
c. Methyl methacrylate pulmonary emboli, one of the most serious potential complications, are estimated to occur in 3% to 23% of patients depending on whether patients are evaluated with a plain chest radiograph or CT. This risk appears to be higher with vertebroplasty than with kyphoplasty. Asymptomatic peripheral embolisms predominate and require no therapy. Symptomatic emboli to the pulmonary arteries are treated with warfarin for 6 months, which appears to stop the progression of the foreign body–induced thrombotic occlusion while the cement theoretically becomes endothelialized. Open thoracic thrombectomy as well as percutaneous vascular retrieval have been used in cases of acute life-threatening cardiopulmonary compromise.
II. OCCURRENCE OF CANCER IN CONNECTIVE TISSUE DISORDERS. The associations of rheumatic conditions with the development of malignancies probably reflect immune dysregulation, chronic immune stimulation, and the use of immunosuppressive drugs in their treatment.
A. Sjögren syndrome is associated with a 44-fold increased risk for non-Hodgkin lymphoma (NHL), particularly of the monocytoid B-cell type. An intermediate stage of “pseudolymphoma” may persist for years.
B. Dermatomyositis and polymyositis. Various kinds of malignancy develop in about 25% of patients with these disorders, particularly dermatomyositis. The cancer may present at the time of diagnosis or at a significantly later time. Thus, an extensive radiographic or invasive search for malignancy at the time of diagnosis is not recommended.
C. Rheumatoid arthritis (RA) is associated with a fourfold increased incidence of malignancies (which are usually lymphoproliferative disorders) in the United States and an increased risk for oropharyngeal carcinomas in Japan. Felty syndrome, which has been extended to include the presence of increased numbers of circulating CD16-positive large granular lymphocytes, is associated with a 13-fold increased occurrence of NHL. The use of cytotoxic agents is believed to be involved in the pathogenesis of malignancies in RA, but patients have developed cancer without such exposure.
D. Scleroderma with pulmonary fibrosis has previously been reported to be associated with bronchoalveolar cell carcinoma, but this association has not been observed in more recent series. Fibrosing disorders that resemble scleroderma and are associated with a significant risk of malignancy include the following:
1. Palmar fibromatosis (or fasciitis) with inflammatory polyarthritis is a rare syndrome accompanied by thickening of the palmar fascia, which can progress to Dupuytren contracture. The syndrome can precede recognition of the malignancy by several months and is most often associated with ovarian carcinoma.
2. Reflex sympathetic dystrophy syndrome shows several clinical features of the palmar fasciitis syndrome and is associated with Pancoast tumor when it affects the upper extremities and with gynecologic tumors when it affects the lower extremities.
E. Vasculitis
1. Cutaneous leukocytoclastic vasculitis is the form of vasculitis that is most strongly associated with coexistent malignancy, including both hematopoietic neoplasms and solid tumors.
2. Systemic necrotizing vasculitis is associated with hairy cell leukemia, which is also associated with a high occurrence of polyarteritis nodosa.
3. Sweet syndrome (acute febrile neutrophilic dermatitis) is associated with malignancy in 15% of cases, usually acute leukemia. Fever, leukocytosis, and a characteristic eruption of painful, erythematous papules on the head, neck, and upper extremities compose the syndrome.
4. Erythema nodosum, a variety of panniculitis, is associated with Hodgkin lymphoma and leukemia.
5. Mixed cryoglobulinemia is associated with hepatocellular carcinoma, NHL, and hepatitis C virus infection.
F. Other connective tissue diseases
1. Systemic lupus erythematosus. About 5% of patients develop malignancies, usually NHL and probably related to the use of immunosuppressive drugs.
2. Polyarthritis or symptoms that mimic polymyalgia rheumatica, which may be the presenting manifestation of the malignancy. Patients with polyarthritis are generally older than those with RA, have asymmetrical arthritis, an explosive onset, and are rheumatoid factor negative. Patients with myelodysplastic syndromes sometime develop polyarthritis that may be confused with seronegative RA.
3. Lymphatoid granulomatosis affects the lungs and may result in NHL.
4. Gout. Two-thirds of patients with myeloproliferative disorders have hyperuricemia and hyperuricosuria. The occurrence of acute gouty arthritis in these patients has been markedly reduced with the routine prescription of allopurinol prophylactically.
III. PARANEOPLASTIC, INFILTRATIVE, AND TREATMENT-RELATED BONE AND JOINT CONDITIONS
A. Hypertrophic osteoarthropathy (HOA) is manifested by clubbing of the fingers, pain and effusion in large joints, and periostosis of tubular bones. The ankles, knees, elbows, and wrists are the most frequently involved joints. The extremely painful periosteal reaction usually involves the extensor surfaces of the legs and forearms. The change in the overlying skin resembles cellulitis with induration, erythema, and peau d’orange.
1. Associated tumors. HOA develops most frequently with lung adenocarcinomas, less frequently with other lung carcinomas, and occasionally with gastrointestinal adenocarcinomas and intrathoracic sarcomas.
2. Benign causes of clubbing include hereditary HOA (Touraine-Solente-Gole syndrome), cyanotic congenital heart disease, lung abscess, bronchiectasis, tuberculosis, endocarditis, biliary cirrhosis, Crohn disease, and arterial vascular prosthesis infections.
3. Diagnosis. Clubbing should be self-evident; patients should be questioned about the duration of the abnormality. Sponginess, by palpation, of the proximal nail beds may indicate early clubbing. Radiographs of painful joints or long bones often show periosteal reactions.
4. Therapy. Control of the associated tumor usually alleviates symptoms of HOA. The pain can be relieved by a variety of nonsteroidal anti-inflammatory drugs (NSAIDs). Pamidronate and zoledronic acid have been reported to be effective. Patients with severe pain may require narcotic analgesics.
B. Other paraneoplastic rheumatic syndromes
1. Pachydermoperiostosis associated with lung cancer consists of a dense over-growth of periosteum resulting in clubbing and leonine facies (see Chapter 28, Section II.M).
2. Joint pain, subcutaneous fat necrosis (panniculitis), and eosinophilia occasionally constitute the presenting features of pancreatic cancer.
3. Hypercalcemia and hypocalcemia (see Chapter 27, Sections I.A and II.A)
4. Myelodysplastic syndromes are associated with a variety of phenomena of suspected autoimmune pathogenesis. Among the rheumatic manifestations are monoarticular arthritis, relapsing polychondritis, Raynaud phenomenon, Sjögren syndrome, and vasculitis.
C. Rheumatic manifestations that suggest an occult malignancy. No distinguishing features of rheumatic syndromes define the coexistence of cancer. Manifestations may improve or disappear with therapy directed at the malignancy. The following syndromes should strongly suggest a thoughtful search for malignancy, particularly if they first occur at ≥50 years of age.
1. Explosive seronegative polyarthritis presenting with swollen and tender joints, with a predilection for the lower extremities sparing the small joints and wrists, and with mild nonspecific synovitis identified by synovial biopsy
2. Monoclonal gammopathy in a patient with typical rheumatoid arthritis
3. Palmar fasciitis and polyarthritis
4. Eosinophilic fasciitis unresponsive to steroidal therapy
5. Raynaud phenomenon (often with asymmetric involvement of the fingers and progression to necrosis)
6. Cutaneous leukocytoclastic vasculitis
D. Direct infiltration of malignancy into articular tissues
1. Sarcomas can present as primary malignancies of any joint.
2. Metastases can affect any joint and mimic inflammatory arthritis.
3. Acute leukemic arthritis is caused by leukemic infiltration of synovium. It is usually symmetric and may resemble rheumatic fever or juvenile rheumatoid arthritis. Effusions may occur. In 25% of cases, adjacent bone may develop osteolytic lesions, osteoporosis, or osteoblastic changes. Brief symptomatic responses can be obtained with ibuprofen or aspirin. Treatment of the underlying leukemia resolves with arthritis.
4. Chronic leukemic arthritis is uncommon; it is usually symmetric but is otherwise similar to the acute type both in radiographic patterns and in response to therapy.
5. Myeloma-induced amyloidosis produces carpal tunnel syndrome and, rarely, a rheumatoid arthritis–like syndrome. Synovial tissues may be densely infiltrated with myeloma cells.
IV. ADVERSE EFFECTS OF RADIATION TO BONE
A. Radio-osteonecrosis of the mandible may complicate RT of head and neck cancers. The problem occurs more often in patients with large tumors, bone invasion, history of large alcohol intake and heavy smoking, poor dentition, poor oral hygiene, and poor nutritional status. The mandible becomes brittle and superinfected, resulting in pain, fractures, and draining fistulas.
1. Diagnostic criteria
a. Localized pain and tenderness
b. Mucosal ulceration or necrosis (occasionally, a fistula) with exposure of bone and, occasionally, cutaneous fistulas
c. Loose teeth in the suspected area
d. Radiographs showing a osteolytic lesion of the mandible, sometimes with a radiodense sequestrum or involucrum
e. Manifestations should not be clinically evident for at least 4 months after completion of treatment.
2. Prevention of radio-osteonecrosis involves proper dental extractions before RT and oral hygiene and fluoride treatment regimen during and after RT. If possible, the patient should not have any dental extractions for 2 years after RT. Even with these precautions, osteonecrosis develops in 5% to 10% of patients when a high-dose RT portal overlies the mandible.
3. Treatment
a. Conservative management
(1) Frequent mouthwashes with dilute hydrogen peroxide or a baking soda and salt solution
(2) Systemic antibiotics, usually penicillin; topical nystatin or bacitracin ointment
(3) Gentle débridement
b. Aggressive management
(1) Hyperbaric oxygen treatments
(2) Surgical resection of the nonviable portion of the mandible
(3) A combination of hyperbaric oxygen and surgical resection
B. Radiation osteitis may mimic bony metastases. Differentiation of these disorders is discussed in Section I.D. Postirradiation pathologic fractures of the femoral neck may rarely complicate pelvic irradiation.
C. Radiation-induced bone sarcomas have been reported after high-dose irradiation of both benign and malignant lesions. The incidence is <0.1% of all 5-year survivors; the latent period is >5 years.
D. Premature closure of bone epiphyses and apophyses can result in shortening, kyphosis, and asymmetry of osseous structures in children who have received RT.
E. Soft tissue radiation injury depends on dose and those structures which are encompassed by the radiation fields directed to the bony site. Bone marrow injury by RT is discussed in Chapter 34, Section I.D in “Cytopenia.”
F. Hypothyroid myopathy. Myalgia, stiffness, and elevation of serum creatine kinase following external neck irradiation may be the result of radiation-induced hypothyroidism. These symptoms may follow radiation therapy by months or even years.
V. RHEUMATIC DISORDERS RELATED TO CHEMOTHERAPY FOR MALIGNANT DISEASE
A. Aseptic necrosis of the hip is a complication of high doses of glucocorticoids. The risk is proportional to the dose of drug and not to the duration of therapy. Increased pressure in the intramedullary space causes the sudden onset of hip pain. Capsular irritability is demonstrated by flexing the hip and medially rotating the thigh. Early diagnosis is best established by MRI. Radionuclide bone scan is the diagnostic test of second choice. Removal of bony cores from the necrotic areas predictably, if incompletely, relieves pain and may favorably alter the natural history of osteonecrosis if done before the occurrence of secondary changes, such as collapse of subchondral bone and articular cartilage.
B. Postchemotherapy rheumatism is a syndrome of myalgias and arthralgias that usually develops within 1 to 3 months after completing adjuvant chemotherapy for breast cancer. Mild periarticular swelling occurs in some cases. NSAIDs are not effective. Symptoms are self-limiting and generally resolve over several months. Extensive workups for breast cancer recurrence or for inflammatory rheumatologic disease are not needed in this setting.
1. Arthralgias associated with taxanes (paclitaxel and docetaxel) usually begin 2 to 3 days after treatment and resolve within 5 days. However, myalgia and arthralgia are sometimes severe.
2. Arthralgias associated with hormonal therapy occur frequently in patients being treated with aryl aromatase inhibitors (anastrozole, letrozole, exemestane) for breast cancer. Arthralgia and subjective joint stiffness are common complaints, occurring in up to 40% of women who are being treated with one of these agents. The problem often is not solved by changing agents within that class of drugs and may lead to discontinuance of such therapy. Arthralgias have also been reported in patients treated with tamoxifen but to a lesser extent and severity. These occurrences remain significant because long-term treatment is affected by their development.
3. Bleomycin. Cases of scleroderma and Raynaud phenomenon have been noted in association with the use of bleomycin.
C. Raynaud phenomenon is a common toxicity of treatment with cisplatin, oxaliplatin, vinblastine, or bleomycin.
D. Osteoporosis. Many therapeutic regimens in cancer treatment carry the risk of promoting osteoporosis. Therapies involving corticosteroids or causing hypogonadism, including androgen-deprivation therapy and aromatase inhibitors, are the most common causes. Cytotoxic drugs that have been implicated in the development of osteoporosis include methotrexate and ifosfamide. The risk of osteoporosis should be assessed with osteodensitometry when indicated. Treatment with hormone replacement, calcium with vitamin D, bisphosphonates, and/or denosumab can be considered when appropriate. Use of high-dose glucocorticoids is also associated with an increased risk of developing osteonecrosis (avascular necrosis of bone).
E. Bisphosphonates. Musculoskeletal pain, occasionally severe, occurs rarely with the use of these agents. Use of bisphosphonates has been associated with ONJ (see above). Furthermore, “atypical fractures” (transverse femoral fractures and metatarsal stress fractures) have been observed with long-term bisphosphonate use in patients both with and without cancer.
Suggested Reading
Bauer HCF. Controversies in the surgical management of skeletal metastases. J Bone Joint Surg Br 2005;87:608.
Berenson J, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol 1998;16:593.
Berenson J, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicenter, randomized controlled trial. Lancet Oncol2011;12:225.
Carsons S. The association of malignancy with rheumatic and connective tissue diseases. Semin Oncol 1997;24:360.
Coleman RE, et al. Zoledronic acid use in cancer patients. More than just supportive care? Cancer. 2011;117:11.
Dougall WC, Chaisson M. The RANK/RANKL/OPG triad in cancer-induced bone diseases. Cancer Metastasis Rev 2006;25:541.
Filleul O, Crompot E, Saussez S. Bisphosphonate-induced osteonecrosis of the jaw: a review of 2,400 patient cases. J Cancer Res Clin Oncol 2010;136:1117.
Fizazi, K, et al. A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol 2010; 28:951s.
Ito T, et al. Hypertrophic pulmonary osteoarthropathy as a paraneoplastic manifestation of lung cancer. J Thorac Oncol 2010; 5:976.
Krueger A, et al. Management of pulmonary cement embolism after percutaneous vertebroplasty and kyphoplasty: a systematic review. Eur Spine J 2009;18(9):1257.
Lipton A. Treatment of bone metastases and bone pain with bisphosphonates. Supportive Cancer Therapy 2007;4:92.
Loprinzi CL, Duffy J, Ingle JN. Postchemotherapy rheumatism. J Clin Oncol 1993;11:768.
Naschitz JE, Rosner I. Musculoskeletal syndromes associated with malignancy (excluding hypertrophic osteoarthropathy). Curr Opin Rheumatol 2008;20:100.
Patchell RA, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005; 366:643
Pelton WM, et al. Methylmethacrylate pulmonary emboli: radiographic and computed tomographic findings. J Thorac Imaging 2009;24:241.
Schneiderbauer MM, et al. Patient survival after hip arthroplasty for metastatic disease of the hip. J Bone Joint Surg Am 2004;86-A(8):1684.
Smith MR, et al Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009; 361:745.