Metastatic Disease of Extremity
Dr. KS Dhillon
INTRODUCTION
Bone is the third most frequent site of metastatic disease. Primary tumors from the lung, breast, prostate, kidney, and thyroid are the most common cause of bone metastases (1). The primary presentation is pain and pathological fracture in 9%–29% of the cases. About 90% of pathological fractures require intervention (2,3). The orthopedic treatment of these bone metastasis significantly impacts both quality of life and probably survival rates (4).
Extremity bone metastases accounts for 66% of skeletal metastasis. Extremity metastases are one of the first presentations of disease in lung cancer, myeloma, renal cancer, and lymphoma (5). The median survival from diagnosis is 6 months in melanoma, 6–7 months in the lung, 6–9 months in the bladder, 12 months in the renal, 12–53 months in the prostate, 19–25 months in the breast, and 48 months in the thyroid carcinoma. The treatment involves a multidisciplinary team which includes an orthopedic surgeon, radiologist, orthopedic oncologist, radiation oncologist, medical oncologist, and other health-care personnel. The treatment varies on the specific site of involvement.
MECHANISMS OF METASTASIS TO BONE
Bone metastasis commonly involves the axial skeleton and they present at multiple sites (3). This could be related to the hematopoietically active red bone marrow and the paravertebral network that may play a role in metastasis (5). Apart from the favorable microenvironment for tumor cell survival, the following are needed once the tumor cells are in circulation (3-7).
Extravasation and adhesion to vascular tissues
Microenvironmental support: As per the seed-and-soil hypothesis, for the growth and survival of cancer cells, the fertile ground is provided by the microenvironment
Epithelial-mesenchymal transition: When the normal epithelial cells lose their epithelial features and transform into mesenchymal cells, they can migrate into new environments. This process of epithelial-mesenchymal transition occurs during embryogenesis. When the cancer cells undergo this transition, they transform into an invasive phenotype.
PRESENTATION AND EVALUATION
A complete workup must precede surgery when there is a pathological fracture (8). It can be the first sign of an unknown primary or it can be seen in cases with an established primary diagnosis. In cases where there is an established primary, the diagnosis of a second primary bone tumor as a differential diagnosis should be considered. Clinical features of multiplicity and typical axial presentation point toward bone metastases. A biopsy should be done to confirm the diagnosis before planning any intervention.
A painful solitary bone lesion without a history of metastatic disease or a primary malignancy needs a more extensive metastatic workup which includes laboratory investigations and imaging before the biopsy. Some of the commonly used laboratory investigations include β2- microglobulin, urine for Bence–Jones proteins and serum electrophoresis for multiple myeloma, CA-125 for ovarian cancer, prostate-specific antigen (PSA) for prostate cancer, CA-19.9 for pancreatic and biliary tumors, CA-15.3/CA-27.29 for breast cancer, carcinoembryonic antigen for colorectal and breast cancer, and calcitonin for medullary thyroid cancer.
Imaging includes X-rays, bone scan, computerized tomography scan (CT), magnetic resonance imaging (MRI), and fluoride/fluorodeoxyglucose-positron emission tomography (PET) scan. Imaging may reveal an easier to access biopsy site or show the tract for a percutaneous biopsy (9). The possibility of bone sarcomas should be kept in mind in cases with a history of prior radiation exposure such as Paget's disease and fibrous dysplasia. The survival and final management depends on the primary tumor.
SURVIVAL PREDICTION
Irrespective of the primary tumor, the presence of skeletal metastases, visceral metastases, and multiplicity is associated with poor prognosis (10-12). The prognosis in patients with metastatic bone disease depends on several factors. For metastasis arising from breast cancer, the extraosseous disease, estrogen receptor status, age, disease-free interval, performance status, and histologic grade play a role in prognosis. In skeletal metastatic prostate cancer, the performance status, extraosseous disease, fall in alkaline phosphatase, and PSA levels are well-approved prognostic factors (13).
In multiple myelomas, β2- microglobulin and C-reactive protein are the main independent prognostic factors. The median survival is 6 months for those with high levels and 54 months for those with low levels (14).
Using predictive models like the Bayesian Belief Network (15), a patient's survival can be predicted which helps in deciding the final treatment plan. The clinical data can be used to calculate survival at 3 and 12 months. For patients with survival of less than 3 months, surgical treatment is not recommended. Those with 3–12 months of survival may require less invasive procedures without long rehabilitation. For those with more than 12 months of survival, a more durable reconstruction method is recommended (16).
Bauer reported that the overall survival of those who underwent fixation for pathological fracture was less than 6 months and was similar to those who received radiotherapy (RT) for bone pain (8,17). The incidence of solitary metastases is lower compared with those with multiple metastases. Solitary metastases have a better prognosis than those with multiple metastases (18,19).
The incidence and median survival of various primary malignancies with skeletal metastasis is as follows:
Mechanical strength prediction
Prediction of mechanical strength and the risk of pathological fracture are considered to be important variables for decision-making when treating bone metastases. Mirel's scoring system is the most commonly used system to predict the risk of pathological fracture (20). The risk of a pathological fracture was 33% for a patient with a score of 9, 15% for a patient with a score of 8, and 4% for a patient with a score of seven. Excessive pain is one of the most significant indicators of an impending pathological fracture. Sometimes plain radiography alone is not diagnostic or a predictor of impending fracture. There is significant pathological fracture risk when more than 50% of trabecular bone is destroyed as seen on X-rays. Lesser trochanter avulsion indicates an impending hip fracture (21). CT rigidity analysis (CTRA) is a new method of predicting the pathological fracture probability. The density of the bone and the cross-sectional area at the maximal weakness point are recorded to estimate bending, torsion, and axial rigidity. Then the data are compared with a gender and size-matched normal femur CT. Reduction in axial, bending, or torsional rigidities of more than 35% are considered a significant risk for fracture (22).
MANAGEMENT
Skeletal metastases are rarely an emergency. The aim of treatment would be to get the patient back to their previous activity level. The following are the treatment strategies available:
Medical management
Radiotherapy (RT)
Surgery.
Medical management
The most common debilitating symptom of malignancy is pain. It has a significant impact on daily activity and social life. Pain can be due to osteoclast activation, nerve compression, substances produced by tumor cells, and inflammatory reactions due to tumor growth and invasion into surrounding tissues. Pain management includes the use of opioids, bisphosphonates, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, RT, and surgical management (23).
With metastasis, osteoclast activation has an essential role in the destruction of bone. Receptor-activated nuclear factor kappa-B ligand (RANKL) attracts tumor cells into the bone. It produces more RANKL (24). This increase in osteoclasts leads to accelerated bone destruction. Bisphosphonate therapy is commonly used to reduce morbidity among patients with skeletal metastases. They benefit the patient by only 30%–40%. They can produce complications such as osteonecrosis of the jaw. Intravenous administration may be required (25).
Denosumab is a monoclonal antibody against RANKL. It has shown improved efficacy in blocking osteoclast formation and osteoclast-mediated bone destruction (26). It is administered subcutaneously and is not excreted through the kidney. This is an advantage for patients with chronic kidney disease. It was reported that Denosumab was superior to zolendronic acid in relation to reduction of the skeletal-related events. The quality of life, pain, and overall survival are similar for both the drugs. Bisphosphonates have an additional antitumor action which may add to survival, especially in patients with breast cancer (26).
Radiotherapy (RT)
RT is often used for pain relief in bone metastases. There are reports of complete pain relief in one-third of the patients. More than 50% of the patients have pain relief beyond 6 months (27). Short-course regimen with 8 Gray (Gy) as a single fraction dose is as effective as the long-course RT regimens. Jeremic et al (28) compared short-course RT regimens (4 Gy vs. 6 Gy vs. 8 Gy) and found that 8 Gy is the “lowest” optimal single fraction.
Hartsell et al (29) compared the 8 Gy in a single fraction with 30 Gy in 10 fractions in 898 patients. They found that the results were comparable with regard to pain and narcotic relief. The risk of pathologic fracture was 4% in the 30-Gy group and 5% in the 8-Gy group. The 8-Gy group had a retreatment rate that was higher than the 30-Gy group (18% vs. 9%, P < 0.001).
The protective role of RT from pathological fractures has not been properly defined. A comparison between the outcomes of the surgical fixation of pathological fractures with or without RT has been done. It was concluded that postoperative RT is the only significant predictor for a successful outcome (30).
RT is started within 2 weeks following surgery and it covers the entire operative field and the whole length of the implant (31). The role of RT is limited in cases with endoprosthesis. One study reported poor bone remodeling distal to the prosthesis and less new bone formation around the prosthesis (32).
Surgical management
Surgical treatment can include intralesional curettage, marginal excision, or wide excision, depending on the aim of the intervention. Preoperative embolization can be carried out while dealing with vascular tumors such as skeletal metastases from renal cell carcinoma or to facilitate en bloc excision. Solitary lesions are treated with curative intent with added emphasis on pain control and functional recovery.
When reconstruction is done the general rule is to protect the whole length of the bone to avoid failure in cases of recurrence. Nailing, plating, or endoprosthesis can be used. There are maximal benefits in metastatic fixations when locked compression plates are fixed using minimally invasive techniques. Locked plates reduce the risk of pullout or loosening. There is reduced postoperative morbidity due to the minimally invasive approach (33).
Instead of allografts and biological cement types, bone cement is used for augmentation of the fixation since the lesion is not expected to heal. Bone cement allows early weight bearing (34). It also improves postoperative pain and function (35).
Intramedullary nailing can be done for lesions involving the diaphysis. Titanium nails have improved mechanical strength and smaller diameter. Repair or reconstruction of the capsule and reattachment of surrounding soft tissue to the implant should be done so that there is good functional strength, range of movement, and joint stability. Fifteen to twenty percent of the patients treated with surgery will have disease progression and loss of fixation, hence postoperative radiation is recommended (30).
Pelvis
The pelvis was classified into three distinct zones by Enneking (36). Zone 1 and 3 are nonweight bearing and the bone is expendable. Lesions involving Zone 2 alone or in combination with adjacent bones require curettage with cementing or reconstruction with custom-made prosthesis, or total hip replacements (37). In lesions requiring resection of Zone 2 and 3, an inverted ice cream cone prosthesis or pedestal cup is used (38).
Lower limb
The proximal femur is the most common site for bone metastases. It involves a significant risk of mechanical failure, hampering the quality of life. For lesions involving the neck and head of the femur, the choice of treatment is typically a bipolar hemiarthroplasty with a long stem. For lesions involving the acetabulum or trochanteric and peri trochanteric regions, endoprosthesis provides the best results. This allows early weight bearing and return to function with a lower failure rate (38,39).
For tibial and femoral diaphyseal lesions, curettage and cementing with nailing can be carried out. To avoid failure due to recurrence in the femoral neck, reconstruction nails that span the entire length of the bone can be used (9). In lesions involving the proximal tibia and distal femur, composite total knee replacement can be done. For lesions involving the proximal tibia, the management principles are essentially similar to the femur. It depends on the size of the lesion varying from curettage to resection and megaprosthesis (40).
Upper limb
After the proximal femur, the humerus is the second most common site of long bone metastases. Mechanical stress on the humerus is far less than that on the lower limb. That is why humeral bone metastases can be managed nonoperatively by external beam irradiation (30). Proximal humerus hemiarthroplasty can be used in patients with lesions involving the neck or proximal humeral head provided the greater tuberosity, lesser tuberosity, and axillary nerve are intact. In large lesions involving the proximal half of the humerus proximal humerus endoprosthesis or nail cement spacer with meshplasty can be done. Soft-tissue repair to prevent subluxation of the humeral head (41). For lesions that extend 2–3 cm distal to the greater tuberosity and 5 cm proximal to the olecranon fossa, intramedullary nailing can be done. Distal humeral metastases can be managed with plating and cement augmentation. If the lesions are large and involve the elbow joint, total elbow replacement can be done. Segmental defects of long bones can be treated with a nail cement spacer. Irrespective of the treatment method more than 90% of patients with humeral metastases have pain relief and functional restoration for activities of daily living. They have restricted range of movements of the shoulder with normal functioning of the elbow and wrist joints (42). Scapular lesions can be treated by a total or partial scapulectomy, depending on the extent of involvement. The forearm is an uncommon site for metastasis which may require resection of the bone.
Minimal invasive modalities
Radiofrequency ablation, cryoablation, high-intensity focused ultrasound, and microwave therapy are percutaneous modalities that can be used to relieve pain and improve bone strength without additional risk of morbidity from open surgery (43,44). For lesions involving the pelvis cementoplasty plays a vital role. They help prevent fractures and provide significant pain relief and functional improvement in 80% of cases (45). Angioembolization can produce devascularization and tumor necrosis (46). Embolization along with antimitotic agents such as adriamycin and platinum, prolongs the analgesia and can produce partial-to-complete tumoral remission (47).
CONCLUSION
Adequate work-up and a biopsy are required to confirm the diagnosis of extremity metastasis. The management involves a multidisciplinary approach. It depends on the primary tumour as well as the expected survival. The aim of treatment ranges from pain relief by medical management or radiotherapy and curative intent in patients with solitary metastases. The final aim is to improve the patient's quality of life.
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