Metastatic Bone Disease Treatment & Management

Most patients with metastatic bone disease should be cared for in conjunction with a medical oncologist and the use of radiation oncology. Because the lifespan of patients with metastatic bone disease is limited, the goal of management must center on returning as much function as possible as rapidly as possible.

For an isolated lesion, proceed with therapy on the assumption that it is a primary tumor (sarcoma) until there is proof to the contrary. This helps to avoid complications, such as the placement of an intramedullary nail through a primary sarcoma of the proximal femur. In general, skeletal sarcomas have a bimodal distribution, with a peak in childhood and adolescence and a smaller peak in the elderly population (the same population in which metastatic disease is common).

Osteoclastic bone resorption can be modified by bisphosphonates; these substances are presently being used in the management of metastatic breast carcinoma and multiple myeloma. ^{[1, 26]} Future research and modification of RANK ligand (RANKL) is expected to produce additional substances that can further arrest or retard bone destruction by metastatic disease.

Image-guided percutaneous cryoablation is a lasting, safe, and effective treatment for the alleviation of painful metastatic tumors involving bone. In a study of 61 adult patients with one or two painful bone metastases (Brief Pain Inventory score ≥4 in a 24-hour period) who had refused or who had had ineffective conventional treatment, pain scores decreased significantly at 1, 4, 8, and 24 weeks following percutaneous image-guided cryoablation. ^[27] Of the 61 patients treated with this procedure, only one had a major complication (osteomyelitis at the ablation site).

Intriguing research has been conducted in the area of angiogenesis inhibition. At present, such efforts are being directed at patients with gastrointestinal (GI) tumors. There is a need for additional research in the areas of combined large-vessel embolization and microscopic angiogenesis inhibition.

Research has suggested that microRNAs (miRNAs) play a role in metastatic bone disease and may prove clinically useful for both diagnostic and therapeutic purposes. ^[28]

Patients with myeloma, leukemia, or metastatic carcinoma may have anemia, thrombocytopenia, and leukopenia secondary to chronic disease and marrow replacement. If liver disease, metastatic or otherwise, is present, then a coagulopathy may be present as well.

Perioperative resuscitation with appropriate factors and cellular elements is essential. With predisposition for thrombosis, provide prophylaxis against deep vein thrombosis (DVT) and pulmonary embolism (PE).

Treat patients with hydration and bisphosphonates or denosumab. ^{[26, 29]} Hypercalcemia is common in these individuals.

When a bony site displays radiographic and clinical evidence of an impending or already completed pathologic fracture, surgical stabilization is indicated. Most current literature supports the prophylactic fixation of impending fractures. Waiting for an impending fracture to occur increases morbidity and mortality and affects the patient's ability to regain function in as short a time as possible.

Radiation therapy remains a primary therapeutic modality for the treatment of spinal metastasis. Nearly 95% of patients who are ambulatory at the start of radiation therapy remain so. Patients who start with limited ambulatory neurologic function have a 60% chance of improvement after radiation therapy. In those persons who have lost sphincter function, the chance of regaining it is no greater than 40%.

The point is that the odds of regaining cord function once it is lost as a result of spinal metastasis are dismal. Every effort must be made to prevent such loss through early diagnosis, nonoperative treatment, and, if indicated, surgical intervention.

The efficacy of radiation therapy is dependent on the radiosensitivity of the tumor. The presence of bone in the spinal canal or of a circumferential epidural tumor limits the success of management with radiation therapy alone. Patients with these conditions and cord compromise have been shown to experience improved outcomes with radical tumor resection and internal fixation/stabilization.

In a multicenter randomized trial involving 1404 patients with at least one breast cancer metastasis to bone and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, treatment with intravenous (IV) zoledronic acid for 96 weeks was superior to treatment with oral ibandronic acid for preventing skeletal events in patients with bone metastases. ^[30]

In the primary per-protocol analysis, the annual rate of skeletal-related events (SREs) per person-year was 0.499 in the ibandronic acid group and 0.435 in the zoledronic acid group. ^[30] In the intention-to-treat analysis, the SRE rate per person-year was 0.507 in the ibandronic acid group and 0.425 in the zoledronic acid group. Both drugs had acceptable side-effect profiles, and the researchers concluded that the more convenient oral drug may still be considered for patients who have a strong preference or who have difficulties with IV infusions.

Denosumab, a human monoclonal antibody targeting and binding to RANKL, has been employed for prevention of SREs in metastatic breast cancer and is approved by the US Food and Drug Administration (FDA) for aromatase inhibitor–induced bone loss. ^[31]  A review by Irelli et al noted that bisphosphonates and denosumab have generally similar toxicity profiles, though pyrexia, bone pain, arthralgia, renal failure, and hypercalcemia are more common with bisphosphonates and hypocalcemia and toothache are more common with denosumab. ^[32]

In January 2018, denosumab was approved by the FDA for prevention of SREs in patients with multiple myeloma. It was originally indicated for SREs in patients with solid tumors. Osteoclast-activating factors, such as RANKL, are implicated in an increased risk for SREs with multiple myeloma.

In a phase 3 trial comparing denosumab with zoledronic acid in 1718 patients with bone metastases, denosumab was noninferior and showed an advantage in significantly reducing the risk for renal adverse events. ^[29] A post-hoc analysis at 15 months was also conducted because many of the SREs (60%) occurred early, within 3 months, which led the authors to speculate that the data reflected events occurring before the treatment had enough time to take effect.

Results did show superiority of denosumab (n = 450) over zoledronic acid (n = 459) in terms of the endpoint of time to the first SRE. ^[29] With regard to median progression-free survival (PFGS), a difference of more than 10 months was observed between the denosumab group (46.09 months) and the zoledronic acid group (35.38 months). No difference in overall survival was noted between the treatment groups.

The spine is the most common location of metastatic disease. The timing of treatment is critical in persons with spinal metastases because patients with spinal disease have a life expectancy of 6 months to more than 2 years, depending on the primary tumor type. ^[18]

In deciding between surgical and nonsurgical management of spinal disease, it is necessary to take the following into account:

• The patient's overall condition
• The patient's chance for improvement with presently available treatment options
• The patient's personal wishes

In general, patients with at least 6-12 weeks of life expectancy may be surgical candidates, depending on the location of the lesion in the spine and the impending neurologic consequences of disease progression at that level.

As a result of advances in interventional radiology and surgery, there is increasing interest in less invasive techniques aimed at achieving the same clinical results as standard surgical procedures with less surgical morbidity. Such techniques include embolization, electrochemotherapy, MRI-guided high-intensity focused ultrasound, and thermal ablation. ^[33]

A study comparing surgery with radiotherapy as a treatment option for patients with spinal metastases determined that motor impairment was the main reason for surgery. ^[34] The investigators also found that better identification of patients with little remaining survival time is needed to avoid the time-consuming treatments of major surgery and long-term radiotherapy in these individuals.

The study reviewed medical records from 903 patients in Norway who were admitted for radiotherapy or surgery for spinal metastasis during an 18-month period between 2007 and 2008. ^[34] Fifty-eight patients were treated with surgery, and 845 were treated with radiotherapy. Eleven of the patients in the surgical group and 244 of the patients in the radiotherapy group died within 2 months after the start of treatment.

Spinal surgery in this setting may be performed for diagnostic or therapeutic purposes.

Diagnostic

Diagnostic management is usually performed with core needle biopsy (CNB) up to the level of T8 and with open biopsy or minimally invasive costotransversectomy above the level of T8.

Obtaining a biopsy is not necessary in all patients with metastatic disease of the spine. In patients with myeloma, CNB of the iliac crest is part of the staging process and is appropriate for diagnosis, which means that biopsy of a defect in a vertebral body is not required.

Percutaneous CNB has successful positive results in 65% of destructive (lytic) lesions of vertebrae metastases but in only 20-25% of blastic ones. Open biopsy has a yield success rate of 85% regardless of the lesion type. It is vital always to obtain a culture and Gram stain on all specimens, because infection is a great imitator of disease in bone, especially in the spine.

Percutaneous needle biopsy of C2 can be performed through a transoral approach. In the author's experience, biopsy of C1 and C3 can also be accomplished through this approach, but the procedure is much more difficult than it is for C2. This procedure must be performed under fluoroscopic control at all times. When the transoral approach is taken, a broad-spectrum antibiotic covering multiple organism types should be administered during the perioperative period to prevent secondary infections.

An open biopsy of the thoracic spine above T8 is best performed through a costotransversectomy. When the biopsy is performed with a needle, control via fluoroscopy or computed tomography (CT) is advisable. Biopsy specimens can be safely obtained from lesions below T8 with a core needle, such as the Craig, by using the Ottolenghi technique.

Therapeutic

Therapeutic spinal surgery is performed to manage pain, decompress neural elements, and restore mechanical stability to the spine. In rare instances of radioresistant tumors, such as those occurring in thyroid and renal cell carcinoma, surgical resection and intercalary stabilization may serve as the only effective treatment modality. ^[35] However, tumor embolization for such metastases has been reported to offer improved longevity in patients with these specific tumors.

Treatment objectives

The objectives of therapeutic surgery for spinal metastases include decreasing or eliminating pain, decompressing neural elements to protect cord function, and mechanically stabilizing the spine. ^{[1, 2]} The most important of these criteria is decompression of neural elements, because the loss of neural function is almost always an unrecoverable catastrophe, especially in anterior cord injury.

Anterior or posterolateral decompression, combined with anteroposterior (AP) reconstruction, allows treatment of a wide variety of patient problems. When such techniques are used, 75-100% of patients experience improved pain outcomes; some neurologic improvement occurs in 50-75% of patients. More important, 95% of patients without preoperative neural deficits maintain their function after these procedures. Once neurologic function is lost, fewer than 40% of patients regain it.

Prognostic indicators

As with long-bone fractures, prognostic indicators can be used in evaluating patients with spinal metastases, helping to predict which patients may progress to vertebral collapse, spinal cord compression, and neurologic dysfunction. Although not ideal, these indicators are very helpful.

The four-column concept, which is based on radiographic criteria and includes the concept of laterality, provides one set of prognostic indicators. Tumor destruction of fewer than three columns suggests stability of the spine; a spine in which three or four columns have been destroyed is considered unstable and in need of stabilization. Tumor biology and location also are helpful indicators.

Indications for therapeutic surgery

Primary surgical intervention is appropriate when adjuvant therapy alone will fail to produce long-lasting success. Patients with radioresistant tumors, mechanical instability from bone destruction, bone in the spinal canal, or circumferential epidural tumors fit the indications for primary surgical treatment.

Therapeutic surgical procedures are also necessary when the progression of neurologic symptoms occurs despite the administration of the primary method of nonoperative treatment (ie, radiotherapy or chemotherapy). In addition, therapeutic surgery is needed when fracture, instability, or tumor progression, with impending or actual spinal cord compression, is present.

Surgery of cervical spine

In the cervical spine, pain and instability are the most common indications of disease. Neurologic deficits are relatively uncommon in the upper cervical spine because of the larger canal diameter, occurring in only 15% of cases of upper spinal disease metastases. In the lower cervical spine, 25-35% of lesions produce spinal cord compression.

Appropriate treatment depends on the degree of involvement. In the C1 and C2 bodies, lateral mass involvement is the critical factor because of the primary role these structures play in the overall stability of this area. Patients with destruction of the lateral mass of C1 do not obtain pain relief from radiation therapy alone, because of rotatory instability. They require posterior stabilization from the occiput to C2, with postoperative radiation therapy.

Patients with C2 body involvement and minimally displaced fractures or with diffuse involvement of the entire body can be treated with radiation therapy and immobilization in a cervical orthosis until fracture stability and bony restitution have occurred.

With gross destruction of the body of C2 and instability, surgery may be indicated as dictated by the patient's condition and neurologic status. The patient may require posterior fusion or a combined anterior and posterior approach. Patients who are not surgical candidates need to be treated with realignment and immobilization with a halo vest and with radiation therapy. Patients with posterior C2 involvement require radiation therapy and an orthosis for pain control. If the spinous processes of C2 are lost, cervical kyphosis can ensue.

Anterior decompression and reconstruction with autologous or allograft bone are effective means of achieving decompression and stabilization with one- or two-level anterior metastatic disease from C3 to C7. Additional posterior stabilization is usually necessary for disease that has more than two levels of involvement.

Surgery of thoracic and lumbar spine

In the thoracic and lumbar spine, metastatic disease occurs most frequently in the vertebral body. Therefore, anterior decompression and stabilization are the most effective means of decompressing the spinal canal. Such surgery allows correction of the deformity caused by the tumor and direct stabilization of the involved portion of the vertebral body.

Depending on the level and extent of the lesion, the surgical approach ranges from an anterior thoracotomy to a thoracoabdominal or retroperitoneal approach. One level of involvement or two contiguous levels can be approached, decompressed, and stabilized. More than two levels of involvement necessitate the addition of posterior segmental stabilization to provide adequate mechanical stability.

The posterior approach (with no anterior stabilization) should be reserved for diffuse disease over many levels or for isolated posterior disease alone. Fixation of two levels above and two levels below the involved areas, using segmental instrumentation, is necessary for proper stabilization. AP decompression and stabilization are required for circumferential disease or after the decompression of multiple levels.

Vertebroplasty

The percutaneous introduction of polymethylmethacrylate (vertebroplasty) may be a minimally invasive treatment alternative for patients with one- or two-level vertebral body compression fractures. ^[3] Originally described for the management of osteoporotic compression fractures, the procedure has risks, which include (particularly) the development of neurologic complications. It was introduced into the orthopedic community as an additional tool to help in the management of patients with the aforementioned compression fractures.

Surgical risks

Surgical intervention has risks because patients with metastatic disease have poor nutritional status, low platelet counts, and low total white blood cell (WBC) counts. These constitutional deficits, combined with radiation therapy, place patients at high risk for wound infections and other complications, including excessive blood loss (with certain tumors, such as myelomas, as well as renal cell and papillary thyroid carcinomas), myocardial infarction, DVT, and pneumonia.

The incidence of such complications ranges from 10% to 15%, depending on the patient's underlying condition.

Open internal fixation of long bones is usually the preferred method of treatment for the management of metastatic long-bone disease accompanied by an impending or completed fracture. Stabilization with a locked intramedullary device followed by radiation therapy to the entire bone as soon as the surgical wounds have healed is preferred. ^[4]

Some locations deserve special consideration. Replacement arthroplasty, unipolar or bipolar, is most appropriate for pathologic fractures of the femoral and humeral head or neck. This is also the preferred management technique for distal femoral or proximal tibial condylar defects. Although the proximal femur and humerus are frequent sites of metastases, it has been found that metastases are less frequent at the distal femoral and proximal tibial locations. The last two sites are usually associated with melanoma, myeloma, or lymphoma. Metastatic bone disease in the distal extremtities is generally rare. ^[36]

When discovered, defects of almost any size in the ulna and radius, though rare, must be fixed, because the ulna and radius are subject to constant torsional loads secondary to the pronation/supination actions of the forearm. Dysfunction of the forearm for the patient with a pathologic fracture of one of these bones is poorly tolerated. If possible, a firmly fixed device is needed to protect these small bones from further stress.

The use of radiation therapy after healing of the surgical wound is critical and can result in the healing of pathologic fractures, especially in the case of lesions related to breast cancer. ^[37]

Standard or cemented stems

Standard or cemented stems, including calcar replacements, are appropriate in the proximal femur. Standard cemented stems are also appropriate in the proximal humerus. Presently, off-the-shelf femoral and humeral devices are available in long, straight or bowed stems. The longest stem possible should be used in these situations to stabilize any actual or potential additional lesions distal to the proximal site.

Good clinical results, rapid return to function, and almost no wear complications are observed because of the shortened lifespan (ie, 4-48 months) of patients with metastatic bone disease.

The use of long cemented stems does carry an increased risk that during the procedure cardiac arrest will occur secondary to pressurization of the cement, and appropriate measures must be taken to minimize such an event during the placement of the stem. ^[38] Such measures include distal venting of the canal with drill holes, meticulous canal preparation, avoidance of hyperpressurization, and the staging of bilateral procedures, as well as the provision of adequate hydration and blood pressure support to the patient during this part of the process.

Dynamic hip screws or plates

In the author's opinion, it is not appropriate to use a dynamic hip screw or plate for fixation of pathologic proximal femoral fractures, because of the increased risk from already existing defects and the potential for additional metastatic defects in the femur distal to the initial lesion. Although successful use of such constructs for surgical management of intertrochanteric femoral fractures has been reported, the frequently deficient medial femoral cortex wall defects, combined with the inability to address any bony disease distal to these constructs, make them a relatively poor choice.

Intramedullary fixation devices

The use of intramedullary fixation devices, such as third-generation cephalomedullary implants in the femur and other designs, is the preferred method of fixation for fractures of the tibia and humerus. The use of cement is still helpful in the filling of large defects in the bone, but present-day locking devices are well suited for stabilization of these bones.

Total hip arthroplasty

The issue of concurrent lateral acetabular metastases with proximal femoral disease is worth mentioning. Microscopic disease of the bone has been found around the acetabulum in 83% of patients during replacement arthroplasty for pathologic femoral neck fractures. On the basis of these data, some authors have recommended routine total hip arthroplasty (THA) for management of this event.

However, this microscopic disease has not been clearly shown to cause clinical failures after femoral side–only replacements, and the goal of this type of surgery, which is to return patients to as much function as possible, is not realized with THA. Additionally, because radiation therapy is used postoperatively to manage such microscopic foci, it is questionable whether THA affords any benefit over the use of unipolar devices.

Continuing to use hemiarthroplasty is probably appropriate for proximal femoral disease management, unless clear evidence of structural compromise is present on preoperative evaluation of these patients.

In the event of a THA, the use of a cemented socket is highly recommended because postoperative irradiation and the primary disease process limit any advantage that might be gained from employing a porous ingrowth device. Larger lesions may require the use of acetabular cages and/or the use of Harrington-type reconstruction with Kirschner wires (K-wires) and cement. ^[19] With more extensive disease, a saddle prosthesis or resection arthroplasty may be needed. ^[39]

A nutritional deficiency may retard wound healing and the potential for rehabilitation.

Activity restrictions are dependent on the location of the lesion, the mechanical integrity of the remaining bone, and the surgical construct. At the first sign of pain in a lower extremity, the patient with a presumed pathologic lesion should be placed on crutches or a walker.

One advantage of prosthetic replacement over internal fixation is the potential for immediate weightbearing and the restoration of preoperative activity levels. ^[39]  This is especially important for patients with limited life expectancy.

Most patients with metastatic bone disease benefit from outpatient physical therapy. For severely debilitated patients, pain palliation may be the primary goal of surgery; the potential for functional recovery is limited. ^{[40, 2, 41, 42, 43]}

Pain relief is probably the best guide to the regression of a lesion. Monitoring the response of skeletal metastases to radiation therapy or medical therapy (eg, chemotherapy or bisphosphonates) is difficult. This is because increased bone deposition from an osteoblastic metastasis (such as that from prostate or breast carcinoma) can, on a bone scan or (often) a radiograph, have an appearance similar to that of deposition from posttreatment consolidation. Metastatic prostate carcinoma is the most common cause of osteoblastic metastases in men.