WORKUP	Section 5 of 9
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Other Tests:

• Diagnostic procedures in evaluation of spinal metastatic disease

• Thorough metastatic workup is paramount in patients with spinal metastasis. This helps to delineate the nature and the extent of the systemic disease. However, the appropriateness of diagnostic tests depends on the time available. In patients with rapidly progressing symptoms, chest radiography and physical examination is all that is warranted. Plain radiography of the entire spine should then be performed, followed by MRI with and without contrast enhancement.

• Plain radiography is used to show erosion of the pedicles or the vertebral body. Owl-eye erosion of the pedicles in the anteroposterior (AP) view of lumbar spine is characteristic of metastatic disease and is observed in 90% of symptomatic patients. However, radiologic findings become apparent only when bone destruction reaches 30-50%. Osteoblastic or osteosclerotic changes are common in prostate cancer and Hodgkin disease; they are occasionally seen in breast cancer and lymphoma.

• CT scanning is useful in determining the integrity of the vertebral column, especially when surgery is anticipated. CT myelography is used if MRI is not available. CT also allows for an examination of paraspinal soft tissues and paraspinal lymph nodes.

• Emergency myelography still is used in situations where MRI is not available. The advantage of MRI is its noninvasive nature, whereas myelography allows for cerebrospinal fluid (CSF) sampling. CSF sampling should be deferred if evidence of near-complete or complete spinal block is noted. The risk of neurologic deterioration after myelography is about 14% but less likely than this with C1-2 puncture.

• With MRI, the sagittal scout image is used for rapid screening of the surrounding soft tissues. MRI is the imaging modality of choice. Contrast-enhanced fat-suppressed images help to differentiate metastasis from degenerative bone marrow. Diffusion-weighted images distinguish metastasis from osteoporotic bone. Osteoporotic fractures are hypointense, and metastases are hyperintense.

• Bone scanning

• Bone scans are positive in 60% of patients but they are not specific.

• Lesions that activate bone metabolism increase technetium-99m uptake.

• Nuclear studies are useful to determine cancer burden and are effective in scanning the entire axial and appendicular skeleton. The use of single photon emission CT (SPECT) and positron emission tomography (PET)–CT allow for rapid screening and staging of systemic disease.

	TREATMENT	Section 6 of 9
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Medical Care: No treatment has been proven to increase the life expectancy of patients with spinal metastasis. The goals of therapy are pain control and functional preservation. The most important prognostic indicator for spinal metastases is the initial functional score. The ability to ambulate at the time of presentation is a favorable prognostic sign. Loss of sphincter control is a poor prognostic feature and mostly irreversible. Other problems associated with metastatic disease include pain related to pathologic fractures, hypercalcemia, and psychological problems.

This discussion focuses on the management of pain, structural stability, local disease, and hypercalcemia. Medical management that addresses the systemic disease, such as chemotherapy and hormonal therapy, are not discussed. Hormonal manipulation, such as the use of tamoxifen to treat breast cancer, preserves bone mineralization because of its estrogen-agonistic effect.

• Treatment of pain

• Patients with spinal metastasis commonly have bone pain. Their pain may be related to bony destruction or pathologic fractures. Local pain is due to stretching of the periosteum and may respond to irradiation. Axial pain can occur when vertebral compression and/or collapse occurs. Axial pain is secondary to mechanical instability. It causes distress and reduces mobility of the patients. In addition, a number of these patients have neuropathic pain. This pain may be related to root irritation and/or meningeal irritation secondary to cancer infiltration. Both steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage bone pain. Use of spinal orthotics and physiotherapy are useful adjuvant therapies for this group of patients.

• Steroid therapy is effective in treating bone pain. Immediate treatment is high-dose dexamethasone. The optimal dose has not been established. However, in practice, the usual dose is a loading dose of 10 mg then 4 mg every 6 hours. Of all the corticosteroids, dexamethasone has the least mineralocorticoid effect and is least likely to be associated with infection or cognitive dysfunction, though it does increase the risk of myopathy. Other adverse effects include psychotic reaction (5%), GI bleeding (<1%), and glucose intolerance (19%).

  The frequency of complications from steroid therapy depends on the duration of the treatment and is associated with hypoalbuminemia. Treatment lasting more than 3 weeks is more likely to be associated with complications. Hypoalbuminemia appears to increase the risks of adverse effects associated with steroid treatment.

  In about 70-80% of patients, symptoms improve within 48 hours of treatment. Approximately 64% of patients report alleviation of pain within 24-48 hours of starting steroid therapy, and 57% report improvement in their motor function. In most patients, steroid use must be continued until radiotherapy is completed.

• Treatment of neuropathic pain

• Emerging evidence shows that antiepileptic drugs are effective in treating pain. Gabapentin is frequently used to treat neuropathic pain and is well tolerated. Other drugs, such as lamotrigine, carbamazepine, levetiracetam, tiagabine, and topiramate have also been used; tricyclic antidepressants are still being used to treat neuropathic pain. However, tricyclic antidepressants cause more adverse effects than the aforementioned antiepileptics.

• Topical preparations, such as the lidocaine patch, are less effective than the drugs previously mentioned. Opioid analgesic is useful. The concern about addiction and tolerance with long-term use should not be a major concern in patients with cancer. Chemical epidural neurolysis was infrequently used to treat medically intractable pain. It is effective for interrupting single or multiple radicular pain, but it poses a risk of acute deterioration especially when structural instability or compression is present.

• Neurosurgical ablation, such as rhizotomy, is indicated in patients with severe sacral pain and bowel and bladder involvement. It involves major surgery and is not commonly done. Likewise, spinothalamic tractotomy or cordotomy are not commonly used to treat spinal metastatic diseases.

• Radiation therapy is also effective in treating pain caused by bone metastasis. A detailed discussion of this modality and its use in treating spinal metastatic disease is discussed in the following section.

• Hypercalcemia is particularly common in patients with lytic metastasis, and it is not infrequently found in those with paraneoplastic syndrome that produces parathyroid hormone–related protein. Patients with hypercalcemia commonly present with polyuria, and some, with pre-renal failure. Initial treatment should be rehydration and administration of a steroid. Bisphosphonate is useful to control the lytic process. It inhibits osteoclast function, decreasing bone resorption.

Surgical Care:

General considerations in controlling local disease

Radiotherapy and now surgical radical resection (spondectomy) are the preferred treatments to control local disease.

Radiation therapy is more effective in achieving pain control (67%) than surgery (36%). Of note, surgery alone is the least effective way to treat spinal metastases. About 20-26% of patients who undergo surgery have further deterioration in terms of mobility or sphincter control, whereas 17% of those receiving radiation therapy have further deterioration.

The advancement of minimally invasive surgery and of new forms of robotic radiation therapy has radically changed the management paradigm of metastasis disease to the spine. Current thinking is to perform early radical resection of a single lesion in the spine and to administer adjuvant stereotactic radiation therapy to eradicate the disease. This approach allows for decompression, stabilization, and suppression of local recurrence.

Indications for surgery

Surgery is indicated only as a stabilization procedure or for tissue diagnosis. In the past, it was used only in patients with disease that progressed despite radiotherapy and in those with tumors known to be resistant to radiotherapy. Some surgeons have advocated vertebral-body resection and stabilization with methacrylate. Others prefer to incorporate hardware, which occasionally poses problems with imaging. Now, early intervention with spondectomy and reconstruction of the vertebral body is being considered in the advancing field of neurospinal oncology.

• Radiotherapy: Radiotherapy remains the mainstay of treatment for spinal metastatic disease. Most of lymphoreticular tumors and prostate carcinoma are relatively insensitive; lung and breast are relatively insensitive. Tumors of the GI system and kidney are resistant to radiotherapy, as are melanomas. Nevertheless, radiotherapy elicits some response in melanomas. About 80% of patients with pretreatment pain have symptomatic relief; 48% of patients with motor or sphincteric dysfunction respond to treatment.

  The common regimen is 30 Gy in 10 fractions. The amount of radiation is empirical and based on the therapeutic ratio, a function of the fractionation dose and biologically effective dose, as well as the tolerance dose of the spinal cord and its associated vasculature, roots, and marrow. The tolerance dose for specific tissue is a function of irradiation volume, the total dose per fraction used, and the level of risk acceptable. The effect of irradiation depends on the proliferative power of the tissue. Hence, skin and bone marrow are affected early, whereas brain and spinal cord are affected late. A subacute effect is due to demyelination secondary to injury to the oligodendrocytes and the vascular tree. For example, the traditional fractionated dose for cord necrosis is 1.8-2.0 cGy/day.

  The efficacy of dose fractionation is derived from biologic reasoning, as follows:

• Repair of sublethal damage: The biologically effective dose is the probability of cell survival after single doses of ionizing radiation. It is a function of the absorbed dose measured in grays and based on the simple fact that irradiation causes double-stranded DNA to break. However, the dose for a single particle to cause a double-strand break is low, whereas that for a single-strand break is high. Yet 2 single-strand breaks occurring closely in space and time may result in double-strand disruption with lethality similar to that of double-strand break and therefore deemed irreparable.

• Reoxygenation of hypoxic cells: Reoxygenation is important because tumor has hypoxic cells, and the fraction of hypoxic cells increase after irradiation. Oxygen is the most powerful radiation sensitizer. Hypoxic cells are radiation resistant by as much as a factor of 3.

• Reassortment of proliferating cells in the cell cycle and repopulation: A single fraction of irradiation eliminates a portion of cells in the G2 and M phases. However, in the next 4-6 hours the cell population resumes cycling and redistribution. The radiation sensitivity varies over the cell cycle by as much as a factor of 3. Hence, with a standard dose is 30-60 Gy. About 18% of patients have a risk of myelopathy.

  Advancement in CT and/or MRI-based planning improves the precision of information regarding the location of tumor and critical normal structures. The traditional treatment plan, or radiation port, is to include 2 vertebral bodies above and 2 below the lesion. This range is based on the fact that recurrence is most common in bodies contiguous to the site of involvement.

  The physical hallmark of radiosurgery is to deliver a relatively high dose of radiation to a small target and with rapid dose fall-off. Highly conformal beams guided with 3-dimensional (3D) imaging are used. Advances in 3D CT allow it to be coupled with treatment planning.

  Other forms of radiation therapy are stereotactic radiosurgery and intensity-modulated radiation therapy (IMRT). IMRT can deliver irradiation with optimized nonuniform intensities in each radiation field. It improves conformation to the tumor and helps spare normal tissue. The advantage is that it can generate concave and complex dose distributions. IMRT optimizes the 3D planning system and includes reverse planning to best deliver a modulated beam-fluence profile. It is accurate to 12-15 mm.

  Emerging technology allows IMRT to be delivered by using a robotic linear accelerator (LINAC) that can move freely in 3D space (CyberKnife: Accuray, Sunnyvale, CA). This method increases the number of possible beam orientations. Real-time target tracking allows for movement within a 1 mm of spatial accuracy. In addition, this form of irradiation therapy has the following advantages: (1) it is a frameless system, (2) it references the target to internal landmarks (eg, radiographic anatomic features, bony landmarks, implanted fiducials), (3) it tracks with a real-time imaging device and dynamically aligns the target with the beams, and (4) it aims each beam individually. The present author favors use of this robotic technology in the treatment of spinal metastasis.

  Study 97-14 from the Radiation Therapy Oncology Group (RTOG97-14) showed that 50-80% of patients have adequate pain control in 3 months with single-fraction irradiation. About 78% patients treated with irradiation remained ambulatory, and 16% of nonambulatory patients and 4% of patients with paralysis regained function. Among those treated with laminectomy followed by irradiation, 83% who were ambulatory remained so, while 29% of nonambulatory patients and 13% of patients with paralysis regained function.

• Spinal stabilization: Axial pain secondary to mechanical instability can causes clinically significant morbidity. Spinal stabilization is the treatment of choice. The traditional treatment is radiation, steroids. In rare cases, surgery is advocated as a last resort.

  With the advancement in spinal stabilization, satisfactory neurologic improvement occurs in 48-88% of patients with 80-100% rates of pain relief. On the contrary, radiation therapy cannot reverse compression secondary to bone, and the therapeutic response is delayed several days, even in patients with highly radiosensitive tumors (lymphoma, neuroblastoma, seminoma, myeloma).

• Radical surgery: Radical surgery was recently advocated for stabilization procedure or tissue diagnosis and also for reduction of the tumor burden. It is applied in patients whose disease progresses despite radiotherapy and in those with known radiotherapy-resistant tumors. Vertebral-body resection and anterior stabilization with methacrylate or hardware (eg, cages) has been advocated. Surgical decompression and stabilization, with radiotherapy, is the most promising treatment. It stabilizes the diseased bone and allows ambulation with pain relief.

  In general, patients who are nonambulatory at diagnosis do poorly, as do patients in whom more than 1 vertebra is involved. Radical resection is indicated in patients with radiation-resistant tumors, spinal instability, spinal compression with bone or disk fragments, progressive neurologic deterioration, previous radiation exposure, and uncertain diagnosis that requires tissue diagnosis. The goal is always palliative rather than curative. The primary aim is pain relief and improved mobility.

  In brief, the author advocates radical resection in most medically fit patients with solitary metastasis with favorable histologic findings, minimal extraspinal disease, and life expectancy of longer than 6 months. Hence, patients with breast, thyroid, prostate, or renal carcinoma are better candidates than those with melanoma and lung cancer. In published series, experienced surgeons used a radical, simultaneous AP posterior approach with resection of the tumor (complete spondylectomy), reconstruction, and stabilization.

• Laminectomy: Laminectomy is indicated less often than the other procedures described above because most lesions are anteriorly based, and posterior decompression may further destabilize the spine. Laminectomy does not address the anterior and middle columns (in the Denis 3-column model of the spine) and may further compromise spinal stability. With laminectomy, postoperative mortality is 10-15%, and morbidity (wound) can be as high as 35%.

  Posterior decompression is not a good solution because of the anatomic involvement of the disease. It provides no additional relief or substantial functional advantage. This approach was evaluated in 84 patients with predominantly dorsal epidural disease. Before surgery, 80% were nonambulatory, and 56% had sphincter dysfunction. After surgery, the overall morbidity rate was 45%, and none of the patients regained neurologic function. The complication rate was 4.7%.

  Laminectomy supplemented with stabilization with neutralizing fixation devices, such as pedicle screws, offers pain relief and a degree of functional recovery in a substantial number of patients.

• Transpedicular approach: The transpedicular approach is popular when tumor involves the dorsal aspect of the vertebral body, especially when the disease extends into the pedicle and associated dorsal elements. Facetectomy coupled with pediculectomy allows access into the vertebral body. Followed with instrumentation a level above and below, this procedure provides an excellent surgical result. Some surgeons suggest that bilateral pediculectomy allows for complete vertebrectomy (spondylectomy), and anterior augmentation with polymethylmethacrylate (PMMA) and plating optimizes surgical goals. However, in some studies, the overall complication rate was high as 50%.

• Posterior approach: The advantages of the posterior approach is (1) it permits early identification of the cord, (2) it can address diseased dorsal elements, (3) it allows the use of rigid constructs or long constructs in posterior areas, and (4) it addresses imbalance of the sagittal plane and pain due to micro instability.

• Costotransversectomy and lateral extracavitary approach: These are posterior lateral approaches that can gain access to the dorsal part of the vertebral body.

• Minimally invasive endoscopic procedures: Some have recently advocated the uses of minimally invasive approaches, including endoscopy-assisted spinal-cord decompression, percutaneous vertebroplasty and/or kyphoplasty, minimally invasive image-guided tumoral resection and spinal reconstruction, and percutaneous approach to place pedicle screws. These techniques have revolutionized the surgical management of spinal metastatic disease.

• Kyphoplasty: Kyphoplasty is a minimal invasive procedure that may play a pivotal role in the treatment of spinal metastases. In a single procedure, the operator can gain access to the vertebral body by means of the pedicles to sample or remove a reasonable amount of tumor. An infusion of PMMA into the affected bone stabilizes and/or restores the diseased bone. This modality can be used in patients with an unfavorable health status and may not be suitable for other forms of open surgery. Kyphoplasty has been used as a conjoined therapy for posterolateral stabilization surgery.

	MEDICATION	Section 7 of 9
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The goals of pharmacotherapy are to reduce morbidity and prevent complications.