Characterization of Pain

Metastatic involvement of the spine can occur anywhere along its axis. These tumors, however, most frequently involve the thoracic spine (70%), followed by the lumbar spine (20%) and cervical spine (10%).^5,21 Pain is the most common symptom and can be characterized as either oncologic or mechanical, or a combination of both.¹⁹ It is essential to determine which type of pain patients are experiencing as this plays a major role in determining the most effective treatment. Pain that is oncologic or biologic in nature is described as dull, constant, and responsive to steroids. It is often worse at night and in the morning but typically does not worsen during the day with activity. As such, patients often complain of pain during sleep. The diurnal variation is thought to be related to the variable secretion of endogenous steroids, which is why this type of pain is responsive to oral steroid administration in the early stages.¹⁹ Though the pathophysiology is uncertain, it is thought to be related to inflammation of tumor within the vertebral body and stretching of the periosteum with tumor growth.

Mechanical pain is associated with activity and worsens with movement.²² In the cervical spine, neck pain that worsens with flexion, extension, and rotation is common and is related to progressive bony destruction. Pain of this type is often suggestive of underlying instability, deformity, or fracture. Rotational pain is suggestive of atlantoaxial instability, whereas pain with flexion and extension is indicative of subaxial pathology. In the thoracic spine, pain is often worse with extension as patients attempt to lie on their back during sleep. Mechanical pain in the lumbar spine is also associated with flexion, extension, and axial loading. Painful radiculopathies may occur as a result of loss of vertebral height and neuroforaminal compression of exiting nerve roots due to either tumor or loss of height with axial loading.

Pain, whether oncologic or mechanical, may be severe enough to make ambulation impossible. Though these patients may have preserved strength in their legs and appear comfortable while supine or on their side, pain may make any movement unbearable. Though a full discussion of the numerous treatment options available for metastatic disease is beyond the scope of this chapter, a number of treatments, including vertebral cement augmentation, surgery, radiation therapy, or SRS, or a combination of these, may play a role in the multimodality treatment of these patients.¹² Each patient requires a specifically tailored treatment plan based on clinical and radiographic findings.

Role of Surgery

To fully appreciate the role of SRS in the management of metastatic spine tumors, an understanding of the current role of surgery for metastatic spine disease is required. In 2005, Patchell et al.⁴ published a prospective randomized trial comparing surgery and conventional external-beam radiation therapy to radiation therapy alone for high-grade spinal cord compression. This study showed that surgery followed by conventional radiation resulted in significant advantages in terms of overall maintenance and recovery of ambulation, continence, narcotic requirements, and survival.

Patients who did not undergo surgery but had radiation upfront had worse outcomes overall than did the surgical group. Fifty-seven percent of ambulatory patients in the radiation arm maintained ambulation for only 13 days compared with 122 days in the surgical arm.⁴ Nonambulatory patients in the radiation group recovered ambulation in 19% (3/16); however, these patients all recovered ambulation only after crossing over to the surgical arm.⁴ Essentially no patient recovered ambulation without surgery due to the radiation insensitivity of solid tumor malignancies. Although the study demonstrated the superiority of surgery and conventional radiation therapy to radiation alone in terms of neurologic function, it did not address the durability of tumor control given the relatively short survival of the patients studied.

Despite the study’s limitations, the current recommendation for optimal functional outcomes in patients with high-grade spinal cord compression resulting from solid tumor malignancies or in situations where gross spinal instability exists, is that surgery should be the first-line treatment when possible.^4,18

Limitations of Conventional External-Beam Radiation Therapy

Many patients with spinal metastases may have significant medical comorbidities that preclude aggressive surgical treatment when otherwise indicated. For this reason, radiation continues to be the mainstay of treatment for many of these patients. The historical benefits of conventional radiation therapy for treating spinal metastases have been demonstrated in numerous retrospective studies showing improvement or maintenance of neurologic function.^11,13–16 Although the Patchell study demonstrated the superiority of surgery, radiation is essential for achieving postoperative local tumor control.²³ In a recent review of the literature, Gerszten et al.²³ found that the ambulatory rate after conventional radiation was 60% to 80%, pain control was achieved in 50% to 70%, and local tumor control was achieved in 20% to 89% of patients. However, though conventional radiation (usually 30 Gy, in 3 Gy/fraction) provides durable control for the hematologic malignancies and breast carcinoma, the majority of solid tumors demonstrate radioresistance or nondurable long-term tumor control when it is used as either a primary or a postoperative treatment.²⁴ In addition, because treatment plans with conventional radiation often include a margin of one healthy vertebral body above and below the area of concern, this results in a large volume of normal tissue being irradiated.^8,25

The variable responsiveness of spinal metastases to radiation was originally reported in a series by Greenberg et al.,²⁶ comparing outcomes of surgery and radiation to radiation alone. Though the surgical approach in this series was mainly laminectomy, thus rendering the surgical results less applicable today with the facile use of advanced decompression and instrumentation techniques, the authors demonstrated marked differences in the response to radiation based on tumor histology. Patients with breast carcinoma and hematologic malignancies showed improved outcomes compared with those with radioresistant tumors such as renal and lung carcinomas.

Maranzano and Latini¹⁶ also demonstrated significant differences in the sensitivity of various tumor types to conventional radiation when used as initial treatment. In a study of 275 patients, those with radioresistant tumors such as non–small-cell lung, bladder, and renal cell carcinoma demonstrated significantly less recovery than those with typically radiosensitive tumors, such as breast and hematologic malignancies. Patients with gross instability were excluded from the study. Overall, 98% of patients maintained ambulation but only 60% recovered. Of those who regained ambulation, 70% had radiosensitive tumors. For example, breast carcinoma demonstrated an 80% response rate compared with hepatocellular carcinoma with a 20% response rate. Furthermore, the durability of the response was 10 to 16 months for radiosensitive tumors compared with 1 to 3 months in radioresistant tumors. A number of other studies have also demonstrated this variable response based on tumor histology.^27–29

Limited surgical studies have evaluated the utility of conventional radiation as a postoperative adjuvant. Klekamp and Samii³⁰ reported on 101 surgeries, of which 91% were aggressive subtotal or complete resections. All patients underwent postoperative radiation therapy. Local recurrences were 57.9% at 6 months, 69.3% at 1 year, and 96% at 4 years. The primary factor predictive of recurrence was tumor histology.

Although surgery and conventional radiation therapy are the current mainstays of treatment for spinal metastases, the major drawback to this approach is the relatively low radiation tolerance of the spinal cord.^31–33 This is particularly relevant in cases of progression or recurrence of metastatic disease following standard radiation therapy. Further conventional radiation at recurrence is typically not an option, and patients who undergo surgery after having previously had radiation are known to do poorly and have increased risk of wound complications and worse functional outcomes.^23,33–35

Issues related to tumor radiosensitivity and the need for higher dosing to achieve effective and durable tumor control as well as limited spinal cord radiation tolerance has fueled the development of advanced radiation delivery systems such as SRS to achieve conformal high-dose radiation delivery and durable tumor control.^{8,23,25,36,37}

Stereotactic Radiosurgery

The failure of conventional radiation to achieve long-standing tumor control for radioresistant tumors has limited its modern day application. Though earlier studies have demonstrated success with pain reduction, local disease control, and neurologic improvement in select tumor types, these results do not apply across all histologies.^2,23,27,38 As mentioned earlier, one of the main limitations to achieving local tumor control with conventional radiation therapy is the high dose required. However, the ability to deliver this dose is limited due to the adjacent spinal cord, where standard radiation tolerance is considered to be 45 to 50 Gy.³¹ Though clinical studies continue to improve our understanding of spinal cord tolerance to radiation, the therapeutic index of radiotherapy limits the radiation dose near the spinal cord to such an extent that tumor control is compromised.^33,34

SRS has emerged as an advanced image-guided technology, allowing for more targeted and higher radiation dosing to tumors adjacent to organs at risk (OAR) such as the spinal cord. With technological advances in image guidance and radiation delivery platforms, it is now possible to deliver SRS in a highly conformal manner with a steep dose fall-off gradient either as a single fraction or as a hypofractionated regimen (two to five fractions).^8,39–44 Such a gradient allows for delivering high doses of radiation within millimeters of vital OAR such as the spinal cord, kidney, and esophagus. This enables the very focused delivery of a potentially cytotoxic tumoral dose that can spare nearby normal tissue.

SRS is increasingly being applied to primary malignant and benign spine tumors; however, its application to spinal metastases represents the largest experience to date.^36,42,45,46 The increased application of SRS is further redefining the term radioresistant as tumors traditionally regarded as radioresistant, such as renal cell carcinoma and melanoma, have demonstrated marked responses with durable tumor control following SRS.³⁷ These improved tumor control rates are seen whether used as stand-alone therapy or as a postoperative adjuvant.^37,47,48

The emergence and effectiveness of SRS as an instrument to achieve durable local control has also fueled the debate regarding the optimal management strategy for solitary metastatic lesions to the spine, which by some investigators have been considered ideal candidates for en bloc resection for potential cure.^17,49,50