Spine radiosurgery for spinal cord compression: the radiation oncologist’s perspective

Abstract

Metastatic spinal cord compression (MSCC) is a common problem afflicting cancer patients. It affects 5-14% of all patients with cancer, and more than 20,000 cases are diagnosed annually in the United States (1-3). Once diagnosed, it is considered to be a medical emergency, and immediate intervention is required with high-dose corticosteroids and radiotherapy (RT), with or without decompressive surgery.

Without therapy, MSCC is a source of significant morbidity and mortality, causing pain, paralysis, incontinence, and an overall decline in quality of life. Even with aggressive therapy, results can often be unsatisfactory. Although most patients will die of their underlying cancer within the first year of the diagnosis of MSCC, up to one-third will survive beyond one year (4-5). Therefore, optimal therapy is required to maintain quality of life.

WHERE HAVE WE COME FROM AND WHERE ARE WE GOING

Palliative RT has long been standard in the management of patients with MSCC, but the radiation oncologist is often faced with multiple competing and complex issues. The need to deliver a meaningful radiation dose to the tumor for adequate palliation must be balanced with the necessity of avoiding undue toxicity, the most serious of which is radiation myelopathy. Furthermore, the fractionation scheme must be weighed against the performance status and expected survival of the patient. These issues may explain the wide range of fractionation schemes reported in multiple retrospective analyses, with a total of 30Gy in 10 daily 3Gy fractions most frequently prescribed/standard. This standard RT approach in combination with corticosteroid results in only about 50% of patients being able to walk and few non-ambulatory patients ever walking again (6-13).

The surgical treatment of MSCC has evolved as discussed by our neurosurgical colleagues. As most spinal metastases causing MSCC involve the vertebral body, anterior to the spinal cord, laminectomy is often not helpful. In addition, the procedure can lead to destabilization of the spine. Direct decompressive surgery (DDS) has become the most effective and frequently used standard approach. This involves removal of the tumor, through an anterior approach, or posterior approach or both depending on the level, and reconstruction of the spine intraoperatively to provide immediate stabilization.

In 2005, Patchell and colleagues reported on the first phase III randomized trial testing the impact of DDS followed by RT in patients with MSCC (14). The study compared the standard 30Gy in 3Gy daily fractions to direct decompressive and stabilization surgery within 24 hours of diagnosis followed by the same RT started within 2 weeks. The trial was terminated early at interim analysis when early-stopping rules were met regarding the primary endpoints of ambulatory rate and time ambulatory after treatment. Ambulatory endpoint was defined as at least two steps with each foot unassisted (4 steps total), with or without aid of cane or walker. Secondary endpoints evaluated motor and neurologic status, continence function, narcotic and corticosteroid usage, and survival. This trial definitively demonstrated the value of DDS for every endpoint at statistically significant levels summarized in Table 1. Regarding the primary endpoint of ambulation, the combined treatment had a median ambulation time of 122 days, compared to 13 days for RT alone (P = 0.003).

Table 1.

Results of Phase III trial of Surgery and Radiation for MSCC (Reference 14)

	Surgery +RT Group (n = 50)	RT Alone Group (n = 51)	P Value
Primary
Ambulatory time (Median)	122 days	13 days	0.003
Secondary
Maintenance of Continence (median)	56 days	17 days	0.016
Maintenance of ASIA*	566 days	72 days	0.001
Score (median)
Maintenance of Frankel	566 days	72 days	0.0006
Score (median)
Survival time (median)	126 days	100 days	0.033
Average daily morphine	0.4	4.8	0.002
Equivalent (mgs) use (median)
Average daily dexamethasone	1.6	4.2	0.009
Equivalent (mgs) use (median)

^*ASIA = American Spinal Injury Association

Furthermore, baseline ambulatory and non-ambulatory patients who had DDS and RT had one-half the likelihood of being non-ambulatory, compared to those who had RT alone. For non-ambulatory patients, the combined treatment patients had a significant higher chance of regaining the ability to walk after therapy (62% versus 19%, P = 0.01). In addition, the combined treatment group patients also maintained continence and functional Frankel and American Spinal Injury Association scores significantly longer than patients in the RT alone group. They also required less steroid and narcotic use. The average daily morphine equivalent (mgs) use in the combined treatment group ranged from 0 – 60 (median = 0.4) vs. 0 – 200 (median = 4.8) in the RT alone group (p = 0.002). The average daily dexamethasone equivalent (mgs) use in the combined treatment group ranged from 0.1 – 44 (median = 1.6) vs. 0 – 50 (median = 4.2) in the RT alone group (p = 0.009). Thus, the RT alone arm in the Patchell study had overall poor results for ambulatory and non-ambulatory patients. This finding, and other studies (15), clearly demonstrates that RT alone for MSCC (including 30Gy in 3Gy daily fractions) are of limited effectiveness. These prospective data serve well in challenging the status quo achieved with RT alone in the management of MSCC (16).

The majority of patients with MSCC are not candidates for DDS or surgery in general. Many patients often present with poor performance status, prolonged/ complete paraplegia or other factors that make them not surgical candidates. Extrapolating from other sites, RT doses are frequently escalated to more than 60Gy for achievement of durable response or adequate local control of gross tumors with the standard 1.8-2.0 Gy daily fractions. If one were to assume the true clinically toxic dose of the spinal cord (5% chance of myelopathy at 5 years) to be 59-61 Gy in 1.8-2.0 Gy daily fraction, based on classical α/β modeling, one must then escalate to a biologic equivalent dose (BED) of 45-48Gy utilizing daily fractions of 3Gy in palliative cases (17-19). Such a strategy of dose escalation for the treatment of MSCC would require a prolongation of standard hypofractionation regimens to as long as 3 weeks. In a described patient population of limited performance status and/or having other sites of metastatic disease, this approach would likely be less than ideal. Beyond further increasing the daily burden of having to come in for RT, it would also likely delay use of systemic therapy in patients where such therapy may still be considered of potential benefit. In addition, such an approach among long-term survivors (> 1 year) would be expected to be associated with a potential “calculated” risk of myelopathy of at least “5%”.

Only with the recent evolution of RT delivery technology and the associated advent and use of Stereotactic Body Radiation Therapy (SBRT)/Radiosurgery in combination with Intensity Modulated Radiation Therapy (IMRT) and Image Guided Radiation Therapy (IGRT), dose escalation using short course (< 5 fractions) radioablative therapy ( such as BED > 100Gy) may now be investigated (20). SBRT/Radiosurgery can allow dose escalation to be done safely by ensuring radioablative dose delivery to tumor while at the same time avoiding excessive dose delivery to surrounding critical normal tissue organs such as lung, esophagus, heart, and spinal cord. Clinical demonstration of this capability was reported earlier this year for the treatment of early stage lung cancer (21). This phase II trial in medically inoperable lung cancer patients demonstrated an actuarial 3-year local tumor control rate of 98% with SBRT utilizing 54Gy delivered in 3 fractions of 18Gy. This now accepted new standard of care in medically inoperable lung cancer patients is a culmination of > 8 years of multi-institutional/clinical trial investigation (21-23). While the challenges faced by use of SBRT/Radiosugery in the management of MSCC are great, the potential rewards/ improvement in quality of life in a “medically inoperable” patient population are tremendous. By definition, MSCC will involve a radiosurgical tumor target which will be intimate with eloquent neural tissue – the Spinal Cord. The consequences of geographic miss, underdosing, or overdosing will result in a singular and devastating patient consequence – radiation myelopathy/ paraplegia. While early clinical investigation of SBRT/ Radiosurgery for MSCC has begun, potential pitfalls and concerns must be clearly understood and recognized.

EARLY CLINICAL INVESTIGATION OF RADIOSURGERY FOR MSCC

MSCC has a clinical spectrum ranging from spine bone metastasis to epidural tumor causing overt cord compression. Accordingly, the primary goals of treatment can be pain control for spine bone metastasis, and epidural decompression of the spinal cord thereby to improve or preserve the neurological function.

For treatment of spine metastasis, clinical trials with spine radiosurgery (SRS)/SBRT have shown excellent pain control with modest single radiation doses or fractionated doses (24-27). The pain control was rapid and durable (28). These results support the use of SRS for a solitary or scattered several spine metastases. Recurrence in the immediately adjacent spine outside of the radiosurgery target was rare (26, 29). Currently, a multi-institutional Radiation Therapy Oncology Group (RTOG) clinical trial is ongoing for use of spine radiosurgery with the primary endpoint of pain control of spine metastasis.

The use of SRS for MSCC is not established. It has been widely accepted that some degree of epidural tumor control may be achieved by various fractionated radiotherapy regimen (8, 15, 30, 31). These treatments were given mostly for the purpose of pure palliation. Recent technical progress of SRS made it possible to deliver a high radiation dose enough to control the epidural soft tissue tumor while minimizing the dose to the spinal cord. The clinical experiences accumulated knowledge of partial volume tolerance of the spinal cord following SRS (32). Therefore, it can hypothesized that SRS can shrink the epidural tumor and achieve epidural decompression. Because of the geographic location of epidural tumor and the spinal cord, the dose to the epidural tumor may be limited. However, even a minimal or partial reduction of, if not complete, epidural volume can lead to spinal cord decompression. With this hypothesis, Ryu et al conducted a prospective clinical trial with single dose radiosurgery in 62 patients who presented with MSCC with or without neurological deficit, to determine quantitatively the magnitude of SBRT decompression of epidural tumor (33). This clinical trial included any patients with previously-untreated MSCC. Patients with progressive systemic tumors with widespread metastasis and with poor performance status with limited expected survival time were also included. This patient population was included because the investigators felt that a single session of SRS could achieve a rapid symptom control of spine metastasis with less inconvenience to the sick patient. Therefore, no stopping rules were applied. Radioresistant tumors such as melanoma and chordoma were also included in this study. The radiosurgery doses were 14-20 Gy (median dose 16 Gy) according to a dose escalation scheme. For the spinal cord tolerance, they used institutional partial volume spinal cord tolerance of 10 Gy to 10% of the spinal cord volume which was defined as 6 mm above and below the radiosurgery target (32). Radiosurgery was performed with rapid dose fall off at the contacting border of the epidural tumor and the spinal cord.

The radiographic epidural tumor control results are encouraging (33). Despite the modest radiosurgery dose and some compromise in some small portion of epidural tumor, the overall epidural tumor response rate was 80% (complete response 27%, partial response 30%, and minimal response 23%). There was no response in 14%, and tumor progression 6%. The rate of overall epidural tumor volume reduction was 65 ± 14% at 2 months after radiosurgery. The tumor response was measured using gadolinium contrast T1-weighted MR images. The epidural tumor was 0.82 ± 0.08 cm² before radiosurgery, and the tumor reduced to 0.41 ± 0.06 cm² at 2 months after radiosurgery (p<0.001). To demonstrate epidural decompression by SRS, they measured the thecal sac area using T2-weighted MRI scan. The thecal sac area improved from 1.05 ± 0.11 cm² to 1.35 ± 0.11 cm² (p<0.001). Ultimately, the thecal sac patency increased from 55 ± 4% to 76 ± 3% by SRS (p<0.01). These were measured at the level of most severe spinal cord compression.

Neurological outcome is important in the treatment of MSCC. With a median clinical followup of 11.5 months for 62 patients, the neurological status remained intact in 94% (33/35) of patients who were intact before radiosurgery. Among the 27 patients who presented with neurological deficit, 52% (14/27) had complete recovery to normal, 11% (3/27) improved, and 11% (3/27) remained stable.

The results of this clinical trial indicate the potential value of epidural decompression by radiosurgery for endpoints of radiographic and neurological levels, as summarized in Table 2. It is also worthwhile to look at the patients who progressed after radiosurgery. Overall, 16% (9/62 total patients) had neurological progression; 2 patients were neurologically intact before radiosurgery, and 7 patients had initial neurological deficit. Radiographically, these failures were in-field failure in 3, immediately adjacent spine in 5, and compression fracture in 1. Because of the small numbers, no correlation could be identified with the severity of initial extent of MSCC or the radiosensitivity of the tumor histology. Upon neurological progression, 5 of these patients underwent surgical resection. Of note is that the surgical specimen of 2 patients with breast and lung cancer showed no tumor. Two patients died of respiratory distress during salvage surgery, and with systemic tumor progression. There were no treatment-related neurological complications.

Table 2.

Outcomes of Radiosurgery for MSCC (Reference 32)

Radiographic Outcome (at 2 months after SRS)	Overall tumor response	80%
	Overall epidural tumor volume reduction	65 ± 14%
	Epidural tumor size*	Pre-SRS	0.82 ± 0.08 cm2	P<0.001
		Post SRS	0.41 ± 0.06 cm2
	Thecal sac area*	Pre-SRS	1.05 ± 0.11 cm2	P<0.001
		Post SRS	1.35 ± 0.11 cm2
	Thecal sac patency*	Pre-SRS	55 ± 4%	P<0.001
		Post SRS	76 ± 3%
Neurological Outcome	Remain intact or improved to normal	75% (47/62)
	Improved but with deficit	10% (6/62)
	Progressed	15% (9/62)

^*measured at the level of most severe spinal cord compression

This clinical trial is challenged by the poor MRI followup rate of 58% with a primary endpoint of radiographic thecal sac decompression. This was because patients with limited survival time and widespread metastases were included in the study. Regardless, the results are encouraging. Overall, more than 80% of the patients with MSCC and minimal neurological signs improved or remained intact. These patients can be treated with radiosurgery. Indeed, majority of the patients in this clinical trial included patients with no neurological deficits and 94% of them remained intact after radiosurgery. Pending further large scale clinical investigation in this critically-ill patient population, it can be a provoking or investigative concept that ambulatory patients with minimal neurological signs can be treated with radiosurgery, whereas surgical exploration should be performed for patients with rapidly progressing or overt neurological deficits.

The merit of spine radiosurgery is that it is non-invasive treatment that has been demonstrated with an initial clinical experience to improve thecal sac patency and neurological function. Overall, the radiosurgery procedure was convenient, well tolerated, and performed on an outpatient basis. In addition, since radiosurgery is administered only to the involved spine and epidural tumor, it has the added benefit of sparing the functioning bone marrow of the spine and facilitates continuation of systemic chemotherapy.

POTENTIAL PITFALLS AND CONCERNS OF USE OF RADIOSURGERY FOR MSCC

Traditionally in the emerging field of SBRT that is still in its formative years, the spinal metastasis patient whose presentation includes impending MSCC has been typically either formally or informally excluded as a candidate for spine SBRT by most practitioners (34). The main reason is that it is thought that clinically significant doses cannot be delivered to the epidural tumor that is in close juxtaposition to the spinal cord or directly abutting or compressing the spinal cord. Because of the physical dose gradients that exist between epidural tumor and the spinal cord organ at risk, the epidural component of the spinal tumor where full prescription dose is needed the most, is in fact underdosed. The epidural component of disease that is underdosed is then likely to progress to frank spinal cord compression with accompanying neurologic sequelae. For these reasons, patients with acute MSCC are best managed by DDS in the form of limited resection of epidural tumor, or total vertebrectomy and stabilization when operable (14)

While surgery is a complex undertaking, spine radiosurgery may be considered an equally complex undertaking, requiring the orchestration of a team comprising the radiation oncologist, medical physicist, neurosurgeon or orthopedic surgeon, pain management specialist, neuroradiologist, radiation therapist, and nurse. The workflow of spine radiosurgery as it is practiced at most academic centers is a multi-day process consisting of body immobilization procedures, CT image acquisition, possible myelogram, MRI fusion, target delineation of target volume and organs at risk, treatment planning, end-to-end physics quality assurance procedures, and finally actual image-guided delivery of radiosurgery. On average, at the M. D. Anderson Cancer Center, it is estimated that the entire above described workflow can take about one week. The current time frame that spine radiosurgery can be performed in most centers is probably not compatible with the urgency of care required for acute MSCC. Thus for the operable patient, surgery followed by conventional radiotherapy remains the standard of care in the management of MSCC. For patients with radioresistant tumors such as renal cell carcinoma and melanoma, studies suggest that radiosurgery may offer improved tumor control over conventional RT (35). For similar reasons, these tumors can be surgically resected and radiosurgery can be applied in the post-operative setting (36).

An important area of investigation that is critical to the optimal application of spine radiosurgery but remains unknown is the spinal cord tolerance. Ryu et al have reported their clinical observation of spinal cord tolerance 10Gy to 10% as a spinal cord constraint with the spinal cord volume defined as 6 mm above and below the radiosurgery target (32). Lovelock et al report their spine SBRT experience using a maximum dose constraint of 14Gy to the spinal cord with no reported cases of spinal cord myelopathy (37). In their patterns of failure dosimetric analysis, a minimum dose of 15Gy was identified as a cut off for achieving tumor control or failure. In addition, the same group of investigators led by Yamada et al found that spinal tumors prescribed to 24Gy in a single session achieved superior tumor control compared to tumors prescribed to under 24Gy (27). From this data, it is apparent that if the spinal cord tolerance could be defined to be at least 15Gy, this would lend support that spine radiosurgery could be used to treat the epidural component that is in close proximity or even abutting the spinal cord since the radiosurgical dose is likely high enough to control the epidural tumor. Defining the spinal cord tolerance is complicated in that it could theoretically vary depending upon the level the index lesion is located is cervical, thoracic or lumbar depending on blood supply. In addition, the degree of spinal cord impingement and volume of epidural tumor may affect spinal cord tolerance depending on the particular case pathophysiology of the MSCC leading to ischemia, direct mechanical compression on neural tissues or both. A mitigating factor may be the short life expectancy of the MSCC patient, in that such patients may not live long enough to fully express the sequelae of radiation induced spinal cord myelopathy.

For the inoperable spine MSCC patient, conventional radiotherapy remains the de facto standard management for patients presenting with MSCC. As mentioned earlier in this article, the results associated with conventional RT are poor in terms of rates of maintaining ambulation (50%), and regaining the ability to ambulate (19%). Thus the most fruitful area of investigation that may lead to greatest potential gain may be for MSCC patients who are inoperable and who are radiation-naïve or previously irradiated and are faced with the prospect of impending neurological deficit. Since these patients are likely to have a suboptimal result with conventional radiotherapy and corticosteroids, or previously irradiated patients getting just steroids alone, the risk/benefit equation is such that accepting a greater risk of radiation-induced myelopathy, with spinal cord constraint dose escalation, is justified since the alternative therapies (excluding surgery) are likely to lead to spinal cord myelpathy secondary to tumor progression.

It is proposed that a rigorous Phase I study be carried out on medical inoperable MSCC patients with two groups, 1) previously irradiated, and 2) radiation naïve. Dose escalation on the spinal cord constraints should be performed in a systematic fashion with adequate followup on each cohort to monitor for radiaton-induced myelopathy, and with formal statistical stopping rules to guard against excessive toxicity. Strict clinical follow-up with MRI of the spine would be mandatory to document radiographic control of the epidural disease, and distinguish between progressive disease and radiation as a cause of myelopathy and paralysis.

For patients who are ambulatory or without neurologic deficit, further clinical trials are warranted to test whether SRS can be as effective as DDS plus radiation. SRS is non-invasive and does not require recovery time, whereas DDS is an invasive open surgery requiring instrumentation for spine stability. If SRS and DDS are proven to be equally successful treatments, it will provide treatment options to properly select for management of MSCC patients with various oncologic or medical problems. For patient selection and treatment decision making, grading the degree of spinal cord compression is essential to establish what grades might treatable with radiosurgery (33). A proposed grading system is summarized in Table 3. Careful patient selection with a pertinent grading system will also help develop individualized treatment strategies.

Table 3.

Proposed Grading System of Spinal Cord Compression

Radiographic Grade		Neurological Grade
Grade	Description	Grade	Description
0	Spine bone involved only	a	No abnormality
I	Tumor involves epidural fat, and can abut the thecal sac.	b	Minor symptoms (eg, radiculopathy, sensory change)
II	Thecal sac compressed, CSF present between tumor and spinal cord	c	Functional paresis with muscle power ≥ 4/5. It can be nerve root sign or spinal cord sign. Involved muscle is functional in the upper extremity, and ambulatory in the lower extremity
III	Tumor abuts or impinges spinal cord	d	Functional paresis with muscle power ≤3/5. Involved muscle is non-functional in the upper extremity, and non-ambulatory in the lower extremity
IV	Spinal cord displaced, CSF visible within dura	e	Paralysis, Incontinence
V	Complete block, Spinal cord compressed, no CSF visible within dura

CONCLUSION

Radiosurgery/SBRT and associated advances in RT technology have now allowed for investigation of its use in the management of MSCC. It is an investigative journey which demands and requires stepwise and rigorous clinical trial testing and reporting. It is an investigative journey that is not for the faint of heart. While the consequences of a lack of rigorous evaluation can be devastating, equally devastating will be the continued consequences of the ongoing lack of a truly effective non-surgical therapy. It is only through well designed clinical trial investigation that we will define the utility of Radiosurgery/SBRT in improving the quality of life for the majority of patients with MSCC.