complication of radiation therapy that can be mini mized with appropriate dose-fractionation schedule selection with conventionally-fractionated
radiotherapy. The spinal cord tolerance to conventionally fractionated radiotherapy to full- thickness cord is relatively well understood, based on early work by Boden ( 1948 ) , Marcus and Million ( 1990 ) , Emami et al. ( 1991 ) , Baumann et al. ( 1994 ) , and more recently by Schultheiss ( 2008 ) . The risk of myelopathy following 50–55 Gy in 2 Gy daily fractions is approximated at less than 1%, with sharply increasing risk at doses exceeding 60 Gy.
Radiation injury at doses below 50 Gy with conventional fractionation is felt to be largely
M. E. Daly (*) • I. C. Gibbs
Department of Radiation Oncology , Stanford University Medical Center , 875 Blake Wilbur Drive , Stanford , CA 94305 , USA
e-mail: [email protected] ; [email protected]
Spinal Radiosurgery: Delayed Radiation-Induced Myelopathy
Megan E. Daly and Iris C. Gibbs
idiosyncratic. It is well accepted that factors infl uencing development of myelopathy included fraction size, total dose, and interfraction interval.
By contrast, tolerance of the human spinal cord to the high dose-per-fraction dosimetry encounter in stereotactic radiosurgery (SRS) is relatively poorly understood. SRS allows for precise delivery of high dose-per-fraction radiotherapy to target lesions, with a steep dose fall off. Thus, SRS dose distributions may provide not only higher doses per fraction than encountered in conventional RT, but also partial cord thickness exposure and a steep dose gradient across width of the cord. In the spinal region, SRS is used most commonly to target metastatic tumors, but has also gained acceptance as a treatment modality for benign and malignant primary spinal tumors and for arteriovenous malformation ablation. Published cord limit guidelines from large spinal SRS series range from a maximum cord dose (cord D max ) of 10 to 14 Gy or a partial volume tolerance of 10 Gy (V10) to 10% of the contoured cord, with spinal myelopathy infrequently reported using these parameters. Appropriate upper limit dose constraints for the spinal cord with single fraction or high dose per fraction radiosurgery remain poorly defi ned, in large part due to the paucity of reported cases of spinal cord myelopathy following SRS. Long-term outcomes data for SRS-induced spinal myelopathy are further impeded by the limited survival of many spinal metastasis patients treated with SRS. However, as improvements in systemic therapy allow for an increased life- expectancy for patients with metastatic cancer, and with the increasing use of spinal SRS in the benign setting, an improved understanding of spinal cord tolerance to this type of dosimetry remains an important goal.
Clinical Considerations Clinical Presentation
First described in the literature by Boden ( 1948 ) , delayed radiation-induced myelopathy typically presents at greater than 6 months following con- ventionally fractionated RT and can develop up
to several years following treatment. Among the few reported cases of myelopathy in the setting of SRS, the time of onset appears similar. Reports of SRS-induced myelopathy from Stanford and the University of Pittsburgh (Gibbs et al. 2009 ) suggested a mean time to onset of 6.3 months.
Clinical symptoms of delayed radiation myelo- pathy include sensory and motor defi cits at and distal to the level of injury, bowel and bladder dysfunction, and, in the most serious cases, para- plegia or quadriplegia. Criteria for diagnosis of delayed radiation myelopathy suggested by Pallis et al. ( 1961 ) propose that the primary neurologic deficits must be accounted for by damage to the exposed region of cord, and that other causes of neurologic dysfunction, particularly tumor progression leading to spinal cord compression, must be excluded.
Magnetic resonance imaging (MRI) is the predominant imaging modality of use in assisting in the diagnosis of radiation myelopathy. Two studies specifi cally evaluating MRI fi ndings in patients with radiation myelitis by Wang et al.
( 1992 ) and Alfonso et al. ( 1997 ) illustrate that focal cord edema evident by hyperintensity on T2-weighted imaging and low signal intensity on T1-weighted imaging are the predominant fi ndings. Other imaging studies such as com- puted tomography (CT), and plain fi lms, have minimal diagnostic utility, although they may assist in excluding other causes of neurologic compromise (Rampling and Symonds 1998 ) . Fluorodeoxyglucose positron emission tomogra- phy (FDG-PET) has been evaluated in limited experimental settings as described by Uchida et al. ( 2009 ) , with some suggestion that it may provide additional diagnostic information, but is not currently part of the routine evaluation for myelopathy.
Treatment
To date, no effective treatment for radiation- induced myelopathy has been established. The clinical course is typically progressive and irre- versible, although cases of spontaneous improve- ment have been documented as case reports.
It is assumed that SRS-induced cases of radiation myelopathy will follow a similarly grim course.
Corticosteroids, anticoagulants, and hyperbaric oxygen have been evaluated as potential treatment modalities without signifi cant clinical effi cacy observed.
Biologic Considerations
Mechanisms of Radiation-Induced Damage
The pathogenesis of SRS-induced spinal cord injury is likely multifactorial, mediated by damage to both white matter tracts and local vasculature as with conventional radiotherapy. Schultheiss et al. ( 1988, 1995 ) have carefully catalogued the myriad pathologic observations noted in conven- tionally-fractionated radiation-induced myelopa- thy, including demyelination, malacia, increased vascularity, telangectasia, hyaline degeneration/
thickening, edema and fi brin exudation, vasculitis, fi brinoid necrosis, thrombosis, and hemorrhage.
In the hypofractionated setting, Bijl et al. ( 2002,
2005 ) have demonstrated in a rat model using high-precision single-fraction proton irradiation that white matter necrosis was the predominant pattern of damage in paralyzed rats. No damage or morphologic change was noted in the peripheral nerve roots or gray matter. Differences in vascular supply and density between white and gray matter may partially explain these fi ndings.
Radiobiologic Models
Radiobiologic models provide an important tool with which to estimate the effects of given radia- tion dose fractionation schemes. The biologically effective dose (BED) is defi ned as the total radia- tion dose delivered by an infi nite number of infi n- itesimally small fractions providing an equivalent biologic effect to a given fractionation scheme, and thus calculation of the BED allows compari- son between different dose fractionation schemes.
Historically, the linear quadratic (LQ) model as fi rst described by Douglas and Fowler ( 1976 ) has
been used to facilitate calculation of a BED via the following formula: BED = nd[1 + d/( a / b )]
where n = number of fractions, d = dose per frac- tion, and a / b = alpha/beta ratio, generally esti- mated as ranging from 2 to 4 for purposes of late cord toxicity. However, a number of empiric observations suggesting that the LQ model does not accurately predict the effects of the high dose-per-fraction schemes used in SRS have led to an interest in alternative models. The multi-target model is an early radiation dose model that describes clonogenic survival as a function of radiation dose. Recently, Park et al. ( 2008 ) have proposed a linear quadratic-linear (LQ-L) model/
Universal survival curve hybridizing the LQ model with the multi-target model, assuming a transition dose, D T , at which the LQ model transi- tions to the multitarget model. Additional efforts with normal tissue complication probability (NTCP) modeling with a variety of models are ongoing, but thus far no radiobiologic model has accurately and fully described clinical observa- tions of tissue effects following SRS.
Animal Models
Excellent data from rat models provide additional insight into the potential upper dose limits of the spinal cord to partial cord, high-dose per fraction radiation such as that encountered in SRS. As previously mentioned, Bijl et al. ( 2002, 2005 ) have described a series of animal experiments performed with single-fraction proton irradiation in a rat model. By treating increasing lengths of full-thickness cord, the authors established a length effect for high dose-per-fraction treatments with a marked increase in the ED 50 (dose at which 50% of the treated animals developed limb paral- ysis) to single-fraction treatment as the length of irradiated cord decreased. For a 20 mm irradiated length of spinal cord, the ED 50 was 20.4 Gy, whereas for 4 and 2 mm lengths of irradiated spinal cord, the ED 50 was 53.7 and 87.8 Gy, respectively. A second set of experiments demon- strated an increase in the partial cord tolerance to focused partial-cord proton irradiation as com- pared to irradiation of the full-thickness spinal cord.
Treatment of the lateral portions of the cord with a tight beam penumbra predicted an ED 50 of 33.4 Gy as compared to an ED 50 of 20.4 Gy for full thickness cord treatment. When the central cord was treated with relative sparing of the lateral cord regions, the ED 50 increased markedly to 71.9 Gy. In aggregate, these studies suggest both a partial volume tolerance model for the rat spinal cord and the presence of regional differences in radiation sensitivity across the cord. However, given the narrow diameter of the rat spinal cord, these animal data may not be directly applicable to humans. A series of experi- ments with a porcine model by Medin et al.
( 2007 ) , an animal with similar spinal anatomy to humans, have thus far suggested that pigs do not display the same high ED 50 noted in rat experiments.
Human Data
Several studies have reported outcomes for spinal SRS with varying spinal cord dose constraints in effect. Chang et al. ( 2007 ) report the results of a prospective phase I/II trial evaluating SRS for treatment of 74 spinal lesions. No cord myel- opathy was observed when the spinal cord D max was restricted to less than 10 Gy. Yamada et al.
( 2008 ) have described a series of 93 patients with 103 spinal lesions in whom the spinal cord D max was limited to 14 Gy with no neurologic seque- lae. Gerszten et al. ( 2007 ) reviewed the use of SRS for 500 metastatic lesions to the spine, with a mean volume of spinal canal of 0.6 cm 3 receiv- ing >8 Gy. No cases of radiation-induced spinal injury were noted. Ryu et al. ( 2007 ) retrospec- tively evaluated 230 metastatic tumors to the spine treated with SRS, limiting the spinal cord volume receiving 10 Gy (V10) to 10% of the cord as contoured 6 mm above and below the target volume. The authors describe one case of radiation-induced spinal cord injury 13 months following treatment in a patient treated with 16 Gy in a single fraction to a C1 lesion with a point-maximum dose of 14.6 Gy. No specifi c patient or treatment plan characteristics were identifi ed to explain the patient’s complication.
Gibbs et al. ( 2009 ) have reported the largest series of patients treated with spinal SRS to date, evaluating 1,075 patients treated in 1–5 fractions for benign or malignant spinal tumors. Goal spinal cord D max limit was 10 Gy and six cases of spinal myelopathy were observed, two of which occurred in patients who had received prior external beam radiation. In review of the treatment plans of the patients developing myelopathy it was noted that three of the six were clear outliers with regards to maximum cord dose, while the other three received 8 Gy in a single fraction to only a small volume of cord and no clear cause for radiation injury was identifi ed. Interestingly, two of the six affected patients had received an antiangiogenic or epidermal growth factor inhibitor within 2 months of development of myelopathy.
The impact of systemic cancer treatments on tissue sensitivity to radiation, particularly newer tar- geted agents and angiogenesis inhibitors, is poorly understood to date. Increasing use of these agents in patients undergoing radiosurgical procedures will necessitate further exploration in this area.
Data from our institution (Daly et al. 2009 ) evaluating patients treated aggressively with SRS for pial-based spinal hemangioblastomas lends a human clinical correlate to partial volume tolerance models observed in animals. A cohort of 19 patients underwent SRS to a total of 27 spinal lesions, with a median spinal cord maximum dose of 22.7 Gy among single fraction treatments.
Despite dramatically exceeding conventional dose limits for SRS, toxicity was mild with one case of grade 3 myelopathy in the form of a unilateral foot drop. The small median target size (92 mm 3 among single fraction targets and 392 mm 3 among multi-fraction targets) likely contributed to the lack of severe myelopathy and supports a partial volume tolerance model.
Discussion
To date, only ten cases of SRS-induced delayed spinal myelopathy have been reported in the lite- rature (Gibbs et al. 2009 ; Gwak et al. 2005 ; Benzil et al. 2004 ; Ryu et al. 2007 ) , perhaps a testament to the relatively conservative dose-constraints
imposed by the majority of SRS groups.
However, given the gravity of this particular com- plication and the increasing frequency of SRS treatments for both benign and malignant lesions of the spine, refi ning our understanding of spi- nal cord dose tolerance to the dosimetry encoun- tered in SRS remains important. The published series of spinal SRS treatments contain a rela- tively heterogeneous patient population, encom- passing both benign and malignant tumors at all spinal levels, some in the setting of tumor-directed systemic therapies. Coupled with the low overall incidence of radiation-induced spinal injury, no specifi c patient or tumor characteristics can be clearly cited as risk factors for myelopathy based upon the present data.
Potent areas of active investigation include further biologic NTCP modeling to better under- stand both dose/volume effects in the cord and to provide accurate BED estimations for high dose-per fraction treatments. To date, no known biologic model fully accounts for the in vivo effects of the dosimetry encountered in SRS.
Elucidating the impact of systemic cancer thera- pies, particularly angiogenesis inhibitors and targeted therapies, also remains an area of active investigation of increasing importance.
In aggregate, both animal and human data to date suggest that current dose guidelines are appropriately conservative to minimize the risk of radiation myelopathy. Given the variation in treatment planning and delivery systems, it is likely that the safest approach is to consider the use of both threshold maximum dose guidelines and volumetric constraints. At our institution, care is made to conform to both a maximum dose constraint of approximately 14 Gy and volumetric constraints that limit the volume of spinal cord treated above 8 Gy biologic equivalent dose to less than 1 cm 3 , and the volume above 10 Gy to less than 0.6 cm 3. Additional efforts to refi ne these guidelines, either via additional animal studies or normal tissue complication probability modeling, will allow improved decision making when weighing likelihood of tumor control against risk of spinal cord damage, particularly in the setting of other mitigating factors such as expo- sure to systemic targeted therapy.
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