Re: LCD DL Draft LCD for Stereotactic Radiation Therapy: Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiation Therapy (SBRT)

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1 June 24, 2014 Dr. Bernice Hecker, MD, MHA, FACC Contractor Medical Director Noridian Healthcare Solutions, LLC nd Street S. P.O. Box 6740 Fargo, ND Re: LCD DL Draft LCD for Stereotactic Radiation Therapy: Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiation Therapy (SBRT) Dear Dr. Hecker: The American Society for Radiation Oncology * (ASTRO) appreciates the opportunity to review and provide comments on the Noridian Healthcare Solutions, LLC Jurisdiction E, draft LCD DL35236 on Stereotactic Radiosurgery (SRS) and Stereotactic Body Radiation Therapy (SBRT). Noridian accepted some of ASTRO s previous recommendations sent on April 17, 2012, but in light of recently published data, ASTRO respectfully submits the following comments. Stereotactic Radiosurgery (SRS) Indications The draft LCD states that patients with more than three primary or metastatic brain lesions must be enrolled in an IRB-approved clinical trial or appropriate clinical registry for coverage. ASTRO recommends the removal of the limit on the number of primary or metastatic lesions to determine medical necessity. We recommend a more nuanced approach in which the number of intracranial lesions is not the essential consideration in making a determination to use SRS. A large body of published literature shows that patients presenting with greater than three lesions and excellent performance status also benefit from SRS 1-5. Recent studies found Karnofsky Performance Status (KPS) score, not the number of brain metastases, significantly correlated with overall survival 2-4. The total intracranial volume rather than the number of metastases has been demonstrated to be an important predictor of survival in two major series 4,5. While ASTRO supports the accrual of additional data and research, including the creation of a national SRS * ASTRO is the premier radiation oncology society in the world, with more than 10,000 members who are physicians, nurses, biologist, physicists, radiation therapists, dosimetrists and other health care professionals that specialize in treating patients with radiation therapies. As the leading organization in radiation oncology, the Society is dedicated to improving patient care through professional education and training, support for clinical practice and health policy standards, advancement of science and research, and advocacy. ASTRO publishes two medical journals, International Journal of Radiation Oncology, Biology, Physics ( and Practical Radiation Oncology ( developed and maintains an extensive patient website, and created the Radiation Oncology Institute ( a non-profit foundation to support research and education efforts around the world that enhance and confirm the critical role of radiation therapy in improving cancer treatment. To learn more about ASTRO, visit

2 ASTRO Comments Noridian Draft LCD (DL35236) for SRS and SBRT Page 2 registry, which we anticipate joining with another professional society, we believe that the limiting criteria listed in items 7,8,and 9 under Indications for SRS/SBRT (for Cranial Lesions only) to be unnecessary and overly restrictive. Likewise, item #3 should be deleted. Additionally, the draft policy declares cobalt-60 pallidotomy a non-covered service. In Chapter 13 of the ASTRO/ACR Guide to Radiation Oncology Coding 2010 under Common Clinical Indications, ASTRO states that SRS may be used as a course of treatment in movement disorders such as Parkinson s disease, essential tremor, and other disabling tremors when open neurosurgical thalamotomy cannot be performed and medical therapy is unsatisfactory. Several studies support this approach 6-8. The draft policy also does not include ICD-9-CM code (Essential and Other Specified Forms of Tremor) in the list of codes that support medical necessity. ASTRO s SRS Model Policy recommends coverage for ICD-9-CM code be limited to the patient who cannot be controlled with medications, has major systemic disease or coagulopathy, and who is unwilling or unsuited for open surgery. Coverage should further be limited to unilateral thalamotomy. While ASTRO agrees that SRS is not the primary treatment for all patients suffering from functional disorders, stereotactic radiotherapy offers an appropriate alternative for select cases. Thus, we recommend removing the cobalt-60 pallidotomy noncoverage statement and adding ICD-9-CM code to the final policy. Stereotactic Body Radiation Therapy (SBRT) Indications ASTRO proposes Noridian remove the requirement that prostate cancer patients be enrolled in an IRB-approved clinical trial or registry. ASTRO updated its SBRT Model Policy in April 2013 to reflect the many clinical studies now supporting SBRT in the treatment of prostate cancer. The clinical data has matured to a point where SBRT represents an appropriate alternative for select patients with low to intermediate risk prostate cancer. A recently published pooled analysis of 1100 patients enrolled on prospective trials of SBRT for prostate cancer demonstrates biochemical relapse-free survival rates and quality of life outcomes that compare favorably with other definitive treatments for prostate cancer 9,10. After a median dose of Gy in 4-5 fractions, the 5-year biochemical relapse free survival rate was 93% for all patients; 95%, 83% and 78% for GS 6, 7 and 8, respectively; and 95%, 84% and 81% for low-, intermediate- and high-risk patients, respectively. A transient decline in the urinary and bowel domains was observed within the first 3 months after SBRT which returned to baseline status or better within 6 months and remained so beyond 5 years. In addition, SBRT s cost effectiveness relative to other forms of radiation therapy of prostate cancer 11,12 in this is appealing in this setting. Additionally, the draft policy lacks crucial ICD-9-CM codes indicated for SBRT including those for recurrent pelvic and head and neck tumors that have recurred after primary irradiation, listed on page seven of the LCD. SBRT may also treat patients with recurrent nodal metastasis who have already undergone prior conventionally fractionated radiotherapy and thus the corresponding diagnosis codes should be included in the policy. ASTRO recommends the following ICD-9-CM codes be added to the final LCD: Malignant neoplasms of the pharynx

3 ASTRO Comments Noridian Draft LCD (DL35236) for SRS and SBRT Page Malignant neoplasms of the nasal cavities, accessory sinuses, and larynx Malignant neoplasms of the rectum and anus Malignant neoplasms of the female reproductive system Malignant neoplasm of abdomen Malignant neoplasm of pelvis Secondary and unspecified malignant nodal neoplasms Stereotactic Radiotherapy Coding Historically, in the hospital outpatient environment, CMS utilized G-codes to distinguish between robotic and non-robotic SBRT and SRS. The agency recently reviewed current radiotherapy equipment technology and found that most linac-based treatment platforms incorporate some type of robotic capability. CMS therefore concluded that it is no longer necessary to continue distinguishing robotic and non-robotic linear accelerators. Beginning January 1, 2014, CMS replaced the existing four HCPCS codes: G0173, G0251, G0339, and G0340 with the SRS CPT code and SBRT code The chart below provides a summary of these changes: 2013 CPT Code G0173 G0251 G0339 G0340 Descriptor 2014 CPT Code Linear accelerator stereotactic radiosurgery, complete course of therapy in one session Linear accelerator based stereotactic radiosurgery, delivery including collimator changes and custom plugging, fractionated treatment, all lesions, per session, maximum five sessions per course of treatment. Image-guided robotic linear acceleratorbased stereotactic radiosurgery, course of therapy in one session, or first session of fractionated treatment Image-guided robotic linear acceleratorbased stereotactic radiosurgery, delivery including collimator changes and custom plugging, fractionated treatment, all lesions, per session, second through fifth sessions, maximum five sessions per course of treatment Descriptor Radiation treatment delivery, stereotactic radiosurgery (SRS), complete course of treatment of cranial lesion(s) consisting of 1 session; linear accelerator based. Stereotactic body radiation therapy, treatment delivery, per fraction to 1 or more lesions, including image guidance, entire course not to exceed 5 fractions.

4 ASTRO Comments Noridian Draft LCD (DL35236) for SRS and SBRT Page 4 The draft coverage policy lists G-codes in the CPT/HCPCS Code section. In order to avoid any confusion, ASTRO recommends Noridian remove all G-codes from the final LCD. Enclosed for your reference are the current version of ASTRO s SRS and SBRT Model Coverage Policies. ASTRO recently mailed Noridian complimentary copies of the ASTRO/ACR Guide to Radiation Oncology Coding 2010: 2014 Supplement. Chapters 13 and 14 provide extensive coding information for these technologies including the codes integral to the process of care. Since no specific codes for SRS planning or for the professional component of SBRT planning exist, other codes such as CPT code (3-dimensional radiotherapy plan, including dose-volume histograms) or IMRT CPT code (Intensity modulated radiotherapy plan, including dose-volume histograms for target and critical structure partial tolerance specifications) are appropriate. Thank you for your consideration of our comments. Should you have any questions or wish to discuss SRS/SBRT and our recommendations further, please contact ASTRO s Assistant Director of Health Policy, Anne Hubbard, at (703) or via at anneh@astro.org. Sincerely, Laura I Thevenot Chief Executive Officer cc: Arthur Lurvey, MD Richard Whitten, MD, MBA, FACP Enclosures: ASTRO SRS Model Policy ASTRO SBRT Model Policy ASTRO/ACR Guide to Radiation Oncology Coding Chapter 13 and 14 Radiotherpetuic and surgical management for newly diagnosed brain metastasis(es): an American Society for Radiaion Oncology evidence based guideline References: 1. Serizawa T, Hirai T, Nagano O, et al. Gamma knife surgery for 1 10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multi-institute study (JLGK0901) inclusion criteria. J Neurooncol. 2010; 98(2): Hunter GK, Suh JH, Reuther AM, et al. Treatment of five or more brain metastases with stereotactic radiosurgery. Int J Radiat Oncol Biol Phys. 2012; 83(5): Raldow AC, Chiang VL, Knisely JP, et al. Survival and intracranial control of patients with 5 or more brain metastases treated with gamma knife stereotactic radiosurgery. Am J Clin Oncol. 2013; 36(5): Bhatnagar AK, Flickinger JC, Kondziolka D, Lunsford LD. Stereotactic radiosurgery for four or more intracranial metastases. Int J Radiat Oncol Biol Phys. 2006; 64(3): Likhacheva A, Pinnix CC, Parikh NR, et al. Predictors of survival in contemporary practice after initial radiosurgery for brain metastases, Int J Radiat Oncol Biol Phys. 2013; 85(3):

5 ASTRO Comments Noridian Draft LCD (DL35236) for SRS and SBRT Page 5 6. Kooshkabadi A, Lunsford LD, Tonetti D, et al. Gamma Knife thalamotomy for tremor in the magnetic resonance imaging era. J Neurosurg. 2013; 118(4): Ohye C1, Higuchi Y, Shibazaki T, et al. Gamma knife thalamotomy for Parkinson disease and essential tremor: a prospective multicenter study. Neurosurgery. 2012; 70(3): Young RF, Li F, Vermeulen S, Meier R. Gamma Knife thalamotomy for treatment of essential tremor: long-term results. J Neurosurg. 2010; 112(6): King CR, Freeman D, Kaplan I, et al. Stereotactic body radiotherapy for localized prostate cancer: pooled analysis from a multi-institutional consortium of prospective phase II trials. Radiother and Oncol. 2013; 109(2): King CR, Collins S, Fuller D, et al. Health-related quality of life after stereotactic body radiation therapy for localized prostate cancer: results from a multi-institutional consortium of prospective trials. Int J Radiat Oncol Biol Phys. 2013; 87(5): Hodges JC, Lotan Y, Boike TP, et al. Cost-effectiveness analysis of stereotactic body radiation therapy versus intensity-modulated radiation therapy: an emerging initial radiation treatment option for organ-confined prostate cancer. J Oncol Practice. 2012; 8(3 Suppl):e31s-37s. 12. Parthan A, Pruttivarasin N, Davies D, et al. Comparative cost-effectiveness of stereotactic body radiation therapy versus intensity-modulated and proton radiation therapy for localized prostate cancer. Front Oncol. 2012; 2:81.

6 American Society for Radiation Oncology (ASTRO) Stereotactic Radiosurgery (SRS) Model Coverage Policy AMA CPT / Copyright Statement CPT codes, descriptions and other data only are copyright 2010 American Medical Association (or such other date of publication of CPT). CPT is a registered trademark of the American Medical Association. All Rights Reserved. Indications and Limitations of Coverage and/or Medical Necessity This Model Policy 1 addresses coverage for Stereotactic Radiosurgery (SRS). Stereotactic Radiosurgery (SRS) is a distinct discipline that utilizes externally generated ionizing radiation in certain cases to inactivate or eradicate a defined target(s) in the head or spine without the need to make an incision. The target is defined by high-resolution stereotactic imaging. To assure quality of patient care, the procedure involves a multidisciplinary team consisting of a neurosurgeon, radiation oncologist, and medical physicist. (For a subset of tumors involving the skull base, the multidisciplinary team may also include a head and neck surgeon with training in stereotactic radiosurgery). The adjective Stereotactic describes a procedure during which a target lesion is localized relative to a fixed three dimensional reference system, such as a rigid head frame affixed to a patient, fixed bony landmarks, a system of implanted fiducial markers, or other similar system. This type of localization procedure allows physicians to perform image-guided procedures with a high degree of anatomic accuracy and precision. Stereotactic radiosurgery (SRS) couples this anatomic accuracy and reproducibility with very high doses of highly precise, externally generated, ionizing radiation, thereby maximizing the ablative effect on the target(s) while minimizing collateral damage to adjacent tissues. SRS requires computer-assisted, three-dimensional planning and delivery with stereotactic and convergent-beam technologies, including, but not limited to: multiple convergent cobalt sources (e.g. Gamma Knife ); protons; multiple, coplanar or non-coplanar photon arcs or angles (e.g. XKnife ); fixed photon arcs; or image-directed robotic devices (e.g. CyberKnife ) that meet the criteria. SRS typically is performed in a single session, using a rigidly attached stereotactic guiding device, other immobilization technology and/or a stereotactic-guidance system, but can be performed in a limited number of sessions, up to a maximum of five. Regardless of the number of sessions, all SRS procedures include the following components: 1. Position stabilization (attachment of a frame or frameless) 2. Imaging for localization (CT, MRI, angiography, PET, etc.) 3. Computer assisted tumor localization (i.e. Image Guidance ) 1 ASTRO model policies were developed as a means to efficiently communicate what ASTRO believes to be correct coverage policies for radiation oncology services. The ASTRO Model Policies do not serve as clinical guidelines and they are subject to periodic review and revision without notice. The ASTRO Model Policies may be reproduced and distributed, without modification, for noncommercial purposes.

7 4. Treatment planning - number of isocenters, number, placement and length of arcs or angles, number of beams, beam size and weight, etc. 5. Isodose distributions, dosage prescription and calculation 6. Setup and accuracy verification testing 7. Simulation of prescribed arcs or fixed portals Radiation oncologists and neurosurgeons have separate CPT billing codes for SRS. CPT Codes , and and are reported for the work attributed to the neurosurgeon. These codes are mutually exclusive with the radiation oncology CPT codes and 77435; therefore the same physician should not bill for both of these codes. A radiation oncologist may bill the SRS management code (stereotactic radiation treatment management of cranial lesion(s) (complete course of treatment consisting of one session) for single fraction intracranial SRS (and only once per treatment course) when and only when fully participating in the management of the procedure. CPT will be paid only once per course of treatment for cranial lesions regardless of the number of lesions. When SRS is administered in more than one but not more than five fractions to the brain or in one through five fractions to the spine, the radiation oncologist should instead bill the Stereotactic Body Radiation Therapy (SBRT) code to cover patient management during that course of therapy. CPT will be paid only once per course of therapy regardless of the number of sessions, lesions or days of treatment. The radiation oncologist may not bill and for the same course of therapy. In addition to the management codes, a radiation oncologist may bill other appropriate radiation oncology (77xxx) codes for services performed prior to the delivery of SRS as indicated by the pattern of care and other Medicare policies. No one physician may bill both the neurosurgical codes , , or and the radiation oncology 77XXX codes. If either the radiation oncologist or the neurosurgeon does not fully participate in the patient s care, that physician must take care to indicate this change by use of the appropriate -54 modifier (followed by any appropriate -55 modifier) on the global procedure(s) submitted. As the services are collegial in nature with different specialties providing individual components of the treatment, surgical assistants will not be reimbursed. The technical charges used by hospital-based and outpatient facilities for SRS delivery are described by the CPT codes listed below. It is not appropriate to bill more than one treatment delivery code on the same day of service, even though some types of delivery may have elements of several modalities (for example, a stereotactic approach with IMRT). Only one delivery code is to be billed. Other radiation oncology professional and technical services required prior to the delivery of SRS are coded separately and may be appropriately billed by the radiation oncologist, when necessary. ASTRO SRS Model Coverage Policy Page 2 Final Approval Updated

8 Indications for SRS: 1. Primary central nervous system malignancies, generally used as a boost or salvage therapy for lesions <5cm. 2. Primary and secondary tumors involving the brain or spine parenchyma, meninges/dura, or immediately adjacent bony structures. 3. Benign brain tumors and spinal tumors such as meningiomas, acoustic neuromas, other schwannomas, pituitary adenomas, pineocytomas, craniopharyngiomas, glomus tumors, hemangioblastomas 4. Arteriovenous malformations and cavernous malformations. 5. Other cranial non-neoplastic conditions such as trigeminal neuralgia and select cases of medically refractory epilepsy. As a boost treatment for larger cranial or spinal lesions that have been treated initially with external beam radiation therapy or surgery (e.g. sarcomas, chondrosarcomas, chordomas, and nasopharyngeal or paranasal sinus malignancies). 6. Metastatic brain or spine lesions, with stable systemic disease, Karnofsky Performance Status 40 or greater (and expected to return to 70 or greater with treatment), and otherwise reasonable survival expectations, OR an Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 or less (or expected to return to 2 or less with treatment). 7. Relapse in a previously irradiated cranial or spinal field where the additional stereotactic precision is required to avoid unacceptable vital tissue radiation. Limitations: SRS is not considered medically necessary under the following circumstances: 1. Treatment for anything other than a severe symptom or serious threat to life or critical functions. 2. Treatment unlikely to result in functional improvement or clinically meaningful disease stabilization, not otherwise achievable. 3. Patients with wide-spread cerebral or extra-cranial metastases with limited life expectancy unlikely to gain clinical benefit within their remaining life. 4. Patients with poor performance status (Karnofsky Performance Status less than 40 or ECOG Performance greater than 3) - see Karnofsky and ECOG Performance Status scales below. 5. For ICD-9-CM code 333.1, essential tremor, coverage should be limited to the patient who cannot be controlled with medication, has major systemic disease or coagulopathy, and who is unwilling or unsuited for open surgery. Coverage should further be limited to unilateral thalamotomy. ASTRO SRS Model Coverage Policy Page 3 Final Approval Updated

9 Karnofsky Performance Status Scale 100 Normal; no complaints, no evidence of disease 90 Able to carry on normal activity; minor signs or symptoms of disease 80 Normal activity with effort; some signs or symptoms of disease 70 Cares for self; unable to carry on normal activity or to do active work 60 Requires occasional assistance but is able to care for most needs 50 Requires considerable assistance and frequent medical care 40 Disabled; requires special care and assistance 30 Severely disabled; hospitalization is indicated although death not imminent 20 Very sick; hospitalization necessary; active supportive treatment is necessary 10 Moribund, fatal processes progressing rapidly 0 Dead Karnofsky DA, Burchenal JH. (1949). "The Clinical Evaluation of Chemotherapeutic Agents in Cancer." In: MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ Press. Page 196. ECOG Performance Status Scale Grade 0: Fully active, able to carry on all pre-disease performance without restriction. Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work. Grade 2: Ambulatory and capable of all self-care but unable to carry out and work activities. Up and about more than 50% of waking hours. Grade 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Grade 4: Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Grade 5: Dead Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. * As published in Am. J. Clin. Oncol.:Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5: , CPT/HCPCS Codes Note: Uses of and are addressed in both this Model Policy and in the Stereotactic Body Radiation Therapy Model Policy Radiation treatment delivery, stereotactic radiosurgery (SRS), complete course of treatment of cranial lesion(s) consisting of 1 session; multi-source Cobalt 60 based ASTRO SRS Model Coverage Policy Page 4 Final Approval Updated

10 77372 Radiation treatment delivery, stereotactic radiosurgery (SRS), complete course of treatment of cranial lesion(s) consisting of 1 session; linear accelerator based Stereotactic body radiation therapy, treatment delivery, per fraction to 1 or more lesions, including image guidance, entire course not to exceed 5 fractions. (Do not report in conjunction with , 77418). (For single fraction cranial lesion, see 77371, 77372) Stereotactic radiation treatment management of cranial lesion(s) (complete course of treatment consisting of 1 session) (The same physician should not report both stereotactic radiosurgery services [ ] and radiation treatment management [77432 or 77435] for cranial lesions) (For stereotactic body radiation therapy treatment, use 77435) Stereotactic body radiation therapy, treatment management, per treatment course, to 1 or more lesions, including image guidance, entire course not to exceed 5 fractions (Do not report in conjunction with ) (The same physician should not report both stereotactic radiosurgery services [63620, 63621] and radiation treatment management [77435] for extracranial lesions) G0173 Linear accelerator based stereotactic radiosurgery, complete course of therapy in one session G0251 Linear accelerator based stereotactic radiosurgery, delivery including collimator changes and custom plugging, fractionated treatment, all lesions, per session, maximum five sessions per course of treatment G0339 Image-guided robotic linear accelerator-based stereotactic radiosurgery, complete course of therapy in one session or first session of fractionated treatment G0340 Image-guided robotic linear accelerator-based stereotactic radiosurgery, delivery including collimator changes and custom plugging, fractionated treatment, all lesions, per session, second through fifth sessions, maximum five sessions per course of treatment ICD-9 Codes that Support Medical Necessity Note: Diagnosis codes are based on the current ICD-9-CM codes that are effective at the time of Model Policy publication. Any updates to ICD-9-CM codes will be reviewed by ASTRO, and coverage should not be presumed until the results of such review have been published/posted. These ICD-9-CM codes support medical necessity under this Model Policy: MALIGNANT NEOPLASM OF SUPERIOR WALL OF NASOPHARYNX MALIGNANT NEOPLASM OF POSTERIOR WALL OF NASOPHARYNX MALIGNANT NEOPLASM OF LATERAL WALL OF NASOPHARYNX MALIGNANT NEOPLASM OF ANTERIOR WALL OF NASOPHARYNX ASTRO SRS Model Coverage Policy Page 5 Final Approval Updated

11 147.8 MALIGNANT NEOPLASM OF OTHER SPECIFIED SITES OF NASOPHARYNX MALIGNANT NEOPLASM OF NASOPHARYNX UNSPECIFIED SITE MALIGNANT NEOPLASM OF NASAL CAVITIES MALIGNANT NEOPLASM OF AUDITORY TUBE MIDDLE EAR AND MASTOID AIR CELLS MALIGNANT NEOPLASM OF MAXILLARY SINUS MALIGNANT NEOPLASM OF ETHMOIDAL SINUS MALIGNANT NEOPLASM OF FRONTAL SINUS MALIGNANT NEOPLASM OF SPHENOIDAL SINUS MALIGNANT NEOPLASM OF OTHER ACCESSORY SINUSES MALIGNANT NEOPLASM OF ACCESSORY SINUS UNSPECIFIED MALIGNANT NEOPLASM OF CEREBRUM EXCEPT LOBES AND VENTRICLES MALIGNANT NEOPLASM OF FRONTAL LOBE MALIGNANT NEOPLASM OF TEMPORAL LOBE MALIGNANT NEOPLASM OF PARIETAL LOBE MALIGNANT NEOPLASM OF OCCIPITAL LOBE MALIGNANT NEOPLASM OF VENTRICLES MALIGNANT NEOPLASM OF CEREBELLUM NOS MALIGNANT NEOPLASM OF BRAIN STEM MALIGNANT NEOPLASM OF OTHER PARTS OF BRAIN MALIGNANT NEOPLASM OF BRAIN UNSPECIFIED SITE MALIGNANT NEOPLASM OF CRANIAL NERVES MALIGNANT NEOPLASM OF CEREBRAL MENINGES MALIGNANT NEOPLASM OF PITUITARY GLAND AND CRANIOPHARYNGEAL DUCT MALIGNANT NEOPLASM OF PINEAL GLAND MALIGNANT NEOPLASM OF AORTIC BODY AND OTHER PARAGANGLIA SECONDARY MALIGNANT NEOPLASM OF BRAIN AND SPINAL CORD 198.4* SECONDARY MALIGNANT NEOPLASM OF OTHER PARTS OF NERVOUS SYSTEM 198.5* SECONDARY MALIGNANT NEOPLASM OF BONE AND BONE MARROW * SECONDARY MALIGNANT NEOPLASM OF OTHER SPECIFIED SITES BENIGN NEOPLASM OF BRAIN BENIGN NEOPLASM OF CRANIAL NERVES BENIGN NEOPLASM OF CEREBRAL MENINGES BENIGN NEOPLASM OF PITUITARY GLAND AND CRANIOPHARYNGEAL DUCT BENIGN NEOPLASM OF PINEAL GLAND BENIGN NEOPLASM OF CAROTID BODY *BENIGN NEOPLASM OF AORTIC BODY AND OTHER PARAGANGLIA HEMANGIOMA OF INTRACRANIAL STRUCTURES NEOPLASM OF UNCERTAIN BEHAVIOR OF PITUITARY GLAND AND CRANIOPHARYNGEAL DUCT NEOPLASM OF UNCERTAIN BEHAVIOR OF PINEAL GLAND 237.3* NEOPLASM OF UNCERTAIN BEHAVIOR OF PARAGANGLIA 237.5* NEOPLASM OF UNCERTAIN BEHAVIOR OF BRAIN AND SPINAL CORD 237.6* NEOPLASM OF UNCERTAIN BEHAVIOR OF MENINGES ASTRO SRS Model Coverage Policy Page 6 Final Approval Updated

12 239.6* NEOPLASM OF UNSPECIFIED NATURE OF BRAIN 239.7* NEOPLASM OF UNSPECIFIED NATURE OF ENDOCRINE GLANDS AND OTHER PARTS OF NERVOUS SYSTEM PARALYSIS AGITANS 333.1** ESSENTIAL AND OTHER SPECIFIED FORMS OF TREMOR GENERALIZED CONVULSIVE EPILEPSY WITH INTRACTABLE EPILEPSY GRAND MAL STATUS EPILEPTIC EPILEPSY UNSPECIFIED WITH INTRACTABLE EPILEPSY TRIGEMINAL NEURALGIA OTHER SPECIFIED TRIGEMINAL NERVE DISORDERS TRIGEMINAL NERVE DISORDER UNSPECIFIED BELL'S PALSY GENICULATE GANGLIONITIS OTHER FACIAL NERVE DISORDERS FACIAL NERVE DISORDER UNSPECIFIED 352.0* DISORDERS OF OLFACTORY (1ST) NERVE 352.1* GLOSSOPHARYNGEAL NEURALGIA 352.2* OTHER DISORDERS OF GLOSSOPHARYNGEAL (9TH) NERVE 352.3* DISORDERS OF PNEUMOGASTRIC (10TH) NERVE 352.4* DISORDERS OF ACCESSORY (11TH) NERVE 352.5* DISORDERS OF HYPOGLOSSAL (12TH) NERVE 352.6* MULTIPLE CRANIAL NERVE PALSIES 352.9* UNSPECIFIED DISORDER OF CRANIAL NERVES * CONGENITAL ANOMALIES OF CEREBROVASCULAR SYSTEM 990*** EFFECTS OF RADIATION UNSPECIFIED * ICD-9-CM codes 198.4, 198.5, , 234.8, 237.5, 237.6, 239.6, 239.7, 333.1, 352.0, 352.1, 352.2, 352.3, 352.4, 352.5, 352.6, and are all limited to use for lesions occurring either above the neck or in the spine. ** ICD-9-CM code is limited to the patient who cannot be controlled with medication, has major systemic disease or coagulopathy, and who is unwilling or unsuited for open surgery. *** ICD-9-CM 990 may only be used where prior radiation therapy to the site is the governing factor necessitating SRS in lieu of other radiotherapy. An ICD-9-CM code for the anatomic diagnosis must also be used. General Information Documentation Requirements The patient's record must support the necessity and frequency of treatment. Medical records should include not only the standard history and physical but also the patient's functional status and a description of current performance status (Karnofsky Performance Status or ECOG Performance Status). See Karnofsky Performance Status or ECOG Performance Status listed under Indications and Limitation of Coverage above. ASTRO SRS Model Coverage Policy Page 7 Final Approval Updated

13 Documentation should include the date and the current treatment dose. A radiation oncologist and a neurosurgeon must evaluate the clinical aspects of the treatment, and document and sign this evaluation as well as the resulting management decisions. A radiation oncologist and medical physicist must evaluate the technical aspects of the treatment and document and sign this evaluation as well as the resulting treatment management decisions. For Medicare claims, the HCPCS/CPT code(s) may be subject to Correct Coding Initiative (CCI) edits. This policy does not take precedence over CCI edits. Please refer to the CCI for correct coding guidelines and specific applicable code combinations prior to billing Medicare. ASTRO SRS Model Coverage Policy Page 8 Final Approval Updated

14 SRS References 1. Adler JR Jr, Gibbs IC, Puataweepong P, Chang SD. Visual field preservation after multisession cyberknife radiosurgery for perioptic lesions. Neurosurgery Aug; 59(2):244-54; discussion American College of Radiology ACR Appropriateness Criteria Brain Metastasis Accessed April Available at: 3. American College of Radiology Practice Guideline for the performance of Stereotactic Radiosurgery. Effective 10/01/2006. Accessed April Available at URL address: SecondaryMainMenuCategories/ quality_safety/guidelines/ro/ stereotactic_radiosurgery.aspx 4. American College of Radiology Practice Guideline for the Performance of Stereotactic Body Radiation Therapy. Amended 2006 Accessed April Available at: /Secondary MainMenuCategories /quality_safety/ guidelines /ro/stereo_body_radiation.aspx 5. American Society for Radiation Oncology (ASTRO). Report of the ASTRO Emerging Technology Committee (ETC) September 19, 2008 Stereotactic Body Radiotherapy (SBRT) For Primary Management of Early-Stage, Low-Intermediate Risk Prostate Cancer Available at: Tpros.pdf. Accessed April American Society for Therapeutic Radiation and Oncology (ASTRO). The ASTRO/ACR Guide to Radiation Oncology Coding Fairfax, VA: ASTRO; Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet May 22; 363(9422): Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA Jun 7; 295(21): Barajas MA, Ramirez-Guzman MG, Rodriguez-Vazquez C, Toledo-Buenrostro V, Cuevas-Solorzano A, Rodriguez-Hernandez G. Gamma Knife surgery for hypothalamic hamartomas accompanied by medically intractable epilepsy and precocious puberty: experience in Mexico. J Neurosurg Jan; 102 Suppl: Barbaro NM, Quigg M, Broshek DK, et al. A multicenter, prospective pilot study of gamma knife radiosurgery for mesial temporal lobe epilepsy: seizure response, adverse ASTRO SRS Model Coverage Policy Page 9 Final Approval Updated

15 events, and verbal memory. Ann Neurol Feb;65(2): Barcia-Salorio JL, Barcia JA, Hernandez G, Lopez-Gomez L. Radiosurgery of epilepsy. Long-term results. Acta Neurochir Suppl (Wien). 1994; 62: Barnett GH, Linskey ME, Adler JR, Cozzens JW, Friedman WA, Heilbrun MP, Lunsford LD, Schulder M, Sloan AE; American Association of Neurological Surgeons; Congress of Neurolofical Surgeons Washington Committee Stereotactic Radiosurgery Task Force. Stereotactic radiosurgery--an organized neurosurgery-sanctioned definition. J Neurosurg Jan; 106(1): Bhatnagar AK, Flickinger JC, Kondziolka D, Lunsford LD. Stereotactic radiosurgery for four or more intracranial metastases. Int J Radiat Oncol Biol Phys Mar 1; 64(3): Brisman R. Microvascular decompression vs. Gamma Knife radiosurgery for typical trigeminal neuralgia: preliminary findings. Stereotact Funct Neurosurg. 2007; 85(2-3): Chang SD, Gibbs IC, Sakamoto GT, Lee E, Oyelese A, Adler JR Jr. Staged stereotactic irradiation for acoustic neuroma. Neurosurgery Jun; 56(6): ; discussion Chougule PB, Burton-WilliamsM, Saris S, Zheng Z, Ponte B, Noren G, et al. Randomized treatment of brain metastases with Gamma Knife radiosurgery, whole brain radiotherapy or both (abstract). International Journal of Radiation Oncology, Biology, Physics 2000; 48: Chua DT, Sham JS, Hung KN, Leung LH, Au GK. Predictive factors of tumor control and survival after radiosurgery for local failures of nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys Dec 1; 66(5): Cohen VM, Carter MJ, Kemeny A, Radatz M, Rennie IG. Metastasis-free survival following treatment for uveal melanoma with either stereotactic radiosurgery or enucleation. Acta Ophthalmol Scand Aug; 81(4): Dieckmann K, Georg D, Bogner J, Zehetmayer M, Petersch B, Chorvat M, et al. Optimizing LINAC based stereotactic radiotherapy of uveal melanomas: 7 years' clinical experience. Int J Radiat Oncol Biol Phys Nov 15; 66(4 Suppl):S Donnet A, Tamura M, Valade D, RJ. Trigeminal nerve radiosurgical treatment in intractable chronic cluster headache: unexpected high toxicity. Neurosurgery Dec; 59(6):1252-7; discussion Dodd RL, Ryu MR, Kamnerdsupaphon P, Gibbs IC, Chang SD Jr, Adler JR Jr. CyberKnife radiosurgery for benign intradural extramedullary spinal tumors. Neurosurgery Apr; 58(4):674-85; discussion ASTRO SRS Model Coverage Policy Page 10 Final Approval Updated

16 22. Duma CM. Movement disorder radiosurgery--planning, physics and complication avoidance. Prog Neurol Surg. 2007; 20: ECRI Institute Health Technology Assessment Information Service (HTAIS). CyberKnife and Gamma Knife Radiosurgery for Trigeminal Neuralgia. Hotline Response. May Archived 24. Elia AE, Shih HA, Loeffler JS. Stereotactic radiation treatment for benign meningiomas. Neurosurg Focus. 2007; 23(4):E Friehs GM, Park MC, Goldman MA, Zerris VA, NorG, Sampath P. Stereotactic radiosurgery for functional disorders. Neurosurg Focus. 2007; 23(6):E Gagnon GJ, Henderson FC, Gehan EA, Sanford D, Collins BT, Moulds JC, Dritschilo A. Cyberknife radiosurgery for breast cancer spine metastases: a matched-pair analysis. Cancer Oct 15; 110(8): Gerszten PC, Burton SA, Ozhasoglu C, Welch WC. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine Jan 15; 32(2): Gerszten PC, Burton SA. Clinical Assessment of Stereotactic IGRT: Spinal Radiosurgery. Med Dosim summer; 33(2): Gerszten PC, Burton SA, Ozhasoglu C, McCue KJ, Quinn AE. Radiosurgery for benign intradural spinal tumors. Neurosurgery Apr; 62(4):887-95; discussion Gerszten PC, Ozhasoglu C, Burton SA, Vogel WJ, Atkins BA, Kalnicki S, Welch WC. CyberKnife frameless stereotactic radiosurgery for spinal lesions: clinical experience in 125 cases. Neurosurgery Jul; 55(1):89-98; discussion Gerszten PC, Ozhasoglu C, Burton SA, Vogel WJ, Atkins BA, Kalnicki S, Welch WC. CyberKnife frameless single-fraction stereotactic radiosurgery for benign tumors of the spine. Neurosurg Focus May 15; 14(5):e Gerszten PC, Burton SA, Welch WC, Brufsky AM, Lembersky BC, Ozhasoglu C, Vogel WJ. Single-fraction radiosurgery for the treatment of spinal breast metastases. Cancer. 2005a Nov 15; 104(10): Gerszten PC, Burton SA, Ozhasoglu C, Vogel WJ, Welch WC, Baar J, Friedland DM. Stereotactic radiosurgery for spinal metastases from renal cell carcinoma. J Neurosurg Spine. 2005b Oct; 3(4): Gerszten PC, Burton SA, Quinn AE, Agarwala SS, Kirkwood JM Radiosurgery for the treatment of spinal melanoma metastases. Stereotact Funct Neurosurg. 2005c; 83(5-6): ASTRO SRS Model Coverage Policy Page 11 Final Approval Updated

17 35. Gerszten PC, Germanwala A, Burton SA, Welch WC, Ozhasoglu C, Vogel WJ. Combination kyphoplasty and spinal radiosurgery: a new treatment paradigm for pathological fractures. J Neurosurg Spine. 2005d Oct; 3(4): Gerszten PC, Burton SA, Belani CP, Ramalingam S, Friedland DM, Ozhasoglu C, Quinn AE, McCue KJ, Welch WC. Radiosurgery for the treatment of spinal lung metastases. Cancer Dec 1; 107(11): Gibbs IC, Kamnerdsupaphon P, Ryu MR, Dodd R, Kiernan M, Chang SD, Adler JR Jr. Image-guided robotic radiosurgery for spinal metastases. Radiother Oncol Feb; 82(2): Giller CA, Berger BD, Fink K, Bastian E. A volumetric study of CyberKnife hypofractionated stereotactic radiotherapy as salvage for progressive malignant brain tumors: initial experience. Neurol Res Sep; 29(6): Gopalan R, Dassoulas K, Rainey J, Sherman JH, Sheehan JP. Evaluation of the role of Gamma Knife surgery in the treatment of craniopharyngiomas. Neurosurg Focus. 2008; 24(5):E Gottfried ON, Liu JK, Couldwell WT. Comparison of radiosurgery and conventional surgery for the treatment of glomus jugulare tumors. Neurosurg Focus Aug 15; 17(2):E Grabenbauer GG, Reinhold Ch, Kerling F, et al. Fractionated stereotactically guided radiotherapy of pharmacoresistant temporal lobe epilepsy. Acta Neurochir Suppl. 2002; 84: Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology Oct 7; 71(15): Han JH, Kim DG, Chung HT, et al. Clinical and neuroimaging outcome of cerebral arteriovenous malformations after Gamma Knife surgery: analysis of the radiation injury rate depending on the arteriovenous malformation volume. J Neurosurg. 2008; 109(2): Hara W, Loo BW Jr, Goffinet DR, Chang SD, Adler JR, Pinto HA, et al. Excellent Local Control with Stereotactic Radiotherapy Boost After External Beam Radiotherapy in Patients with Nasopharyngeal Carcinoma. Int J Radiat Oncol Biol Phys Dec Hayes, Inc. HAYES Medical Technology Directory. Stereotactic Radiosurgery for Arteriovenous Malformations and Intracranial Tumors. Lansdale, PA: Hayes, Inc. January ASTRO SRS Model Coverage Policy Page 12 Final Approval Updated

18 46. Ikeda H, Jokura H, Yoshimoto T. Transsphenoidal surgery and adjuvant Gamma Knife treatment for growth hormone-secreting pituitary adenoma. J Neurosurg Aug; 95(2): International RadioSurgery Association. Radiosurgery practice guideline initiative: stereotactic radiosurgery for patients with vestibular schwannomas. Issued May Accessed April Available at: International RadioSurgery Association. Radiosurgery practice guideline initiative: stereotactic radiosurgery for patients with intractable typical trigeminal neuralgia who have failed medical management. Issued: September Accessed April Available at: TN%20Guideline.pdf. 49. International RadioSurgery Association. Radiosurgery practice guideline initiative: stereotactic radiosurgery for patients with pituitary adenomas. Issued: April Accessed April Available at: /Pituitary%20 Guideline.pdf 50. International RadioSurgery Association, The. Radiosurgery practice guideline initiative: stereotactic radiosurgery for patients with intracranial arteriovenous malformations. Issued September Accessed April Available at: Ishihara H, Saito K, Nishizaki T, Kajiwara K, Nomura S, Yoshikawa K, Harada K, Suzuki M. CyberKnife radiosurgery for vestibular schwannoma. Minim Invasive Neurosurg Oct; 47(5): Kajiwara K, Saito K, Yoshikawa K, Kato S, Akimura T, Nomura S, Ishihara H, Suzuki M. Image-guided stereotactic radiosurgery with the CyberKnife for pituitary adenomas. Minim Invasive Neurosurg Apr; 48(2): Karpinos M, Teh BS, Zeck O, Carpenter LS, Phan C, Mai WY, Lu HH, Chiu JK, Butler EB, Gormley WB, Woo SY. Treatment of acoustic neuroma: stereotactic radiosurgery vs. microsurgery. Int J Radiat Oncol Biol Phys Dec 1; 54(5): Stereotactic radiotherapy. Front Radiat Ther Oncol. 2007; 40: Kim SH, Weil RJ, Chao ST, Toms SA, Angelov L, Vogelbaum MA, Suh JH, Barnett GH. Stereotactic radiosurgical treatment of brain metastases in older patients. Cancer Aug 15; 113(4): Kondziolka D, Ong JG, Lee JY, Moore RY, Flickinger JC, Lunsford LD. Gamma Knife thalamotomy for essential tremor. J Neurosurg Jan; 108(1): Kondziolka D, Patel A, Lunsford LD, Kassam A, Flickinger JC. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys Sep 1; 45(2): ASTRO SRS Model Coverage Policy Page 13 Final Approval Updated

19 57. Kong DS, Lee JI, Lim do H, Kim KW, Shin HJ, Nam DH, et al. The efficacy of fractionated radiotherapy and stereotactic radiosurgery for pituitary adenomas: long-term results of 125 consecutive patients treated in a single institution. Cancer Aug 15; 110(4): Lee M, Kalani MY, Cheshier S, Gibbs IC, Adler JR, Chang SD. Radiation therapy and CyberKnife radiosurgery in the management of craniopharyngiomas. Neurosurg Focus. 2008; 24(5):E Lee JY, Kondziolka D, Flickinger JC, Lunsford LD. Radiosurgery for intracranial meningiomas. Prog Neurol Surg. 2007; 20: Lim M, Bower R, Nangiana JS, Adler JR, Chang SD. Radiosurgery for glomus jugulare tumors. Technol Cancer Res Treat Oct; 6(5): Lim M, Cotrutz C, Romanelli P, Schaal D, Gibbs I, Chang SD, Adler JR. Stereotactic radiosurgery using CT cisternography and non-isocentric planning for the treatment of trigeminal neuralgia. Comput Aided Surg Jan; 11(1): Lim M, Villavicencio AT, Burneikiene S, Chang SD, Romanelli P, McNeely L,McIntyre M, Thramann JJ, Adler JR. CyberKnife radiosurgery for idiopathic trigeminal neuralgia. Neurosurg Focus May 15; 18(5):E Linskey ME, Davis SA, Ratanatharathorn V. Relative roles of microsurgery and stereotactic radiosurgery for the treatment of patients with cranial meningiomas: a singlesurgeon 4-year integrated experience with both modalities. J Neurosurg Jan; 102 Suppl: Lipani JD, Jackson PS, Soltys SG, Sato K, Adler JR. Survival Following CyberKnife Radiosurgery and Hypofractionated Radiotherapy for Newly Diagnosed Glioblastoma Multiforme. Technol Cancer Res Treat Jun; 7(3): Madsen BL, Hsi RA, Pham HT, Fowler JF, Esagui L, Corman J. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results. Int J Radiat Oncol Biol Phys Mar 15; 67(4): Mathieu D, Kondziolka D, Niranjan A, Flickinger J, Lunsford LD. Gamma knife radiosurgery for refractory epilepsy caused by hypothalamic hamartomas. Stereotact Funct Neurosurg. 2006; 84(2-3): McClelland S 3rd, Gerbi BJ, Higgins PD, Orner JB, Hall WA. Safety and efficacy of fractionated stereotactic radiotherapy for acoustic neuromas. J Neurooncol Jan; 86(2): Meijer OW, Vandertop WP, Baayen JC, Slotman BJ. Single-fraction vs. fractionated ASTRO SRS Model Coverage Policy Page 14 Final Approval Updated

20 linac-based stereotactic radiosurgery for vestibular schwannoma: a single-institution study. Int J Radiat Oncol Biol Phys Aug 1; 56(5): Muacevic A, Wowra B, Siefert A, Tonn JC, Steiger HJ, Kreth FW. Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial. J Neurooncol May; 87(3): Muragaki Y, Nakamura R, Iseki H, Hori T, Takakura K. Outcome after pituitary radiosurgery for thalamic pain syndrome. Int J Radiat Oncol Biol Phys Nov 1; 69(3): Myrseth E, MP, Pedersen PH, Vassbotn FS, Wentzel-Larsen T, Lund-Johansen M. Vestibular schwannomas: clinical results and quality of life after microsurgery or Gamma Knife radiosurgery. Neurosurgery May; 56(5):927-35; discussion National Comprehensive Cancer Network (NCCN).Web site. Clinical Practice Guidelines in Oncology. Central Nervous System Cancers V Accessed April Available at National Comprehensive Cancer Network (NCCN).Web site. Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. V Accessed April Available at: National Institute for Clinical Excellence. Stereotactic radiosurgery for trigeminal neuralgia using the Gamma Knife. August National Institute for Health and Clinical Excellence. Interventional procedure Guidance IPG085 Stereotactic radiosurgery for trigeminal neuralgia using the Gamma Knife - guidance. August Accessed April Available at: National Institute for Health and Clinical Excellence. Systematic review of the clinical efficacy and safety of stereotactic radiosurgery (Gamma Knife) in the treatment of trigeminal neuralgia. 27 April Accessed April Available at: /nicemedia /pdf/ip/173 systematic review.pdf. 77. Niranjan A, Jawahar A, Kondziolka D, Lunsford LD. A comparison of surgical approaches for the management of tremor: radiofrequency thalamotomy, Gamma Knife thalamotomy and thalamic stimulation. Stereotact Funct Neurosurg. 1999; 72(2-4): Nishizaki T, Saito K, Jimi Y, Harada N, Kajiwara K, Nomura S, Ishihara H, Yoshikawa K, Yoneda H, Suzuki M, Gibbs IC. The role of cyberknife radiosurgery/radiotherapy for brain metastases of multiple or large-size tumors. Minim Invasive Neurosurg Aug; 49(4): ASTRO SRS Model Coverage Policy Page 15 Final Approval Updated

21 79. Ogilvy CS, Stieg PE, Awad I, Brown RD Jr, Kondziolka D, Special Writing Group of the Stroke Council, American Stroke Association, et al. AHA Scientific Statement: Recommendations for the management of intracranial arteriovenous malformations: a statement for healthcare professionals from a special writing group of the Stroke Council, American Stroke Association. Stroke Jun; 32(6): Okun MS, Stover NP, Subramanian T, Gearing M, Wainer BH, Holder CA, Watts RL, Juncos JL, Freeman A, Evatt ML, Schuele SU, Vitek JL, DeLong MR. Complications of Gamma Knife surgery for Parkinson disease. Arch Neurol Dec; 58(12): Pan DH, Guo WY, Chung WY, et al. Gamma knife radiosurgery as a single treatment modality for large cerebral arteriovenous malformations. J Neurosurg. 2000; 93(suppl 3): Patil CG, Veeravagu A, Bower RS, Li G, Chang SD, Lim M, Adler JR Jr. CyberKnife radiosurgical rhizotomy for the treatment of atypical trigeminal nerve pain. Neurosurg Focus. 2007; 23(6):E Picozzi P, Losa M, Mortini P, Valle MA, Franzin A, Attuati L, Ferrari da Passano C, Giovanelli M. Radiosurgery and the prevention of regrowth of incompletely removed nonfunctioning pituitary adenomas. J Neurosurg Jan; 102 Suppl: Pollock BE, Stafford SL, Utter A, Giannini C, Schreiner SA. Stereotactic radiosurgery provides equivalent tumor control to Simpson Grade 1 resection for patients with small- to medium-size meningiomas. Int J Radiat Oncol Biol Phys Mar 15; 55(4): Pollock BE. Stereotactic radiosurgery in patients with glomus jugulare tumors. Neurosurg Focus Aug 15; 17(2):E Pollock, BE. An evidence-based medicine review of stereotactic radiosurgery. Prog Neurol Surg. 2006; Pollock BE, Lunsford LD, Flickinger JC, Clyde BL, Kondziolka D. Vestibular schwannoma management. Part I. Failed microsurgery and the role of delayed stereotactic radiosurgery. J Neurosurg Dec; 89(6): Quigg M, Barbaro NM. Stereotactic radiosurgery for treatment of epilepsy. Arch Neurol Feb; 65(2): Rades D, Bohlen G, Pluemer A, Veninga T, Hanssens P, Dunst J, Schild SE. Stereotactic radiosurgery alone versus resection plus whole-brain radiotherapy for 1 or 2 brain metastases in recursive partitioning analysis class 1 and 2 patients. Cancer Jun 15; 109(12): Regis J, Arkha Y, Yomo S, Bartolomei F, Peragut JC, Chauvel P. Radiosurgery for drugresistant epilepsies: state of the art, results and perspectives. Neurochirurgie May; ASTRO SRS Model Coverage Policy Page 16 Final Approval Updated

22 54(3): Regis J, Bartolomei F, Rey M, et al. Gamma knife surgery for mesial temporal lobe epilepsy. J Neurosurg. 2000; 93(Suppl 3): Regis J, Pellet W, Delsanti C, Dufour H, Roche PH, Thomassin JM, Zanaret M, Peragut JC. Functional outcome after Gamma Knife surgery or microsurgery for vestibular schwannomas. J Neurosurg Nov; 97(5): Regis J, Rey M, Bartolomei F, Vladyka V, Liscak R, Schrottner O, Pendl G. Gamma knife surgery in mesial temporal lobe epilepsy: a prospective multicenter study. Epilepsia May;45(5): Regis J, Scavarda D, Tamura M, et al. Epilepsy related to hypothalamic hamartomas: Surgical management with special reference to Gamma Knife surgery. Childs Nerv Syst. 2006; 22(8): Regis J, Bartolomei F, de Toffol B, Genton P, Kobayashi T, Mori Y, et al. Gamma knife surgery for epilepsy related to hypothalamic hamartomas. Neurosurgery Dec; 47(6): ; discussion Regis J, Rey M, Bartolomei F, Vladyka V, Liscak R, Schrottner O, Pendl G. Gamma knife surgery in mesial temporal lobe epilepsy: a prospective multicenter study. Epilepsia May; 45(5): Roche PH, Robitail S, Delsanti C, Marouf R, Pellet W, RJ. Radiosurgery of vestibular schwannomas after microsurgery and combined radio-microsurgery Neurochirurgie Jun; 50(2-3 Pt 2): Romanelli P, Anschel DJ. Radiosurgery for epilepsy. Lancet Neurol Jul; 5(7): Romanelli P, Heit G, Chang SD, Martin D, Pham C, Adler J. Cyberknife radiosurgery for trigeminal neuralgia. Stereotact Funct Neurosurg. 2003; 81(1-4): Ryu S, Jin R, Jin JY, Chen Q, Rock J, Anderson J, Movsas B. Pain control by imageguided radiosurgery for solitary spinal metastasis. J Pain Symptom Manage Mar; 35(3): Sahgal A, Chou D, Ames C, Ma L, Lamborn K, Huang K, Chuang C, Aiken A, Pett P, Weinstein P, Larson D.Image-guided robotic stereotactic body radiotherapy for benign spinal tumors: the University of California San Francisco preliminary experience. Technol Cancer Res Treat Dec; 6(6): Schaeuble B, Cascino GD, Pollock BE, Gorman DA, Weigand S, Cohen-Gadol AA, McClelland RL. Seizure outcomes after stereotactic radiosurgery for cerebral arteriovenous ASTRO SRS Model Coverage Policy Page 17 Final Approval Updated

23 malformations. Neurology Aug 24; 63(4): Selch MT, Gorgulho A, Mattozo C, Solberg TD, Cabatan-Awang C, DeSalles AA. Linear accelerator stereotactic radiosurgery for the treatment of gelastic seizures due to hypothalamic hamartoma. Minim Invasive Neurosurg Oct; 48(5): Serizawa, Toru; Hirai, Tatsuo; Nagano, Osamu; Higuchi, Yoshinori; Matsuda, Shinji; Ono, Junichi; Saeki, Naokatsu. Gamma knife surgery for 1 10 brain metastases without prophylactic whole-brain radiation therapy: analysis of cases meeting the Japanese prospective multi-institute study (JLGK0901) inclusion criteria. Journal of Neuro-Oncology (2010) 98: , June 10, Sinclair J, Chang SD, Gibbs IC, Adler JR Jr. Multisession CyberKnife radiosurgery for intramedullary spinal cord arteriovenous malformations. Neurosurgery Jun; 58(6):1081-9; discussion Souhami L, Seiferheld W, Brachman D, Podgorsak EB, Werner-Wasik M, Lustig R, Schultz CJ, Sause W, Okunieff P, Buckner J, Zamorano L, Mehta MP, Curran WJ Jr. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group protocol. Int J Radiat Oncol Biol Phys Nov 1; 60(3): Steinvorth S, Wenz F, Wildermuth S, et al. Cognitive function in patients with cerebral arteriovenous malformations after radiosurgery: prospective long-term follow-up. Int J Radiat Oncol Biol Phys. 2002; 54(5): Tsao MN, Lloyd N, Wong R, Chow E, Rakovitch E, Laperriere N. Whole brain radiotherapy for the treatment of multiple brain metastases. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD Tsao MN, Mehta MP, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, Mills M, Rogers CL, Souhami L. The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys Sep 1; 63(1): Villavicencio AT, Lim M, Burneikiene S, Romanelli P, Adler JR, McNeely L, Chang SD, Fariselli L, McIntyre M, Bower R, Broggi G, Thramann JJ. Cyberknife radiosurgery for trigeminal neuralgia treatment: a preliminary multicenter experience. Neurosurgery Mar; 62(3):647-55; discussion Whang CJ, Kwon Y. Long-term follow-up of stereotactic Gamma Knife radiosurgery in epilepsy. Stereotact Funct Neurosurg. 1996; 66(Suppl 1): Weil M. Stereotactic Radiosurgery for Brain Tumors. Hematology/Oncology Clinics of North America. 2001; 15(6). ASTRO SRS Model Coverage Policy Page 18 Final Approval Updated

24 113. Wu SX, Chua DT, Deng ML, Zhao C, Li FY, Sham JS, Wang HY, Bao Y, Gao YH, Zeng ZF. Outcome of fractionated stereotactic radiotherapy for 90 patients with locally persistent and recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys Nov 1; 69(3): Yang KJ, Wang KW, Wu HP, Qi ST. Radiosurgical treatment of intractable epilepsy with low radiation dose. Di Yi Jun Yi Da Xue Xue Bao. 2002; 22(7): Yoshikawa K, Saito K, Kajiwara K, Nomura S, Ishihara H, Suzuki M. CyberKnife stereotactic radiotherapy for patients with malignant glioma. Minim Invasive Neurosurg Apr; 49(2): Young RF, Jacques S, Mark R, Kopyov O, Copcutt B, Posewitz A, Li F. Gamma knife thalamotomy for treatment of tremor: long-term results. J Neurosurg Dec; 93 Suppl 3: Young RF, Vermeulen S, Posewitz A, Shumway-Cook A. Pallidotomy with the Gamma Knife: a positive experience. Stereotact Funct Neurosurg Oct; 70 Suppl 1: Young RF, Vermeulen SS, Grimm P, Posewitz AE, Jacques DB, Rand RW, Copcutt BG. Gamma Knife thalamotomy for the treatment of persistent pain. Stereotact Funct Neurosurg. 1995; 64 Suppl 1: Zesiewicz TA, Elble R, Louis ED, Hauser RA, Sullivan KL, Quality Standards Subcommittee of the American Academy of Neurology, et al. Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology Jun 28; 64(12): ASTRO SRS Model Coverage Policy Page 19 Final Approval Updated

25 Model Policies STEREOTACTIC BODY RADIATION THERAPY (SBRT) This Model Policy 1 addresses coverage for Stereotactic Body Radiation Therapy (SBRT). Description SBRT is a treatment that couples a high degree of anatomic targeting accuracy and reproducibility with very high doses of extremely precise, externally generated, ionizing radiation, thereby maximizing the cell-killing effect on the target(s) while minimizing radiation-related injury in adjacent normal tissues. SBRT is used to treat extra-cranial sites as opposed to stereotactic radiosurgery (SRS) which is used to treat intra-cranial and spinal targets. However, some of the CPT codes discussed here are also utilized in the billing process for SRS and are discussed accordingly in the SRS model policy. The adjective stereotactic describes a procedure during which a target lesion is localized relative to a known threedimensional reference system that allows for a high degree of anatomic accuracy and precision. Examples of devices used in SBRT for stereotactic guidance may include a body frame with external reference markers in which a patient is positioned securely, a system of implanted fiducial markers that can be visualized with low-energy (kv)x-rays and CT-imaging-based systems used to confirm the location of a tumor immediately prior to treatment. Treatment of extra-cranial sites requires accounting for internal organ motion as well as for patient motion. Thus, reliable immobilization or repositioning systems must often be combined with devices capable of decreasing organ motion or accounting for organ motion e.g. respiratory gating. Additionally, all SBRT is performed with at least one form of image guidance to confirm proper patient positioning and tumor localization prior to delivery of each fraction. The ASTRO/ACR Practice Guidelines for SBRT outline the responsibilities and training requirements for personnel involved in the administration of SBRT. SBRT may be delivered in one to five sessions (fractions). Each fraction requires an identical degree of precision, localization and image guidance. Since the goal of SBRT is to maximize the potency of the radiotherapy by completing an entire course of treatment within an extremely accelerated time frame, any course of radiation treatment extending beyond five fractions is not considered SBRT and is not to be billed using these codes. SBRT is meant to represent a complete course of treatment and not be used as a boost following a conventionally fractionated course of treatment. 1 ASTRO model policies were developed as a means to efficiently communicate what ASTRO believes to be correct coverage policies for radiation oncology services. The ASTRO model policies do not serve as clinical guidelines and they are subject to periodic review and revision without notice. The ASTRO Model Policies may be reproduced and distributed, without modification, for noncommercial purposes. CPT copyright 2012 American Medical Association. All rights reserved. Approved Updated

26 STEREOTACTIC BODY RADIATION THERAPY (SBRT) MODEL POLICY Page 2 Indications and Limitations of Coverage and/or Medical Necessity This Model Policy addresses only the CPT codes for SBRT treatment management , and SBRT treatment delivery , G0251, G0339 and G0340. When billing for SBRT delivery, it is not appropriate to bill more than one treatment delivery code on the same day of service, even though some types of delivery may have elements of several modalities (for example, a stereotactic approach with intensity-modulated static beams or arcs). Also, only one delivery code is to be billed even if multiple lesions are treated on the same day. Indications for SBRT: SBRT is indicated for primary tumors of and tumors metastatic to the lung, liver, kidney, adrenal gland or pancreas as well as for pelvic and head and neck tumors that have recurred after primary irradiation when and only when each of the following criteria are met, and each specifically documented in the medical record. Multiple ICD diagnosis codes (ICD-9 or ICD-10) fit this description and are listed in this coverage policy. 1. The patient s general medical condition (notably, the performance status) justifies aggressive treatment to a primary cancer or, for the case of metastatic disease, justifies aggressive local therapy to one or more discrete deposits of cancer within the context of efforts to achieve total clearance or clinically beneficial reduction in the patient s overall burden of systemic disease. 2. The tumor burden can be completely targeted with acceptable risk to critical normal structures. Other Neoplasms Prostate Cancer: Many clinical studies supporting the efficacy and safety of SBRT in the treatment of prostate cancer have been published. At least one study has shown excellent five year biochemical control rates with very low rates of serious toxicity. Additionally, numerous studies have demonstrated the safety of SBRT for prostate cancer after a follow-up interval long enough (two to three years) to provide an opportunity to observe the incidence of late GU or GI toxicity. While it is necessary to observe patients treated for prostate cancer for extended intervals to gauge the rate of long term (beyond 10 years) biochemical control and overall survival, the interim results reported appear at least as good as other forms of radiotherapy administered to patients with equivalent risk levels followed for the same duration post-treatment. It is ASTRO s opinion that data supporting the use of SBRT for prostate cancer have matured to a point where SBRT could be considered an appropriate alternative for select patients with low to intermediate risk disease. Bone Metastases: SBRT has been demonstrated to achieve durable tumor control when treating lesions in vertebral bodies or the paraspinous region, where extra care must be taken to avoid excess irradiation of the spinal cord when tumor-ablative doses are administered. There is an important clinical distinction between the status of patients described above and a patient with widely metastatic disease for whom palliation is the major objective. In one setting, a patient with limited metastatic disease and good performance status is treated with the intention of eradicating all known active disease or greatly reducing the total disease burden in a manner that can extend progression-free survival. For such a patient, SBRT can be a reasonable therapeutic intervention. However, for uncomplicated, previously untreated bone metastases in a patient with widespread progressive disease in the spine or elsewhere, where the prognosis is unfavorable, it is generally appropriate to use a less technically complex form of palliative radiotherapy rather than SBRT. CPT copyright 2012 American Medical Association. All rights reserved.

27 STEREOTACTIC BODY RADIATION THERAPY (SBRT) MODEL POLICY Page 3 Other Indications for SBRT: For patients with tumors of any type arising in or near previously irradiated regions, SBRT may be appropriate when a high level of precision and accuracy is needed to minimize the risk of injury to surrounding normal tissues. Also, in other cases where a high dose per fraction treatment is indicated SBRT may be appropriate. The necessity should be documented in the medical record. Limitations: SBRT is not considered medically necessary under the following circumstances: 1. Treatment unlikely to result in clinical cancer control and/or functional improvement. 2. The tumor burden cannot be completely targeted with acceptable risk to critical normal structures. 3. Patients with poor performance status (Karnofsky Performance Status less than 40 or Eastern Cooperative Oncology Group (ECOG) Status of 3 or worse) - see Karnofsky Performance Status and ECOG Status below. Karnofsky Performance Status Scale 100 Normal; no complaints, no evidence of disease 90 Able to carry on normal activity; minor signs or symptoms of disease 80 Normal activity with effort; some signs or symptoms of disease 70 Cares for self; unable to carry on normal activity or to do active work 60 Requires occasional assistance but is able to care for most needs 50 Requires considerable assistance and frequent medical care 40 Disabled; requires special care and assistance 30 Severely disabled; hospitalization is indicated although death not imminent 20 Very sick; hospitalization necessary; active supportive treatment is necessary 10 Moribund, fatal processes progressing rapidly 0 Dead Karnofsky DA, Burchenal JH. (1949). The Clinical Evaluation of Chemotherapeutic Agents in Cancer. In: MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ Press. Page 196.

28 STEREOTACTIC BODY RADIATION THERAPY (SBRT) MODEL POLICY Page 4 ECOG Performance Status Scale Grade 0: Grade 1: Grade 2: Grade 3: Grade 4: Grade 5: Fully active, able to carry on all pre-disease performance without restriction. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work. Ambulatory and capable of all self-care but unable to carry out and work activities. Up and about more than 50% of waking hours. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Dead Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair. * As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5: , PHYSICIANS CURRENT PROCEDURAL TERMINOLOGY (CPT )/HCPCS SECTION [(Note CPT is a trademark of the American Medical Association (AMA)] CPT/HCPCS Codes: Stereotactic body radiation therapy, treatment management, per treatment course, to 1 or more lesions, including image guidance, entire course not to exceed 5 fractions (The same physician should not report both the stereotactic radiosurgery services [32701, 63620, 63621] and radiation treatment management [77435]) This code will be paid only once per course of treatment and should not be reported in conjunction with any other treatment management codes ( ) Stereotactic body radiation therapy, treatment delivery, per fraction to 1 or more lesions, including image guidance, entire course not to exceed 5 fractions (For single fraction cranial lesions, see 77371, 77372) This code should not be reported in conjunction with any other treatment delivery codes e.g , This code will be paid only once per day of treatment regardless of the number of sessions or lesions. G0339 Image-guided robotic linear accelerator-based stereotactic radiosurgery, complete course of therapy in one session, or first session of fractionated treatment This code includes all image guidance on the days of treatment delivery, so do not report G0339 in conjunction with or on the days of treatment delivery. This code will be paid only once per day of treatment regardless of the number of sessions or lesions. CPT copyright 2012 American Medical Association. All rights reserved.

29 STEREOTACTIC BODY RADIATION THERAPY (SBRT) MODEL POLICY Page 5 G0340 G0251 Image-guided robotic linear accelerator-based stereotactic radiosurgery, delivery including collimator changes and custom plugging, fractionated treatment, all lesions, per session, second through fifth sessions, maximum five sessions per course of treatment For reporting fractions 2 through 5 after reporting G0339 for the first fraction. This code includes all image guidance on the days of treatment delivery, so do not report G0340 in conjunction with or on the days of treatment delivery. This code will be paid only once per day of treatment regardless of the number of sessions or lesions. Linear accelerator based stereotactic radiosurgery, delivery including collimator changes and custom plugging, fractionated treatment, all lesions, per session, maximum five sessions per course of treatment This code should be utilized only by hospital outpatient departments to report non-robotic Linac based treatments for fractions two through five. This code is excluded from MPFS by regulation. The CPT codes discussed in this Model Policy are applicable to all diagnoses listed in the ASTRO SRS Model Policy, a companion document to the SBRT model policy. ICD Diagnosis Codes that Support Medical Necessity Note: Diagnosis codes are based on the current ICD-9-CM codes that are effective at the time of Model Policy publication. Any updates to ICD-9-CM or ICD-10-CM codes will be reviewed by ASTRO, and coverage should not be presumed until the results of such review have been published/posted. These ICD diagnosis codes support medical necessity under this Model Policy: Diagnosis ICD-9 Code(s) ICD-10 Code(s) Comment Primary lung cancer C34.00 C34.92 Thoracic lymph nodes C77.1 Lung metastasis C78.00 C78.02 Primary liver or bile duct 155.0, 155.1, C22.0 C22.9 cancer Liver metastasis C78.7 Primary Pancreas cancer C25.0 C25.9 Kidney cancer or metastasis 189.0, 189.1, C64.1 C65.9, C79.00 C79.02 Adrenal Gland primary or metastasis 194.0, 194.6, C74.00 C74.92, C75.5, C79.70 C79.72 Prostate cancer 185 C61 Pelvic cancer Abdomen and Pelvis Gynecological Rectum and Anus Effects of Radiation Head & Neck cancer, multiple primary sites 195.2, * , 990* C76.2, C76.3 C51.0 C58 C19 C21.8 T66.XXXA* C00.0 C10.8, T66.XXXA* recurrent after prior conventionally fractionated RT recurrent after prior conventionally fractionated RT Nodal metastasis C77.0 C77.9 recurrent after prior conventionally fractionated RT *ICD-9-CM 990 or ICD-10-CM T66.XXXA (Effects of Radiation, Unspecified) may only be used where prior radiation therapy to the site is the governing factor necessitating SBRT in lieu of other radiotherapy. An ICD diagnosis code for the anatomic diagnosis must also be used. CPT copyright 2012 American Medical Association. All rights reserved.

30 STEREOTACTIC BODY RADIATION THERAPY (SBRT) MODEL POLICY Page 6 General Information Documentation Requirements The patient s record must support the necessity and frequency of treatment. Medical records should include not only the standard history and physical but also the patient s functional status and a description of current performance status (Karnofsky Performance Status or ECOG Performance Status). See Karnofsky Performance Status or ECOG Performance Status listed under Limitations above. A radiation oncologist must evaluate the clinical and technical aspects of the treatment, and document this evaluation as well as the resulting management decisions. Documentation of the technical aspects of treatment planning and delivery should include details of target dose and relevant dose-limiting normal structures. Documentation should include the date and the current treatment dose. All documentation must be available upon request of the insurer. For Medicare claims, the HCPCS/CPT code(s) may be subject to Correct Coding Initiative (CCI) edits. This policy does not take precedence over CCI edits. Please refer to the CCI for correct coding guidelines and specific applicable code combinations prior to billing Medicare. CPT copyright 2012 American Medical Association. All rights reserved.

31 STEREOTACTIC BODY RADIATION THERAPY (SBRT) MODEL POLICY Page 7 References General 1. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation therapy: The report of AAPM Task Group 101. Med Phys. 2010; 37(8): Chang R, Timmerman R. Stereotactic Body Radiation Therapy : A Comprehensive Review. Am J Clin Oncol. 2007; 30(6): Corbin KS, Hellman S, Weichselbaum RR. Extracranial oligometastases: a subset of metastases curable with stereotactic radiotherapy. J Clin Oncol. 2013; 31(11): Halperin EC, Perez, CA, Brady LW. Principles and Practice of Radiation Therapy, 5th edition. Philadelphia, PA: Lippincott Williams & Wilkins; Kavanagh BD and Timmerman RD (Eds.) Stereotactic Body Radiation Therapy, Philadelphia, PA: Lippincott Williams & Wilkins; Lo S, Fakiris A, Chang E, et al. Stereotactic body radiation therapy: a novel treatment modality. Nat Rev Clin Oncol. 2010; 7(1): Martin A, Gaya A, Stereotactic Body Radiotherapy: A Review. Clin Oncol (R Coll Radiol). 2010; 22(3): Milano MT, Katz A, Muhs, AG et al. A prospective pilot study of curative-intent stereotactic body radiation therapy in patients with 5 or fewer oligometastatic lesions. Cancer. 2008; 112(3): Potters L, Kavanagh B, Galvin JM, et al. American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) practice guideline for the performance of stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys. 2010; 76(2): Timmerman RD, Kavanagh BD, Cho LC, et al. Stereotactic Body Radiation Therapy in Multiple Organ Sites. J Clin Oncol. 2007; 25(8): Bone Metastasis 11. Chang EL, Shiu AS, Lii MF, et al. Phase I clinical evaluation of nearsimultaneous computed tomographic image-guided stereotactic body radiotherapy for spinal metastases. Int J Radiat Oncol Biol Phys. 2004; 5 9(5): Chang EL, Shiu AS, Mendel E, et al. Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. 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Stereotactic radiosurgery may contribute to overall survival for patients with recurrent head and neck carcinoma. Radiat Oncol. 2010; 5: Rwiegema J, Heron D, Ferris R, et al. Fraactionated stereotactic body radiation therapy in the treatment of previously-irradiated recurrent head and neck carcinoma. Updated report of the University of Pittsburgh experience. Am J Clin Oncol. 2009; 33(3): Unger KR, Lominska CE, Deeken JF, et al. Fractionated Stereotactic Radiosurgery for Reirradiation of Head-and-Neck Cancer. Int J Radiat Oncol Biol Phys. 2010; 77(5): Kidney 26. Svedman C, Karlsson K, Rutkowska E, et al. Stereotactic body radiotherapy of primary and metastatic renal lesions for patients with only one functioning kidney. Acta Oncol. 2008; 47(8): Liver 27. Choi BO, Choi IB, Jang HS, et al. Stereotactic body radiation therapy with or without transarterial chemoembolization for patients with primary hepatocellular carcinoma: preliminary analysis. 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32 STEREOTACTIC BODY RADIATION THERAPY (SBRT) MODEL POLICY Page Lee MT, Kim JJ, Dinniwell R, et al. Phase I study of individualized stereotactic body radiotherapy for liver metastases. J Clin Oncol. 2009; 27: McCammon R, Schefter TE, Gaspar LE, et al. Observation of a dose-control relationship for lung and liver tumors after stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys. 2009; 73(1): Méndez Romero A, Wunderink W, Hussain SM, et al. Stereotactic body radiation therapy for primary and metastatic liver tumors: A single institution phase i-ii study. Acta Oncol. 2006; 45(7): Méndez Romero A, Wunderink W, van Os RM, et al. Quality of life after stereotactic body radiation therapy for primary and metastatic liver tumors. Int J Radiat Oncol Biol Phys. 2008; 70(5): Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol. 2009; 27: Rusthoven KE, Kavanagh BD, Cardenes H, et al. Multi-institutional phase I/ II trial of stereotactic body radiation therapy for liver metastases. J Clin Oncol. 2009; 27(10): Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE. A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. Int J Radiat Oncol Biol Phys. 2005; 62(5): Tse RV, Hawkins M, Lockwood G, Kim JJ, Cummings B, Knox J, Sherman M, Dawson LA. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2008; 26(4): Lung 38. Collins BT, Vahdat S, Erickson K, et al. Radical cyberknife radiosurgery with tumor tracking: an effective treatment for inoperable small peripheral stage I non-small cell lung cancer. J Hematol Oncol. 2009; 2: Banki F, Luketich JD, Chen H, et al. Stereotactic radiosurgery for lung cancer. Minerva Chir. 2009; 64(6): Baumann P, Nyman J, Hoyer M, et al. 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Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008; 72(4): Chen Y, Guo W, Lu Y,et al.. Dose-individualized stereotactic body radiotherapy for T1-3N0 non-small cell lung cancer: long-term results and efficacy of adjuvant chemotherapy. Radiother Oncol. 2008; 88(3): Fakiris, AJ, McGarry RC, Yiannoutsos CT, et al. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys. 2009; 75(3): Fritz P, Kraus HJ, Blaschke T, et al. Stereotactic, high single-dose irradiation of stage I non-small cell lung cancer (NSCLC) using fourdimensional CT scans for treatment planning. Lung Cancer. 2008; 60(2): Guckenberger M, Wulf J, Mueller G, et al. Response Relationship for Image-Guided Stereotactic Body Radiotherapy of Pulmonary Tumors: Relevance of 4d Dose Calculation. 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Once-weekly, high-dose stereotactic body radiotherapy for lung cancer: 6-year analysis of 60 early-stage, 42 locally advanced, and 7 metastatic lung cancers. Int J Radiat Oncol Biol Phys. 2008; 72(3): Schefter TE, Kavanagh BD, Raben D, et al. A Phase I/II trial of Stereotactic Body Radiation Therapy (SBRT) for Lung Metastases: Initial report of dose escalation and early toxicity. Int J Radiat Oncol Biol Phys. 2006; 66(4 Suppl): S120-S Coons D, Gokale A, Burton A, et al. Fractionated stereotactic body radiation therapy in the treatment of primary, recurrent, and metastatic lung tumors: the role of positron emission tomography/computed tomography-based treatment planning. Clin Lung Cancer. 2008; 9(4):

33 STEREOTACTIC BODY RADIATION THERAPY (SBRT) MODEL POLICY Page Scorsetti M, Navarria P, Facoetti A, et al. Effectiveness of stereotactic body radiotherapy in the treatment of inoperable early-stage lung cancer. Anticancer Res. 2007; 27(5B): Senan S, Lagerwaard F. Stereotactic radiotherapy for stage I lung cancer: Current results and new developments. Cancer Radiother. 2010; 14(2): Sonke JJ, Rossi M, Wolthaus J,. et al. Frameless stereotactic body radiotherapy for lung cancer using four dimensional cone beam CT guidance. Int J Radiat Oncol Biol Phys. 2009; 74(2): Takeda A, Sanuki N, Kunieda E, et al. Stereotactic Body Radiotherapy for Primary Lung Cancer at a Dose of 50 Gy Total in Five Fractions to the Periphery of the Planning Target Volume Calculated Using a Superposition Algorithm. Int J Radiat Oncol Biol Phys. 2009; 73(2): van der Voort van Zyp NC, Prevost J-B, Hoogeman MS, et al. Stereotactic radiotherapy with real-time tumor tracking for non-small cell lung cancer: clinical outcome. Radiother Oncol. 2009; 91(3): van der Voort van Zyp NC, van der Holt B, van Klaveren RJ, et al. Stereotactic body radiotherapy using real-time tumor tracking in octogenarians with non-small cell lung cancer. Lung Cancer. 2010; 69(3): Zimmermann F, Wulf J, Lax I, et al. Stereotactic Body Radiation Therapy for Early Non-Small Cell Lung Cancer. Front Radiat Ther Oncol. 2010; 42: Pancreas 69. Chang DT, Schellenberg D, Shen J, et al. Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer. 2009; 115(3): Prostate 76. Buyyounouski MK, Price RA, Harris EER, et al. Stereotactic body radiotherapy for primary management of early-stage, low-to intermediate-ris prostate cancer: Report of the American Society for Therapeutic Radiology and Oncology Emerging Technology Committee. Int J Radiat Oncol Biol Phys. 2010; 76(5): Freeman DF, King CR. Stereotactic body radiation for low-risk prostate cancer: five year outcomes. Radiat Oncol. 2011; 6: Ishiyama H, Teh BS, Lo SS, et al. Stereotactic body radiation therapy for prostate cancer. Future Oncol. 2011; 7(9): King CR, Brooks JD, Gill H, et al. Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2012; 82(2); King CR, Brooks JD, Gill H, et al. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II ` clinical trial. Int J Radiat Oncol Biol Phys. 2009; 73(4): Katz AJ, Santoro M, Ashley R, et al. Stereotactic body radiotherapy for organ-confined prostate cancer. BMC Urol. 2010; 10(1) (doi: / ). 82. Madsen BL, Hsi RA, Pham HT, et al. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results. Int J Radiat Oncol Biol Phys. 2007; 67(4): Parthan A, Pruttivarasin N, Davies D, et al. Comparative cost-effectiveness of stereotactic body radiation therapy versus intensity-modulated and proton radiation therapy for localized prostate cancer. Front Oncol. 2012; 2: Mahadevan A, Jain S, Goldstein M, et al. Stereotactic Body Radiotherapy and Gemcitabine for Locally Advanced Pancreatic Cancer. Int J Radiat Oncol Biol Phys. 2010; 78(3): Rwigema J, Parihk S, Heron D, et al. Stereotactic body radiotherapy in the treatment of advanced adenocarcinoma of the pancreas. Am J Clin Oncol. 2011; 34(1): Schellenberg D, Goodman KA, Lee F, et al. Gemcitabine chemotherapy and single-fraction stereotactic body radiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2008; 72: Schellenberg D, Quon A, Yuriko Minn A et al. 18 Fluorodeoxyglucose PET is prognostic of progression-free and overall survival in locally advanced pancreas cancer treated with stereotactic radiotherapy. Int J Radiat Oncol Biol Phys. 2010; 77(5): Pelvic 74. Choi C, Cho C, Yoo S, et al. Image-guided Stereotactic Body Radiation Therapy in Patients with Isolated Para-aortic Lymph Node Metastases from Uterine Cervical and Corpus Cancer. Int J Radiat Oncol Biol Phys. 2009; 74(1): Kim MS, Choi C, Yoo S, et al. Stereotactic body radiation therapy in patients with pelvic recurrence from rectal carcinoma. Jpn J Clin Oncol. 2008; 38(10):

34 Practical Radiation Oncology (2012) 2, CME Special Article Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline May N. Tsao MD a,, Dirk Rades MD b, Andrew Wirth MD c, Simon S. Lo MD d, Brita L. Danielson MD e, Laurie E. Gaspar MD, MBA f, Paul W. Sperduto MD, MPP g, Michael A. Vogelbaum MD, PhD h, Jeffrey D. Radawski MD i, Jian Z. Wang PhD n, Michael T. Gillin PhD j, Najeeb Mohideen MD k, Carol A. Hahn MD l, Eric L. Chang MD m a Department of Radiation Oncology, University of Toronto, Odette Cancer Centre, Toronto, Ontario, Canada b Department of Radiation Oncology, University Hospital Schleswig-Holstein, Luebeck, Germany (ESTRO representative) c Peter MacCallum Cancer Center, Trans Tasman Radiation Oncology Group (TROG), East Melbourne, Australia d Department of Radiation Oncology, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, Ohio e Department of Radiation Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Canada (CARO representative) f Department of Radiation Oncology, University of Colorado, Aurora, Colorado g University of Minnesota Gamma Knife Center and Minneapolis Radiation Oncology, Minneapolis, Minnesota h Department of Neurological Surgery, Cleveland Clinic, Cleveland, Ohio i Department of Radiation Oncology, Ohio State University, Columbus, Ohio j Department of Radiation Oncology, M.D. Anderson Cancer Center, Houston, Texas k Department of Radiation Oncology, Northwest Community Hospital, Arlington Heights, Illinois l Department of Radiation Oncology, Duke University Medical School, Durham, North Carolina m Department of Radiation Oncology, University of Southern California Keck School of Medicine, Los Angeles, California n Department of Radiation Oncology, Ohio State University, Columbus, Ohio (deceased) Received 27 October 2011; revised 9 December 2011; accepted 15 December 2011 Note: An online CME test for this article can be taken at Conflicts of interest: Before initiation of this Guideline, all members of the Guidelines Task Group were required to complete disclosure statements. These statements are maintained at the American Society for Radiation Oncology (ASTRO) headquarters in Fairfax, Virginia and pertinent disclosures are published with the report. The ASTRO Conflict of Interest Disclosure Statement seeks to provide a broad disclosure of outside interests. Where a potential conflict is detected, remedial measures to address any potential conflict are taken and will be noted in the disclosure statement. Dirk Rades has received research grants from Merck Serono and Novartis, and serves as a consultant for Amgen and Astra Zeneca. Michael Vogelbaum has received research funding from Schering-Plough, Genentech, Brainlab, and Astra Zeneca; he owns stock in Johnson and Johnson. Jian Wang has received a prostate cancer research grant from the Ohio Cancer Research Associates. Expert reviewers were also required to complete disclosure statements, which are maintained at ASTRO Headquarters. The Task Group Chairs reviewed all disclosures and determined that they were not relevant to the subject matter of the Guideline. Corresponding author. Odette Cancer Centre, 2075 Bayview Ave, Toronto, ON M4N 3M5. address: may.tsao@sunnybrook.ca (M.N. Tsao) /$ see front matter 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. doi: /j.prro

35 Practical Radiation Oncology: July-September 2012 Brain metastases: An ASTRO guideline 211 Abstract Purpose: To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases. Methods and Materials: Key clinical questions to be addressed in this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management. Results: The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation). Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/ radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3). Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3). Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3). It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosisspecific graded prognostic assessment may be helpful. Conclusions: Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone) American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. Introduction Brain metastases represent a significant health care problem. It is estimated that 20% to 40% of cancer patients will develop brain metastases during the course of their illness. 1 Systematic reviews based on randomized phase III controlled trials for the management of single or multiple brain metastases in adult patients have been published. 1-8 Various treatment modalities exist, including whole brain radiotherapy (WBRT), resection, stereotactic radiosurgery, and best supportive care with the use of dexamethasone. A series of articles performing a systematic review and evidence-based clinical practice guidelines have been published from the perspective of the modalities listed above under the auspices of the American Association of Neurological Surgeons/Congress of Neurosurgeons (AANS/CNS). 4-8 The conclusions from this American Society for Radiation Oncology (ASTRO) Guideline are congruent with the conclusions put forth by the AANS/CNS. While these articles are important in that they are modality-based, it was also felt important to develop guidelines from an international perspective with international representation on the Brain Metastases Task Group. Additional key questions are posed (not necessarily previously addressed) such as prognostic classification systems, radiotherapy fractionation schemes, comparison of surgery and radiosurgery, neurocognition as an outcome variable in decision-making, palliative supportive care, and radiation sensitizers. Treatment recommendations are based on patient factors (such as age, performance status), tumor factors (such as number and size of brain metastases, tumor type, extracranial disease activity), and available treatment options (such as access to neurosurgery or stereotactic radiosurgery). This Guideline builds on the previous ASTRO Health Services Research Committee publication, The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases. 1 This present guideline has been endorsed by the CNS.

36 212 M.N. Tsao et al Practical Radiation Oncology: July-September 2012 Methods and materials Process The Guidelines Subcommittee of the Clinical Affairs and Quality Committee, in accordance with established ASTRO policy, recruited a Task Group composed of recognized experts in the fields of radiotherapy, surgery, and radiosurgery for brain metastases. These experts represent radiation oncology, neurosurgery, physics, outcomes, and health services research. The Task Group was asked to systematically review the literature on the radiotherapeutic and surgical management for patients with newly diagnosed metastatic disease to the brain. In June 2009, the ASTRO Board of Directors approved a proposal to develop a Guideline on radiotherapeutic and surgical management for newly diagnosed brain metastases. In January 2010, the Board authorized the Task Group membership. The Task Group participated in a series of communications by and conference calls to review the relevant publications, to discuss controversial issues, and formulate the Guidelines contained herein. The Task Group agreed by consensus on the various recommendations based on the randomized trials and relevant publications. The initial draft of the manuscript was reviewed by 3 expert reviewers and was placed on the ASTRO website during the month of April 2011 for public comment. Upon integration of the feedback, the document was then submitted to the ASTRO Board of Directors for their final review and approval in October Literature search MEDLINE (1966-Nov. 3, 2010), EMBASE ( week 46), and the CENTRAL databases (issue 4, 2010) were searched (Appendix 1). The search strategies resulted in 1826 publications, 597 publications, and 425 publications from MEDLINE, EMBASE, and CENTRAL, respectively (search strategy courtesy of the Cochrane Library). Only randomized phase III trials pertinent to the management of newly diagnosed brain metastases were included. Trials dealing with the use of WBRT, surgery, radiosurgery, chemotherapy, radiosensitizers, and palliative care alone were considered. Trials that examined the use of prophylactic cranial irradiation were excluded. A total of 36 randomized controlled trials were retrieved. One trial was excluded as it was published in abstract form in the year 2000 but never fully reported. 9 Two duplicate publications of the same trial 10,11 were included. Lead representatives from international radiation oncology groups, ASTRO, Canadian Association of Radiation Oncology (CARO), European Society for Therapeutic Radiology and Oncology (ESTRO), and Trans-Tasman Radiation Oncology Group (TROG), reviewed the 36 retrieved trials. As a result of feedback received from public comments, the literature search was further expanded to include nonrandomized studies (prospective or retrospective) dealing with the use of either radiosurgery or fractionated radiation to the postoperative surgical cavity. The MED- LINE (1947 to May week 2, 2011) search resulted in 1549 nonrandomized publications and EMBASE ( week 20) gave 3721 nonrandomized publications. The CENTRAL search resulted in 0 randomized controlled trials. Titles and abstracts were screened and a final total of 15 relevant publications were retrieved. Of note, all the radiosurgery trials used frame-based single fraction radiosurgery techniques with either a linear accelerator or gamma knife unit. Management options were graded by the level of evidence available using the U.S. Preventative Services Task Force levels. 12 Due to the lack of high-quality studies, management of patients with recurrent metastatic disease to the brain is not included in this report. The U.S. Preventative Services Task Force levels of evidence 12 are as follows. Level I: Evidence obtained from at least 1 properly designed randomized controlled trial. Level II-1: Evidence obtained from well-designed controlled trials without randomization. Level II-2: Evidence obtained from well-designed cohort or case-controlled analytic studies, preferably from more than 1 center or research group. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results from uncontrolled trials might also be regarded as this type of evidence. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees. The medical management issues associated with brain metastases will not be addressed by this Guideline as they are outside the scope of this review. Optimal follow-up brain imaging for patients with brain metastases has not been evaluated using high-quality trials. Based on expert opinion, in patients with good prognostic features and where there is potential for future salvage brain metastases treatment, enhanced magnetic resonance imaging followup every 2 to 4 months should be considered. Results Table 1 and Table 2 summarize common scenarios related to patients presenting initially with either single or multiple brain metastasis(es). These tables include not only the level 1 evidence but also other treatment options based on panel opinion and supported by literature of lower quality evidence.

37 Practical Radiation Oncology: July-September 2012 Brain metastases: An ASTRO guideline 213 Table 1 Single brain metastasis initial management Prognostic category ( a ) Other features Treatment options (evidence grade) references Good prognosis Expected survival 3 mo or more Complete resection possible Clinical benefit S LC WB control Neurocognition If brain metastasis 3-4 cm: Surgery and WBRT (level 1) 10,11,22,23,42,43,b Radiosurgery and WBRT (level 1) 51,53 Radiosurgery alone (Level 1) 23,54 Surgery with radiosurgery/radiation boost (with WBRT) to the resection cavity with or without WBRT (level 3) 26-41,b If brain metastasis N3-4 cm: Surgery and WBRT (level 1) 10,11,22,23,42,43,b Surgery with radiosurgery/radiation boost to the resection cavity with or without WBRT (level 3) 26-41,b (with WBRT) Good prognosis Expected survival 3 mo or more Not resectable If brain metastasis 3-4 cm: Radiosurgery and WBRT (level 1) 51,53 Radiosurgery alone (level 1) 23,54 If brain metastasis N3-4 cm: WBRT (level 3), with consideration of biopsy, if primary unknown 59,85,86 Poor prognosis WBRT (level 3) 59,85 Expected survival Palliative care without WBRT (level 3) 59,85 less than 3 mo KPS, Karnofsky performance status; LC, local control; S, survival; WB, whole brain; WBRT, whole brain radiotherapy. Surgery may be favored if the diagnosis is uncertain (eg, no known primary cancer or remote history of cancer and no known extracranial metastases or metastasis). a Prognostic category based on known prognostic factors (see clinical question 1, references 13-21). b Excluding radiosensitive histologies (eg, small cell lung cancer, leukemia, lymphoma, germ cell tumor). A 6%-9% minority of patients in Radiation Therapy Oncology Group (RTOG) 9508 trial had small cell lung cancer. The questions and guideline statements regarding the radiotherapeutic and surgical management for newly diagnosed brain metastases are listed below. 1. What prognostic factors are important for assessing and managing patients with newly diagnosed brain metastases? Interpretative summary Several prognostic indices have been reported in the literature for survival duration among patients with newly diagnosed brain metastases. These are useful in categorizing patients into survival time strata for treatment decisions, for predicting the results of therapeutic interventions, and for comparing treatment results. The Radiation Therapy Oncology Group (RTOG) devised 3 prognostic groups using recursive partitioning analysis 13,14 based on 1200 patients treated on prospective clinical trials with WBRT alone or additionally with radiosensitizers: class I, patients with Karnofsky performance status (KPS) 70 years, less than 65 years of age with controlled primary (3-month stability on imaging or newly diagnosed), and no extracranial metastases; class III, KPS b70; class II, All others. Median survival was 7.1 months, 4.2 months, and 2.3 months for class I, II, and III, respectively. Brain metastases are a heterogeneous population. The purpose of the graded prognostic assessment (GPA) was to identify significant diagnosis-specific prognostic factors in an updated era ( ) as compared with the RTOG recursive partitioning analysis (RPA) ( ). The original GPA was based on 4 criteria 15 : age, KPS, number of brain metastases, and presence or absence of extracranial metastases. Each of the 4 criteria is given a score of 0, 0.5, or 1.0 and these 4 scores are summed to determine the GPA score. Patients with the best prognosis have a GPA score of 4.0. The authors established this prognostic index based on 1960 patients treated with WBRT alone, WBRT and radiosensitizers, or WBRT and radiosurgery in the

38 214 M.N. Tsao et al Practical Radiation Oncology: July-September 2012 Table 2 Multiple brain metastases-initial management Prognostic category ( a ) Other features Treatment options (evidence grade) references Good prognosis Expected survival 3 mo or more All brain metastases 3-4 cm b Clinical benefit S LC WB control Neurocognition Radiosurgery and WBRT (level 1) 51,53 Radiosurgery alone 23,54 (level 1) WBRT (level 1) 59,85 Good prognosis Expected survival 3 mo or more Brain metastasis/ metastases causing significant mass effect c Safe surgical resection of the brain metastasis/metastases causing significant mass effect and postoperative WBRT (level 3) 25,b WBRT (level 3) 59,85 Poor prognosis WBRT (level 3) 59,85 Expected survival less than 3 mo Palliative care without WBRT (level 3) 59,85 KPS, Karnofsky performance status; LC, local control; S, survival; WB, whole brain; WBRT, whole brain radiotherapy. Surgery may be favored if the diagnosis is uncertain (eg, no known primary cancer or remote history of cancer and no known extracranial metastases or metastasis). a Prognostic category based on known prognostic factors (see clinical question 1, references 13-21). b Excluding radiosensitive histologies (eg, small cell lung cancer, leukemia, lymphoma, germ cell tumor). A 6%-9% minority of patients in RTOG 9508 trial had small cell lung cancer. c The maximum number or total volume of brain metastases best treated with radiosurgery (or surgery) is unknown. Randomized trials which have examined the use of radiosurgery, included selected patients with up to 4 brain metastases, while retrospective reports document use of radiosurgery that exceed 4 brain metastases. 52,55 A retrospective study 25 suggested that surgery significantly improves survival if all brain metastases can be removed. RTOG database, with all patients and data coming from prospective clinical trials. The GPA was then refined based on a multiinstitutional analysis of 4259 other patients with brain metastases treated with surgery, WBRT, radiosurgery, or various treatment combinations. New diagnosisspecific prognostic indices (diagnosis-specific graded prognostic assessment) were defined based only on the Table 3 Diagnosis-specific GPA 15,20,21 GPA Significant prognostic factors GPA scoring criteria NSCLC/SCLC Age N b50 KPS b ECM Present Absent #BM N Melanoma/RCC KPS b #BM N Breast cancer KPS b ER/PR/Her2 Triple negative ER/PR + Her2 - ER/PR Her2 + Triple positive Age 70 b70 GI KPS b ECM, extracranial metastases; ER, estrogen receptor; GPA, graded prognostic assessment; Her2, human epidermal growth factor receptor 2; KPS, Karnofsky performance status; #BM, number of brain metastases; NSCLC, non-small cell lung cancer; PR, progesterone receptor; RCC, renal cell carcinoma; SCLC, small cell lung cancer.

39 Practical Radiation Oncology: July-September 2012 Brain metastases: An ASTRO guideline 215 Table 4 Median survivals stratified by diagnosis and diagnosis-specific GPA score for patients with newly diagnosed brain metastases 15,20,21 Diagnosis Overall median survival (mo) Diagnosis-specific GPA GPA: 0-1 GPA: GPA: GPA: Median Median Median Median survival (mo) survival (mo) survival (mo) survival (mo) NSCLC SCLC Melanoma Renal cell GI Breast Total GI, gastrointestinal; GPA, graded prognostic assessment; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer. statistically significant prognostic factors for each individual diagnosis. 20 A subsequent analysis of 400 breast cancer patients refined the breast-gpa scoring system. 21 Table 3 shows the GPA scoring criteria for each of the significant prognostic factors by diagnosis. Table 4 shows the associated range of median survival by GPA and diagnosis. Other prognostic indices such as the score index for radiosurgery, the basic score for brain metastases, the Golden grading system, and the Rades prognostic scoring system have also been published Caveats Most published randomized trials that deal with the management of patients with brain metastases included patients with various primary cancers (non-small cell lung cancer, breast cancer, etc). Physicians should consider histology-specific indices in regard to clinical decision making. The use of histology-specific indices help guide estimated prognosis, useful in deciding on whether aggressive therapies (eg, radiosurgery, surgery) for selected patients should be considered (Tables 1 and 2). At present, there are insufficient level 1 data to recommend protracted WBRT schedules for certain histologies or higher radiosurgery doses for radioresistant lesions (such as melanoma, renal cell carcinoma). Future clinical trials should consider these histology-specific indices for purposes of stratification. It should be noted that the original RTOG RPA system did not find histology to be statistically significant for survival prediction. However, the revised GPA has found histology to be statistically significant based on retrospective data in a more recent era ( ) compared with the database used to derive the RTOG RPA ( ). The difference may be due to newer and more effective chemotherapy used to treat systemic disease. Newly diagnosed brain metastases: Single brain metastasis, role for surgery 2. For patients with single brain metastasis (excluding radiosensitive histologies such as small cell lung cancer, leukemia, lymphoma, and germ cell tumor), does surgical resection and whole brain radiotherapy improve survival or brain control compared with whole brain radiotherapy alone or compared with surgical resection alone? Interpretative summary For selected patients with good performance status (eg, KPS 70), limited extracranial disease, and a resectable brain metastasis, complete resection of the single brain metastasis improves the probability of extended survival. The addition of postoperative whole brain radiotherapy improves treated brain metastasis control and overall brain control without improving overall survival or duration of functional independence. These interpretations are consistent with the AANS guidelines on the use of surgery. 5 Phase III randomized trials evidence summary WBRT and surgery versus WBRT alone Three randomized controlled trials 10,11,42,43 examined the use of WBRT with or without resection for a single brain metastasis. [References 10 and 11 are duplicate publications of the same trial]. Two of the 3 trials 10,11,43 found significant improvement in survival with the addition of surgery to WBRT as compared with WBRT alone. The benefit for surgery may be lost in patients with poor prognostic factors such as advanced extracranial disease or lower performance status. Decreased median

40 216 M.N. Tsao et al Practical Radiation Oncology: July-September 2012 survival was reported in 2 randomized trials 10,11,42 in patients with a greater systemic involvement of their primary malignancy. Noordijk et al 10 reported a 5-month median survival in patients with progressive systemic disease in both the WBRT plus surgery versus WBRT alone arms. Patients with stable systemic disease had a 12-month survival with WBRT and surgery versus 7 months with WBRT alone. Mintz et al 42 reported a significant difference (P =.009) in the Cox regression analysis for mortality in patients having extracranial metastases versus no evidence of primary tumor (risk ratio 2.3). Forty-five percent of the patients in the study by Mintz et al 42 had extracranial metastases compared with only 37.5% in the trial by Patchell et al 43 and 31.7% in the trial by Vecht et al. 11 WBRT and surgery versus surgery alone Two randomized trials 22,23 have been completed that found a significant improvement in brain control (primary endpoint) in patients treated with WBRT and surgery as compared with surgery alone. The first trial 22 showed that postoperative WBRT significantly prevented brain recurrence at the site of the original metastasis (10% vs 46%, P b.001) and at other sites in the brain (14% vs 37%, P b.01). The authors found no difference in survival with the use of WBRT and surgery versus surgery alone, although the study was not powered for survival (a secondary endpoint of this trial). 22 The second trial, 23 the European Organization for Research and Treatment of Cancer (EORTC) study, found that WBRT reduced the 2-year relapse at the initial site of surgery from 59% to 27% (P b.001), and at new sites from 42% to 23% (P =.008). In addition, salvage therapies were used more frequently after observation, compared with after WBRT. 23 Caveats There are 2 completed randomized trials that examine WBRT and surgery versus surgery alone. 22,23 The first trial 22 was small and not powered for survival. The second trial by the EORTC 23 included patients randomized to receive postoperative WBRT. A total dose of 30 Gy in 10 fractions at 3 Gy per fraction within 6 weeks of surgery was administered. The Trans-Tasman Radiation Oncology Group trial (TROG 98.05) was closed early due to poor accrual. 24 The accrual target was a total of 130 patients. The authors reported on the 9 patients randomized to observation after surgery or radiosurgery and 10 patients randomized to WBRT after surgery or radiosurgery for single brain metastasis. However, no conclusions could be made from this severely underpowered study. No prospective studies have evaluated whether resection of more than one metastasis conveys meaningful clinical benefit. A retrospective case control series suggests the hypothesis that resection of multiple metastases may convey a similar benefit as conferred by resection of a single brain metastasis. 25 Furthermore, the benefit of excising multiple brain metastases causing mass effect has not been definitively proven with level 1 evidence. However, it was felt by the guideline authors that safe resection of multiple brain metastases causing mass effect should be included as an option for good prognosis patients. There is a lack of level 1 evidence relating to the use of surgery and radiation boost to the surgical cavity with or without WBRT, although there are publications (with lower level of evidence) supporting its use Fourteen publications reported on the use of surgery and local radiation (radiosurgery in 10 series and conformal fractionated radiation therapy in 4 series), with the rationale to defer or avoid WBRT, without compromising survival. One publication reported on the use of surgery, WBRT, and radiosurgery to the surgical cavity, with the rationale to maximize whole brain and local tumor bed control. 26 However, due to the paucity of randomized data, it is unknown whether the omission of postoperative WBRT (with a strategy of close radiographic and clinical follow-up and the use of salvage radiosurgery or WBRT at relapse) reduces neurocognitive decline compared with patients undergoing immediate postoperative WBRT. On the other hand, in a post hoc analysis of a randomized trial, distant brain metastases recurrence (a higher risk with radiosurgery alone) may have a bigger impact on neurocognitive decline. 57 Newly diagnosed brain metastases: Single brain metastasis, surgery versus radiosurgery 3. Is survival or brain control different in selected patients with single brain metastasis (excluding radiosensitive histologies such as small cell lung cancer, leukemia, lymphoma, and germ cell tumor) treated with surgery or radiosurgery? Interpretative summary There have been no high quality randomized trials that have assessed whether selected patients with a small single brain metastasis, in surgically accessible sites, should undergo radiosurgery or resection. Adding WBRT did not improve overall survival or functional independence. Evidence summary WBRT and surgery versus radiosurgery alone One trial 44 randomized patients with single (less than 3 cm) resectable brain metastasis to resection plus WBRT versus radiosurgery alone. Due to poor patient accrual, the

41 Practical Radiation Oncology: July-September 2012 trial was stopped early and reported 33 patients in the surgery and WBRT arm and 31 patients in the radiosurgery alone arm. This trial was too underpowered for any conclusions to be made. WBRT and radiosurgery versus WBRT and surgery One randomized trial examined the use of radiosurgery and WBRT versus surgery and WBRT. 45 This trial was closed due to slow accrual. Results were reported for 11 patients randomized to radiosurgery and WBRT and 10 patients randomized to surgery and WBRT. Unfortunately, the trial was too underpowered to make any conclusions. There have been 2 retrospective series 46,47 and 2 retrospective matched pair analyses 48,49 that examined the use of WBRT and radiosurgery versus WBRT and surgery for a single brain metastasis. These publications suggested no difference in overall survival between the 2 study groups. Radiosurgery for radioresistant histologies A phase II trial of radiosurgery for 1 to 3 newly diagnosed brain metastases (4 cm or less in maximum dimension) from histologies (renal cell carcinoma, melanoma, and sarcoma) that historically have been deemed radioresistant to fractioned external beam radiotherapy, was reported by the Eastern Cooperative Oncology Group. 50 Thirty-one eligible patients were treated with radiosurgery alone. Three-month intracranial failure with radiosurgery alone was 25.8%; in-field failure rate at 3 months was 19.3%. Distant intracranial failure rate at 3 months was 32.2%. Survival was consistent with other published series of similar patients treated with surgery, radiosurgery, WBRT, or a combination of these therapies. The intracranial relapse rate was moderately high in this study of patients treated with radiosurgery alone. Whether surgery has better local control or survival as compared with radiosurgery for radioresistant single brain metastasis could not be answered by this study due to lack of direct comparisons with a surgical group. Caveats In good prognosis patients with single brain metastasis (less than 3 to 4 cm in maximum dimension and amenable to gross total resection), either surgery or radiosurgery may be considered. Surgery may be favored in patients with unknown primary, or in patients with single brain metastasis causing significant mass effect. In good prognosis patients with single brain metastasis less than 3 to 4 cm in maximum dimension (in eloquent brain areas not amenable to safe total resection or in patients who are unfit for surgery), radiosurgery may be considered. Brain metastases: An ASTRO guideline 217 Newly diagnosed brain metastases: Single or multiple brain metastasis(es), WBRT with or without radiosurgery boost 4. Is there a survival or brain control difference in patients treated with WBRT and radiosurgery boost versus WBRT alone? Interpretative summary For good prognosis patients with single brain metastases (less than 4 cm in size, in patients with good performance status and controlled extracranial disease), the use of radiosurgery added to WBRT improves survival, treated brain lesion control, and overall brain control as compared with WBRT alone. In good prognosis patients with multiple brain metastases (all less than 4 cm in size and up to 4 brain metastases in number), radiosurgery boost when added to WBRT improves treated brain lesion and overall brain control as compared with WBRT alone. As there is no survival advantage with radiosurgery added to WBRT in patients with multiple brain metastases, WBRT alone may be considered. One randomized trial 51 (RTOG 9508) that included patients with up to 3 brain metastases found an improvement in KPS and decreased steroid use at 6 months with the use of radiosurgery boost added to WBRT. These interpretations are consistent with the AANS guidelines on the use of radiosurgery boost. 7 Phase III randomized trials evidence summary WBRT alone versus WBRT and radiosurgery boost The multi-institutional, cooperative RTOG 9508 trial 51 examined the use of WBRT and radiosurgery boost (n = 167) versus WBRT alone (n = 164). This trial included selected patients with 1 to 3 newly diagnosed brain metastases with a maximum diameter of 4 cm (for the largest lesion) and additional lesions not exceeding 3 cm in diameter. Median survival was significantly improved in patients with single brain metastasis treated with radiosurgery boost (6.5 months) as compared with 4.9 months in patients treated with WBRT alone. Higher response rates at 3 months and better control of treated lesions at 1 year were observed in the WBRT and radiosurgery group versus WBRT alone (82% vs 71%, P =.01). One single institution fully published trial 53 stopped at an interim evaluation of 60% accrual (14 patients randomized to WBRT alone and 13 patients randomized to WBRT plus radiosurgery). There was no survival benefit with the use of radiosurgery boost as compared with WBRT alone in patients with multiple brain metastases. Patients treated with WBRT and radiosurgery boost were reported to have better brain control versus those patients treated with WBRT alone.

42 218 M.N. Tsao et al Practical Radiation Oncology: July-September 2012 Caveats None of the trials have examined validated quality of life outcomes with patients managed with WBRT alone versus WBRT and radiosurgery boost. Given no expected survival benefit, either option of WBRT alone with possible salvage treatment or upfront WBRT and radiosurgery boost may be offered for selected patients with multiple brain metastases. It is unclear from these published trials whether there is benefit with radiosurgery boost to more than 4 lesions. However, there are level 3 data on patients undergoing radiosurgery for 4 or more intracranial metastases suggesting a survival benefit, and that total intracranial volume rather than number of brain metastases may be the more important predictor of survival. 52 At present, there are insufficient high-quality data on whether certain histologies benefit from the use of radiosurgery to treat more than 4 intracranial metastases. When new brain metastases are seen on the planning scan the day of radiosurgery, it may be reasonable to proceed and complete the radiosurgical procedure to all the lesions visualized even if they exceed a total of 4 brain metastases. Alternatively, not performing radiosurgery and proceeding with WBRT would also be considered a reasonable option in these patients. Newly diagnosed brain metastases: Single or multiple brain metastasis(es), radiosurgery alone versus WBRT and radiosurgery 5. Is there survival, brain control difference, or neurocognitive difference in patients treated with radiosurgery alone versus WBRT and radiosurgery? Interpretative summary Selected patients with brain metastasis(es) may be treated with radiosurgery alone. A further alternative is WBRT and radiosurgery boost. A third option for selected patients with multiple brain metastases is WBRT alone. There have been no convincing survival differences among the 3 options listed above, although none of the trials have been adequately powered to detect anything other than very large survival differences. More trials are needed to assess whether there are differences in neurocognitive and quality of life outcomes when WBRT is omitted in selected patients who are treated with radiosurgery alone. There is level 3 evidence that the increased risk of brain recurrence with a strategy of radiosurgery alone (if patients are not monitored and followed adequately) may be associated with symptomatic recurrence, which may not recover fully despite salvage treatment. 88 Evidence summary Radiosurgery alone versus WBRT and radiosurgery One fully published trial 56 reported on the use of radiosurgery alone versus WBRT and radiosurgery in selected patients with 1 to 4 brain metastases. The number of patients with single brain metastases (n = 68) was too small to perform meaningful subset analyses. As such, results were reported for both single and multiple brain metastases patients. No overall survival difference between the 2 groups was found, with a median survival of 7.5 months (WBRT and radiosurgery) versus 8 months (radiosurgery alone) (P =.42). However, the 12-month brain tumor recurrence rate was 48.6% in the WBRT and the radiosurgery group compared with 76.4% for the radiosurgery alone group (P b.001). Deterioration in mini-mental score examination (MMSE) occurred in 14 of 36 WBRT and radiosurgery patients (39%) versus 12 of 46 radiosurgery alone patients (26%; P =.21), and there was no difference in actuarial curves of freedom-from-3-point drop in MMSE (P =.73). Among patients with MMSE decline, the average duration until deterioration of the MMSE was 16.5 months in the WBRT and radiosurgery group as compared with 7.6 months in the radiosurgery alone group (P =.05). The shorter duration to neurocognitive decline (as measured by the MMSE) was felt by the authors to be attributable to the increased risk of brain relapse in the radiosurgery alone group. 57 It should be noted, however, that the MMSE is a poor measure of neurocognition as it lacks adequate sensitivity. 58 Chang et al 54 reported a randomized trial that examined patients with 1 to 3 brain metastases treated with WBRT and radiosurgery versus radiosurgery alone. The study was stopped according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive WBRT and radiosurgery were more likely to show a decline in learning and memory at 4 months compared with patients assigned to receive radiosurgery alone. At 4 months, patients treated with WBRT and radiosurgery had measurable decline in learning and memory as compared with patients treated with radiosurgery alone (52% vs 24%, respectively) despite higher rates of local and distant brain control in patients treated with WBRT and radiosurgery. It remains to be reported whether neurocognitive outcomes are different between the strategy of radiosurgery alone versus WBRT and radiosurgery at different time points (other than 4 months). Additionally, there was a survival difference between the 2 arms not readily explained by treatment selection, raising the possibility of inadvertent randomization or selection differences between the 2 groups. An imbalance in the arms of the trial with respect to medications (such as anti-seizure medications and benzodiazepines) may also affect neurocognitive outcomes.

43 Practical Radiation Oncology: July-September 2012 The subset of patients with single brain metastasis was not analyzed separately. Radiosurgery or surgery alone versus WBRT and radiosurgery or surgery The EORTC trial 23 included patients with 1 to 3 brain metastases. Three hundred fifty-nine patients were recruited. One hundred ninety-nine patients underwent radiosurgery and 160 underwent surgery. For the radiosurgery group, 100 patients were allocated to post-radiosurgery observation and 99 patients were allocated to post-radiosurgery WBRT. In the surgery group, 79 patients were allocated to postsurgery observation and 81 patients were allocated to adjuvant WBRT. Patients eligible for radiosurgery had 1 to 3 metastases of solid tumors (small cell lung cancer, lymphoma, leukemia, myeloma, and germ cell tumors were excluded) and brain metastasis size 3.5 cm in diameter for a single lesion ( 2.5 cm for 2 to 3 lesions). A complete resection was required for patients who underwent surgery. Overall survival (10.9 months vs 10.7 months) was similar in both arms (P =.89). WBRT reduced the 2-year relapse rate both at initial sites (surgery: 59% to 27%, P b.001; radiosurgery: 31% to 19%, P =.040) and at new sites (surgery: 42% to 23%, P =.008; radiosurgery: 48% to 33%, P =.023). In well-performing patients with stable systemic disease and 1 to 3 brain metastases, treated with initial radiosurgery or surgery, WBRT can be withheld if serial imaging for follow-up is performed. For patients undergoing surgery for a single brain metastasis, postoperative local irradiation is an option that should be investigated as adjuvant irradiation substantially reduces the risk of tumor bed recurrence. Caveats There is a suggestion based on 1 randomized trial 54 that omission of WBRT after radiosurgery for single brain metastasis is associated with better neurocognitive outcomes based on formal neurocognitive testing. More trials addressing the question of neurocognitive outcomes in the setting of radiosurgery alone and omission of upfront WBRT are needed. These radiosurgery trials assessed selected patients with small oligometastases to the brain (up to 4 metastases). It is unknown if there is a cutoff for the maximum number of targets appropriate for radiosurgery. Total target volume as well as number of targets may be important for safety and efficacy. A prospective nonrandomized series of patients 55 with 1 to 10 brain metastases treated with initial radiosurgery (without WBRT) required less than 10 cc volume for the largest tumor and less than 15 cc total tumor volume. Median survival was 0.83 years, 0.69 years, 0.69 years, 0.59 years, and 0.62 years for 1, 2, 3-4, 5-6, and 7-10 metastases, respectively. A phase II trial of radiosurgery for 1 to 3 newly diagnosed brain metastases from histologies (renal cell carcinoma, melanoma, and sarcoma), which historically have been deemed radioresistant to fractioned external beam radiotherapy, was reported by the Eastern Cooperative Oncology Group 50 (ECOG) as discussed previously. Because the intracranial relapse rate was moderately high in this study using radiosurgery alone (25.8% at 3 months and 48.3% at 6 months), the authors concluded that delaying WBRT may be appropriate for some subgroups of patients with radioresistant histologies, but routine avoidance of WBRT should be approached judiciously. Whether WBRT should be routinely omitted in radiosurgery eligible patients with radioresistant histologies remains controversial. There is level 3 evidence that the increased risk of brain relapse with radiosurgery alone may be associated with symptomatic recurrences that may not be reversible with salvage brain treatment. 88 In this ECOG trial, the actuarial incidence of failure within the radiosurgery field at 3 months was 19.3% and at 6 months was 32.2%. The brain relapse rate and radiosurgery failure rate in the ECOG trial were similar to the radiosurgery alone arm in the Aoyama et al, 56 Kocher et al, 23 and Chang et al 54 trials. The trials reported have examined the use of radiosurgery alone versus WBRT and radiosurgery boost. There have been no trials that have examined patients treated with radiosurgery alone versus WBRT alone. Newly diagnosed brain metastases: Multiple brain metastases 6. What is the role of comfort measures or palliative supportive care alone versus WBRT in patients with multiple brain metastases? Interpretative summary For selected patients with poor life expectancy (less than 3 months), the use of whole brain radiotherapy may or may not significantly improve symptoms from brain metastases. Comfort measures only, or short course (20 Gy in 5 daily fractions) whole brain radiotherapy, are reasonable options. Evidence summary Brain metastases: An ASTRO guideline 219 WBRT plus supportive care versus supportive care alone Only 1 older randomized trial, 59 performed in the precomputed tomographic era, compared WBRT plus supportive care versus supportive care alone (oral prednisone). Median survival in the prednisone alone arm was 10 weeks as compared with 14 weeks in the combined arm (P value not stated).

44 220 M.N. Tsao et al Practical Radiation Oncology: July-September 2012 There is 1 on-going Medical Research Council trial (Quartz) 87 that randomizes patients to optimal supportive care using dexamethasone versus optimal supportive care using dexamethasone and whole brain radiotherapy for patients with inoperable brain metastases from non-small cell lung cancer. Outcomes of interest include quality of life, overall survival, and side effects. Caveats There are consistent predictors for poor survival of brain metastases patients that include poor performance status and active uncontrolled disease Until better therapy is available for these poor prognostic patients, supportive comfort measures without WBRT can be considered. 7. What is the optimal WBRT dose fractionation schedule? Interpretative summary No differences in overall survival or symptom control have been demonstrated among the commonly used fractionation schemes, including 30 Gy in 10 daily fractions or 20 Gy in 5 daily fractions. Other common dose fractionation schedules of WBRT are 37.5 Gy in 15 daily fractions and 40 Gy in 20 daily (or twice daily) fractions. This interpretation is consistent with the AANS guideline on whole brain radiotherapy. 4 Evidence summary Altered WBRT dose fractionation schedules Numerous trials have examined various dose fractionation schedules of WBRT No altered dose fractionation scheme has shown improvement in either survival or symptom control (neurologic functional status, neurologic symptom relief, palliative index, or performance status) as compared with 20 Gy in 5 fractions or 30 Gy in 10 fractions of daily WBRT. One trial randomized patients of good performance status with brain metastases not suitable for surgical excision to either 40 Gy in 20 fractions of 2 Gy twice daily versus 20 Gy in 5 daily fractions. 68 There was no difference in median survival (19 weeks in both arms). Another randomized trial examined the use of 40 Gy in 20 twice daily fractions versus 20 Gy in 4 daily fractions. 69 The primary endpoint of brain progression favored patients treated with 40 Gy in 20 twice daily fractions (44% vs 64%, P =.03). The secondary endpoint of death from brain progression was no different between the 2 groups, P =.17. The authors concluded that intracranial disease control was improved in patients treated with 40 Gy in 20 twice daily fractions as compared with 20 Gy in 4 daily fractions. Caveats Differences in neurocognitive outcomes have not been well studied among the different fractionation schemes. These trials also did not examine different dose fractionation schedules in the setting of single brain metastasis treated with surgery. In addition, optimal dose fractionation schedules of WBRT were not examined in the setting of upfront WBRT with radiosurgery or in the setting of WBRT at the time of salvage after radiosurgery alone. 8. What is the role of WBRT and radiosensitizers versus WBRT alone in the management of patients with brain metastases? Interpretative summary There is no evidence of survival benefit with the use of radiosensitizers and whole brain radiotherapy. Evidence summary WBRT plus radiosensitizers versus WBRT alone There have been a few randomized trials that have examined the use of radiosensitizers (lonidamine, metronidazole, misonidazole, bromodeoxyuridine, motexafin gadolinium, and efaproxyn or RSR-13). Overall, no radiosensitizer has improved survival. Although, the use of motexafin gadolinium was reported to reduce neurologic progression in patients with non-small cell lung cancer metastatic to the brain, 76 the U.S. Food and Drug Administration did not approve the use of motexafin gadolinium for non-small cell lung cancer patients with brain metastases in A subset analysis of breast cancer patients treated with RSR-13 and WBRT was reported to show an improvement in survival and quality of life as compared with WBRT alone. 70 However, the subsequent larger trial designed specifically with breast cancer patients failed to show benefit with the use of RSR-13 and WBRT. 71 In 2004, the U.S. Food and Drug Administration Oncologic Drugs Advisory committee did not recommend approval of RSR- 13 as an adjunct to WBRT in patients with brain metastases from breast cancer. Caveats More trials are needed to assess the role (if any) of novel radiosensitizers in patients with brain metastases. 9. What is the role of chemotherapy and WBRT? Interpretative summary Although chemotherapy trials reported improved brain response rates with the use of combined chemotherapy and WBRT, this was at the cost of toxicity and no overall survival advantage was found with the addition of chemotherapy There currently is no high quality evidence to support the routine use of chemotherapy in the management of brain metastases.

45 Practical Radiation Oncology: July-September 2012 Evidence summary Chemotherapy and WBRT There have been 8 trials examining the use of chemotherapy for brain metastases The chemotherapy agents used were chloroethylnitrosoureas, teniposide, fotemustine, temozolomide, thalidomide, and topotecan. One trial examined the use of early versus delayed WBRT with chemotherapy in patients with metastatic non-small cell lung cancer. 83 No survival difference was seen between early versus delayed WBRT with chemotherapy. Another trial 84 examined the use of primary chemotherapy for newly diagnosed non-small cell lung cancer with synchronous brain metastases (with delayed WBRT at brain relapse) versus WBRT administered first. No survival difference was reported between the 2 arms. Caveats Further trials are needed to assess the role of chemotherapy (including novel systemic agents) in the management of patients with brain metastases. Conclusions Treatment options for brain metastases more than 30 years ago were limited to steroids and whole brain radiotherapy and rarely surgery. Management options today have expanded to include comfort measures (including the use of steroids), WBRT and, in selected patients, surgery or radiosurgery. Optimal management depends on patient factors (such as age, performance status), tumor factors (such as extracranial cancer activity, as well as number, size, location, and histopathology of brain metastases) and available treatment options (such as experienced radiosurgery services and neurosurgeons). The most important endpoint should be the deciding factor for which treatment is most appropriate. For selected patients with single brain metastasis, the use of surgery or radiosurgery has been shown to improve survival and this should be the primary consideration. Treatment options which have been shown to improve whole brain control (such as the use of WBRT) or local brain control (such as the use of radiosurgery) without survival benefit for selected multiple brain metastases patients are more difficult in terms of best treatment choice. The most important outcome likely is quality of life (taking into account the morbidity of symptomatic brain recurrence and the morbidity of treatment such as neurocognitive decline, which may be associated with the use of WBRT or the side effects associated with the prolonged use of dexamethasone). Quality of life has inconsistently been measured in these trials and drop-outs are a problem with assessing this endpoint. Numerous research opportunities exist to improve outcomes (survival, quality of life, brain control, and neurocognitive function) not only in the initial management of patients with brain metastases but also in the area of salvage treatment. Acknowledgments The authors would like to thank the following individuals who served as expert reviewers of the manuscript: Steven N. Kalkanis, MD, Penny K. Sneed, MD, and Minesh Mehta, MB, ChB. This paper is dedicated and in memoriam of Jian Z. Wang, PhD. We also acknowledge Shari Siuta for her administrative assistance. This document was prepared by the Guidelines Subcommittee of the Clinical Affairs and Quality Committee (CAQC) of ASTRO in coordination with the Third International Consensus Conference on Palliative Radiotherapy. ASTRO Guidelines present scientific, health, and safety information and may to some extent reflect scientific or medical opinion. They are made available to ASTRO members and to the public for educational and informational purposes only. Any commercial use of any content in this Guideline without the prior written consent of ASTRO is strictly prohibited. Adherence to this Guideline will not ensure successful treatment in every situation. Furthermore, this Guideline should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all circumstances presented by the individual patient. ASTRO assumes no liability for the information, conclusions, and findings contained in its Guidelines. In addition, this Guideline cannot be assumed to apply to the use of these interventions performed in the context of clinical trials, given that clinical studies are designed to evaluate or validate innovative approaches in a disease for which improved staging and treatment are needed or are being explored. This Guideline was prepared on the basis of information available at the time the Task Group was conducting its research and discussions on this topic. There may be new developments that are not reflected in this Guideline, and that may, over time, be a basis for ASTRO to consider revisiting and updating the Guideline. Appendix 1 Brain metastases: An ASTRO guideline 221 MEDLINE search strategy: Medline Ovid 1966 to Nov. 3, 2010

46 222 M.N. Tsao et al Practical Radiation Oncology: July-September exp Brain Neoplasms/ 2. ((brain or brainstem or intracranial or posterior fossa) adj3 (cancer or carcinom or tumor or tumour or neoplasm )).mp or 2 4. exp Neoplasm Metastasis/ or metastas.mp. 5. Radiotherapy/ 6. Radiotherapy, Adjuvant/ 7. (radiotherapy or radiat or radiosurg ).mp. 8. Combined Modality Therapy/ 9. Radiosurgery/ 10. gamma knife.mp. 11. or/ and 4 and randomized controlled trial.pt. 14. controlled clinical trial.pt. 15. randomized.ab. 16. placebo.ab. 17. radiotherapy.fs. 18. randomly.ab. 19. trial.ab. 20. groups.ab. 21. or/ and limit 22 to yr = (animals not (humans and animals)).sh not 24 key: mp = title, original title, abstract, name of substance word, subject heading word, unique identifier pt = publication type ab = abstract fs = floating subheading sh = subject heading EMBASE search strategy: Embase Ovid 1980 to 2010 week exp Central Nervous System Tumor/ 2. exp brain cortex/ 3. ((brain or brainstem or intracranial or posterior fossa) adj3 (neoplasm or cancer or carcinoma or tumor or tumour )).mp. 4. or/ Brain Metastasis/ or metastas.mp and 5 7. exp radiosurgery/ 8. multimodality cancer therapy/ 9. Radiotherapy/ 10. Cancer radiotherapy/ 11. (radiotherap or radiosurg ).mp. 12. gamma knife.mp. 13. radiat.mp. 14. or/ and random.ti,ab. 17. factorial.ti,ab. 18. (crossover or cross over or cross-over ).ti,ab. 19. placebo.ti,ab. 20. (doubl adj blind ).ti,ab. 21. (singl adj blind ).ti,ab. 22. assign.ti,ab. 23. allocat.ti,ab. 24. volunteer.ti,ab. 25. crossover procedure/ 26. double blind procedure/ 27. randomized controlled trial/ 28. single blind procedure/ 29. or/ and animal/ or nonhuman/ or animal experiment/ 32. human/ and not not limit 35 to yr = key: mp = title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name ti = title ab = abstract CENTRAL search strategy: CENTRAL Issue 4, 2010 #1. MeSH descriptor Brain Neoplasms explode all trees #2. brain near/3 (cancer or carcinoma or tumor or tumour or neoplasm ) #3. brainstem near/3 (cancer or carcinoma or tumor or tumour or neoplasm ) #4. intracranial near/3 (cancer or carcinoma or tumor or tumour or neoplasm ) #5. posterior fossa near/3 (cancer or carcinoma tumor or tumour or neoplasm ) #6. (#1 OR #2 OR #3 OR #4 OR #5) #7. MeSH descriptor Neoplasm Metastasis explode all trees #8. metastas #9. (#7 OR #8) #10. MeSH descriptor Radiotherapy explode all trees #11. MeSH descriptor Radiotherapy, Adjuvant explode all trees #12. radiotherapy or radiat or radiosurg #13. MeSH descriptor Combined Modality Therapy explode all trees #14. MeSH descriptor Radiosurgery explode all trees #15. gamma knife #16. (#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15) #17. (#6 AND #9 AND #16) #18. (#17), from 1980 to 2010 (Literature search courtesy of the Cochrane Library.)

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