STEREOTACTIC RADIOSURGERY & STEREOTACTIC BODY RADIATION THERAPY

STEREOTACTIC RADIOSURGERY & STEREOTACTIC BODY RADIATION THERAPY Protocol: NEU017 Effective Date: November 1, 2017 Table of Contents Page COMMERCIAL & MEDICAID COVERAGE RATIONALE... 1 MEDICARE COVERAGE RATIONALE... 5 BACKGROUND... 8 CLINICAL EVIDENCE... 8 U.S. FOOD AND DRUG ADMINISTRATION (FDA)... 14 APPLICABLE CODES... 15 REFERENCES... 16 PROTOCOL HISTORY/REVISION INFORMATION... 24 INSTRUCTIONS FOR USE This protocol provides assistance in interpreting UnitedHealthcare benefit plans. When deciding coverage, the enrollee specific document must be referenced. The terms of an enrollee's document (e.g., Certificate of Coverage (COC) or Evidence of Coverage (EOC)) may differ greatly. In the event of a conflict, the enrollee's specific benefit document supersedes this protocol. All reviewers must first identify enrollee eligibility, any federal or state regulatory requirements and the plan benefit coverage prior to use of this Protocol. Other Protocols, Policies and Coverage Determination Guidelines may apply. UnitedHealthcare reserves the right, in its sole discretion, to modify its Protocols, Policies and Guidelines as necessary. This protocol is provided for informational purposes. It does not constitute medical advice. This policy does not govern Medicare Group Retiree members. UnitedHealthcare may also use tools developed by third parties, such as the MCG Care Guidelines, to assist us in administering health benefits. The MCG Care Guidelines are intended to be used in connection with the independent professional medical judgment of a qualified health care provider and do not constitute the practice of medicine or medical advice. COMMERCIAL & MEDICAID COVERAGE RATIONALE For information regarding medical necessity review, when applicable, see MCG Care Guidelines, 21 st Edition, 2017. Accessed October 2017. Stereotactic Radiosurgery, A-0423 (AC) Stereotactic Body Radiotherapy, A-0694 (AC) MCG Care Guideline: Stereotactic Radiosurgery, A-0423 (AC) Clinical Indications for Procedure Stereotactic radiosurgery is may be indicated for 1 or more of the following: Stereotactic Radiosurgery and SBRT.doc Page 1 of 24

o Acoustic neuroma (vestibular schwannoma, acoustic schwannoma) smaller than 3 cm, as indicated by 1 or more of the following: Postoperative residual or recurrent tumor Signs of brainstem compression (eg, facial weakness, numbness or hypesthesias, diplopia, fixation nystagmus) Signs of cerebellar compression (eg, loss of balance, ataxia) Tumor growth seen with MRI monitoring Unilateral sensorineural hearing loss or tinnitus Vertigo or dizziness o Arteriovenous malformation (intracranial), as indicated by 1 or more of the following: Arteriovenous malformation location makes microsurgery high-risk approach (e.g., deep area of brain or speech center); Patient not at significant risk of hemorrhage during period between stereotactic radiosurgery and obliteration of arteriovenous malformation; Unacceptable operative risk (e.g., advanced age, comorbidity). o Brain metastasis, as indicated by ALL of the following: Absence of large tumor (e.g., 4 cm) on diagnostic imaging; Absence of mass effect (e.g. midline shift) on diagnostic imaging; Four or fewer brain metastases; Stable extracranial disease (i.e., cancer absent or controlled in other organ systems). o Chordoma, as indicated by 1 or more of the following: Contraindications to microsurgical resection (e.g., unacceptable operative risk or tumor adjacent to critical structures); Residual tumor following surgery. o Epilepsy, as indicated by ALL of the following: Brain MRI findings concordant with EEG findings; EEG shows localized epileptogenic source (e.g., mesial temporal lobe); o Seizures refractory to at least 2 different anticonvulsant medications. Essential tremor, as indicated by ALL of the following: Deep brain stimulation is not option due to 1 or more of the following: Patient declines deep brain stimulation; Patient has coagulopathy or uses anticoagulants; Patient has contraindication to permanent hardware implantation (e.g., chronic infection, immunocompromised); Patient is elderly; Patient is unable to keep mandatory, regular, frequent follow-up appointments (e.g., due to living long distance from medical care). Disability of one or more limbs from resting, positional, or kinetic tremor that affects safety, functional status, or quality of life; Tremor refractory to 1 year or more of standard medication. o Glomus jugulare tumor, as indicated by 1 or more of the following: Contraindications to microsurgical resection (e.g., unacceptable operative risk or tumor adjacent to critical structures); Residual or recurrent glomus jugulare tumor following microsurgical resection. o Intracranial cavernous malformation, as indicated by ALL of the following: Associated symptoms including 1 or more of the following: Stereotactic Radiosurgery and SBRT.doc Page 2 of 24

o o Intractable epilepsy; Progressive neurologic deterioration; Recurrent hemorrhage. Contraindications to microsurgical resection (e.g., unacceptable operative risk or tumor adjacent to critical structures). Intracranial hemangioblastoma, as indicated by 1 or more of the following: Contraindications to microsurgical resection (e,g,, unacceptable operative risk or tumor adjacent to critical structures); New tumor associated with von-hippel Lindau disease; Progression of residual intracranial hemangioblastoma following microsurgical resection Recurrent sporadic hemangioblastoma following microsurgery resection. o Intracranial meningioma, as indicated by 1 or more of the following: Contraindications to microsurgical resection (eg, unacceptable operative risk or tumor adjacent to critical structures) Residual or recurrent intracranial meningioma following microsurgical resection Skull base meningioma Pituitary adenoma, as indicated by ALL of the following: Conventional surgery not indicated, due to 1 or more of the following: Tumor extension or size prohibits more traditional surgical approach; Unacceptable operative risk (e.g., advanced age, comorbidity); Unacceptable risk of re-resection. Failed medical treatment or inadequate response to pituitary microsurgery. o Spinal cord metastasis, as indicated by ALL of the following: Additional conventional irradiation or surgery not appropriate; No evidence of spinal cord compression; No clinically significant spinal instability; Well-circumscribed lesion (i.e., easily outlined for treatment planning). o Trigeminal neuralgia, as indicated by ALL of the following: Patient declines microvascular decompression or has unacceptable operative risk (e.g., advanced age, comorbidity); Symptoms persist despite maximal medical treatment. Stereotactic radiosurgery is not medically necessary for: o Central neurocytoma; o Cluster headaches; o Facial nerve schwannoma o Intracranial ependymoma; o Malignant glioma; o Obsessive-Compulsive disorder; o Pineal tumor. There is insufficient, conflicting, or poor evidence to support the use of SRS in central neuroma, cluster headaches, facial nerve schwannoma, intracranial ependymoma, obsessive-compulsive disorder, and pineal tumors. In addition, the net benefit versus harm assessment is incomplete. The evidence for malignant glioma fails to demonstrate a net benefit, additional research is needed. Stereotactic Radiosurgery and SBRT.doc Page 3 of 24

MCG Care Guideline: Stereotactic Body Radiotherapy A-0694 (AC) Clinical Indications for Procedure Stereotactic body radiotherapy may be indicated for 1 or more of the following: o Liver cancer (primary or metastatic), as indicated by ALL of the following: Need for additional treatment (e.g., limited disease, palliation of symptoms); Sufficient amount of uninvolved liver to tolerate treatment course; Patient is not candidate for or refuses surgery and ablation. o Locoregional recurrence or tumors arising near previously irradiated regions. o Lung metastases, as indicated by ALL of the following: One to three lung metastases present; Extrathoracic disease absent or stable on imaging studies (e.g., CT scan, PET-CT) prior to beginning treatment; Need for additional treatment (e.g., curative intent, palliation of symptoms); Performance status adequate (e.g., less than 2 on Eastern Cooperative Oncology Group (ECOG) Performance Status scale); Pulmonary function adequate (both FEV 1 and DLCO (diffusing capacity of lung for carbon monoxide) higher than 40% of predicted values); Tumors less than or equal to 5 cm in diameter; Patient is not candidate for or refuses surgery. o Non-small cell lung cancer, as indicated by ALL of the following: Need for additional treatment (e.g., curative intent); Non-small cell lung cancer by cytology or histology; PET, PET-CT, or CT scan evidence of ALL of the following: Tumor size of 2 to 5 cm; No distant metastasis; No regional lymph node metastasis. Patient is not candidate for or refuses surgery. o Prostate cancer, as indicated by ALL of the following: Gleason score of 6 or less; Life expectancy greater than or equal to 10 years; Pretreatment PSA less than 10 ng/ml (mcg/l); Stage T1 or T2a prostate cancer. o Spine metastases, as indicated by ALL of the following: Metastasis resistant to conventional external beam radiotherapy (e.g., sarcoma, melanoma, renal cell carcinoma, non-small cell lung cancer, colon carcinoma); Need for additional treatment (e.g., palliation of symptoms); No cord compression; No spinal fracture or instability. Stereotactic body radiation therapy is not medically necessary for: o Adrenal metastases; o Gynecologic cancer; o Head and neck cancer; o Pancreatic cancer; o Renal cell carcinoma (primary or metastatic). Stereotactic Radiosurgery and SBRT.doc Page 4 of 24

There is insufficient, conflicting, or poor evidence to support the use of SBRT in these conditions. In addition, the net benefit versus harm assessment is incomplete. **End of MCG MEDICARE COVERAGE RATIONALE Medicare does not have a National Coverage Determination for Stereotactic Radiosurgery or Stereotactic Body Radiation Therapy. There are Local Coverage Determinations for Nevada for both (Accessed October 2017) and they are as follows: Stereotactic Radiosurgery (L34223) Local Coverage Determination Indications for SRS 1. Primary central nervous system malignancies, generally under 5 cm. 2. Primary and secondary tumors involving the brain or spine parenchyma, meninges/dura, or immediately adjacent boney structures. 3. Benign brain tumors and spinal tumors such as meningiomas, acoustic neuromas, pituitary adenomas, and pineal cytomas. 4. Cranial arteriovenous malformations and hemangiomas. 5. Other cranial non-neoplastic conditions for which it has been proven effective, e.g., movement disorders such as Parkinson s disease, essential tremor and other disabling tremor that are refractory to conventional therapy, such as severe, sustained trigeminal neuralgia not responsive to other modalities. 6. As a boost treatment for larger cranial or spinal lesions that have been treated initially with external beam radiation therapy or surgery (i.e., grade III and IV gliomas, oligodendrogliomas, sarcomas, chondrosarcomas, chordomas, and nasopharyngeal or paranasal sinus malignancies). 7. Metastatic brain or spine lesions, generally limited in number, with stable systemic disease, Karnofsky Performance Status 70 or greater (or expected to return to 70 or greater with treatment), and otherwise reasonable survival expectations. 8. Relapse in a previously irradiated cranial or spinal field where the additional stereotactic precision is required to avoid unacceptable vital tissue radiation. Limitations Coverage will be denied for each of the following: 1. Treatment for anything other than a severe symptom or serious threat to life or critical functions, not responsive or reasonably amenable to another therapy. 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 4. Patients with poor performance status (Karnofsky Performance Status less than 40), - see Karnofsky Performance Status below. 5. A claim for stereotactic cingulotomy as a means of psychotherapy, is considered to be investigational. Stereotactic Radiosurgery and SBRT.doc Page 5 of 24

6. For ICD-10-CM code G25.0, essential tremor, coverage 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. Coverage is further limited to unilateral thalamotomy. Gamma Knife pallidotomy remains non-covered and will be denied. Karnofsky Performance Scale (Perez and Brady, p 225) 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 Stereotactic Body Radiation Therapy (L34224) Indications for SBRT for lung, liver, kidney, adrenal gland, pancreas or prostate neoplasms: This A/B MAC covers primary and metastatic tumors of the lung, liver, kidney, adrenal gland, or pancreas when and only when each of the following criteria are met, and each specifically documented in the medical record: 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 discreet 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. Typically, such a patient would have also been a potential candidate for alternate forms of intense local therapy applied for the same purpose (e.g. surgical resection, radiofrequency ablation, cryotherapy, etc). 2. Other forms of radiotherapy, including but not limited to external beam and IMRT, cannot be as safely or effectively utilized, and 3. The tumor burden can be completely targeted with acceptable risk to critical normal structures 4. If the tumor histology is germ cell or lymphoma, effective chemotherapy regimens have been exhausted or are otherwise not feasible. 5. Other forms of focal therapy, including but not limited to radiofrequency ablation and cryotherapy, cannot be as safely or effectively utilized. The clinical experience with SBRT for carcinoma of the prostate is of short term duration relative to the natural history of prostate cancer. Published peer reviewed studies of the success and complication rates are still small and of short or medium term duration. Prominent specialty societies and academicians suggest SBRT is still investigational, while others who currently use the equipment feel SBRT has some selected advantages. We will cover SBRT for prostate cancer only when: 1. Other forms of first line therapy are not available or feasible since other forms have known long term success and complication rates; and 2. All of the criteria listed above are documented in the medical record; or Stereotactic Radiosurgery and SBRT.doc Page 6 of 24

3. The patient is enrolled in an approved clinical study listed in ClinicalTrials.Gov. Other neoplasms Lesions of bone, adrenal, breast, uterus, ovary and other internal organs not listed above are not covered for primary definitive SBRT as literature does not support an outcome advantage over other conventional radiation modalities, but may be appropriate for SBRT in the setting of recurrence after conventional radiation modalities. Malignant lesions of the head & neck or paranasal sinuses may be appropriate for SBRT following other conventional radiation modalities to complete initial definitive therapy. Other Indications for SBRT Except as above, any lesion with a documented necessity to treat using a high dose per fraction of radiation. When using high radiation doses per fraction, high precision is required to avoid surrounding normal tissue exposure. Lesions which have received previous radiotherapy or are immediately adjacent to previously irradiated fields, where the additional precision of stereotactic radiotherapy is required to avoid unacceptable tissue radiation will be covered when other conditions of coverage are met (see Limitations below) and this necessity is documented in the medical record. Limitations: Coverage will be denied for each of the following: 1. Treatment unlikely to result in clinical cancer control and/or functional improvement. 2. Patients with wide-spread cerebral or extra-cranial metastases 3. Patients with poor performance status (Karnofsky Performance Status less than 40), - see Karnofsky Performance Status below. Karnofsky Performance Scale (Perez and Brady, p 225) 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 For Medicare and Medicaid Determinations Related to States Outside of Nevada: Please review Local Coverage Determinations that apply to other states outside of Nevada. http://www.cms.hhs.gov/mcd/search Important Note: Please also review local carrier Web sites in addition to the Medicare Coverage database on the Centers for Medicare and Medicaid Services Website. Stereotactic Radiosurgery and SBRT.doc Page 7 of 24

BACKGROUND Stereotactic radiosurgery is a form of external beam radiotherapy in which a high dose of radiation is tightly focused on a lesion within or immediately adjacent to the brain. It allows, when required, for focused radiation to be delivered over several sessions instead of in a single session. When high-energy photons used in stereotactic radiosurgery have been sourced from a radionuclide, the technique is commonly termed "gamma knife." Alternative techniques use photons, which are sourced from a linear accelerator, or protons, which are sourced from charged nuclei particles. Stereotactic body radiotherapy, also known as stereotactic ablative radiotherapy, is a form of external beam radiotherapy in which a high dose of radiation is tightly focused on primary or metastatic extracranial or spinal malignancies ( Lyengar et al., 2013) (Shultz et al., 2014). In contrast to stereotactic radiosurgery of the brain and skull base, stereotactic body radiotherapy addresses tumors that move relative to bony structures, which makes them more difficult to visualize and target, (Kirkpatrick et al., 2014) and the radiation is generally administered in 1 to 5 fractions (Timmerman & Herman, 2014) (NCCN, 2014). Stereotactic body radiotherapy allows for delivery of radiation at higher doses than conventional radiation and retreatment of previously irradiated patients while protecting critical structures that are contiguous with the target tissue (e.g., bowel, bladder, spinal cord, lung) and at risk for radiation toxicity with use of other radiation therapy modalities (ASTRO, 2013, Pan et al., 2011, Ip et al., 2010). When high-energy photons used in stereotactic body radiotherapy have been sourced from a radionuclide, the technique is commonly termed "gamma knife" (Tipton, et al., 2011). Alternative techniques use photons, which are sourced from a linear accelerator, or protons, which are sourced from charged nuclei particles. CLINICAL EVIDENCE Stereotactic Radiosurgery For arteriovenous malformations (intracranial), evidence demonstrates at least moderate certainty of at least moderate net benefit. Treatment options for intracranial arteriovenous malformations include open surgical resection of the nidus, embolization, stereotactic radiosurgery, or a combination of these (Foy, et al., 2010, Yashar, et al., 2011). Risks of surgery are greater for arteriovenous malformations located in the deep subcortical regions (such as the basal ganglia, internal capsule, and the thalamus) and for the eloquent areas of the brain (motor, sensory, visual, and speech centers) due to the potential for functional impairment (Javalkar, et al., 2009). Evidence-based guidelines support the use of stereotactic radiosurgery for those patients who are not candidates for surgical excision or who have an arteriovenous malformation that is considered unsuitable for complete obliteration by embolization (Niranjan, 2013,). A review article stated that the primary disadvantage of stereotactic radiosurgery is that thrombosis does not occur for 2 to 3 years after surgery, placing the patient at risk for interval hemorrhage. Rate of thrombosis is dependent upon lesion size, with cure rates ranging from 94% (less than 1 cc) to 36% (greater than 10 cc), with retreatment for initial failures increasing the cure rates (Friedman, et al., 2011). For brain metastasis, evidence demonstrates at least moderate certainty of at least moderate net benefit. A systematic review and practice guideline supports stereotactic radiosurgery for patients with 4 or Stereotactic Radiosurgery and SBRT.doc Page 8 of 24

fewer brain metastases that are not causing mass effect (Linskey, et al., 2010). A systematic review of 16 studies (including 2 randomized controlled trials, 2 meta-analyses, and 12 retrospective studies) concluded that stereotactic radiosurgery plus whole brain radiation was associated with improved local tumor control and neurologic functioning as compared with either treatment alone (Muller- Riemenschneider, et al., 2009). Another systematic review identified 5 randomized controlled trials (with a total of 663 patients with 1 to 4 brain metastases) that assessed the efficacy of stereotactic radiosurgery or surgery alone or with the addition of whole brain radiation therapy; the authors found that there was low-quality evidence that adding whole brain radiation decreased intracranial disease progression at 1 year, and no evidence that whole brain radiation had an effect on overall and progression-free survival (Soon, et al., 2014). For chordomas, evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. Retrospective analysis of 71 patients treated at 6 institutions reported that although surgical resection is the initial treatment option, complete resection is not achieved in the majority of cases due to anatomic constraints from surgical access or adjacent critical structures, and stereotactic radiosurgery provides adjuvant tumor control (Kano, et al., 2011). For epilepsy, evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. (RG A2) Stereotactic radiosurgery may be an alternative to open temporal lobectomy for treatment of medically refractory mesial temporal lobe epilepsy; however, the anticonvulsant effect has a 12-month to 24-month latency from treatment to seizure remission (Chang, et al., 2010). For essential tremor, evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. A case series of 172 patients with medically refractory essential tremor who were not candidates for deep brain stimulation reported that 81% of patients showed improvements in drawing scores and 77% showed improvements in writing scores after stereotactic radiosurgery of the ventral intermediate nucleus of the thalamus (Young, et al., 2010). For glomus jugulare tumor, evidence demonstrates at least moderate certainty of at least moderate net benefit. A retrospective study and systematic review with pooled patient data (229 total patients) concluded that although surgery has a control rate of 90%, it has significant morbidity; therefore, stereotactic radiosurgery may be an alternative to treat these vascular skull base lesions in selected individuals (Chen, et al., 2010). A meta-analysis of 19 stereotactic radiosurgery studies (335 patients) found, at a mean or median follow-up of greater than 3 years, that 95% of patients were clinically unchanged or improved, and 96% of the tumors were unchanged or reduced in size (Guss, et al., 2011). Although complete microsurgical resection is considered optimal treatment, stereotactic radiosurgery is an option for tumors near critical structures or in patients with unacceptable operative risk. It is also utilized for residual or recurrent tumor after resection (Lieberson, et al., 2012). For intracranial cavernous malformation, evidence demonstrates at least moderate certainty of at least moderate net benefit. An evidence-based guideline supports the use of stereotactic radiosurgery for patients who are not candidates for resection and have associated symptoms of recurrent hemorrhage, progressive neurologic deterioration, or intractable epilepsy (Nirajan, 2013). Stereotactic Radiosurgery and SBRT.doc Page 9 of 24

For intracranial meningioma, evidence demonstrates at least moderate certainty of at least moderate net benefit. (RG A1) A retrospective analysis of a cohort of 972 patients with 1045 meningiomas followed over an 18-year period reported that the overall stereotactic radiosurgery control rate for grade 1 meningiomas was 93%, whereas for grades 2 and 3 meningiomas, the control rates were only 50% and 17%, respectively (Kondziolka, et al., 2008). Although complete microsurgical resection is considered optimal treatment, stereotactic radiosurgery is an option for tumors near critical structures or in patients with unacceptable operative risk. It is also utilized for residual or recurrent tumor after resection (Kondziolka, et al., 2008, Bloch, et al., 2012, Hamm, 2008). For pituitary adenomas, evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. Stereotactic radiosurgery is indicated for either symptomatic inoperable tumors or for regrowth of tumor tissue following resection (Stapleton, et al., 2010, Yang, et al., 2010, Kobayashi, 2009). A literature review identified 26 studies with 970 patients with pituitary adenomas that produced growth hormone; after radiosurgery, the overall disease control rate without medication was 48% to 53% (Yang, et al., 2010). For spinal cord metastases, evidence demonstrates at least moderate certainty of at least moderate net benefit. Stereotactic radiosurgery, as compared with conventional radiation, permits delivery of a relatively high dose of radiation to target tissue while minimizing exposure to surrounding healthy tissue (Chang & Lee, 2013). A literature review stated that stereotactic radiosurgery may be used as a primary treatment option for metastatic tumors of the spinal cord without evidence of cord compression (Hsu, et al., 2010). A review of 31 studies (with a total of 2241 patients) found that there is support to use stereotactic radiosurgery as a primary treatment for spinal epidural metastases, tumors that are poor responders to conventional radiotherapy (e.g., melanoma, renal cell carcinoma), and as salvage treatment after conventional radiotherapy (Joaquim, et al., 2013). For trigeminal neuralgia, evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. Two large series of patients treated with stereotactic radiosurgery for idiopathic trigeminal neuralgia, one with 365 patients and the other with 503 patients, reported adequate pain relief of 75% and 80%, respectively, at 1 year, and 58% and 46%, respectively, at 5 years; the authors of both studies acknowledged that these results are not as favorable as reports in the literature for pain relief of 70% at 10 years with microvascular decompression. Both studies concluded that microvascular decompression is the preferred treatment for young and healthy patients, and that stereotactic radiosurgery may be an option for elderly patients or those who are not surgical candidates (Verheul, et al., 2010, Conley & Hirshc, 2010). For vestibular schwannoma, evidence demonstrates at least moderate certainty of at least moderate net benefit. A meta-analysis identified 14 studies that included patients with more than 5 years of followup and compared conservative management (observation by serial MRI and audiogram) to stereotactic radiosurgery; it was determined that although there was no significant difference in hearing preservation outcome, stereotactic radiosurgery was associated with increased tumor control rate (tumor stable or decreased in size) (Maniakas & Saliba, 2012). Another meta-analysis of 16 studies comparing microsurgery to stereotactic radiosurgery that included patients with more than 5 years of follow-up found that although stereotactic radiosurgery was associated with better long-term hearing preservation, there was no significant difference with regard to tumor control or procedural failure Stereotactic Radiosurgery and SBRT.doc Page 10 of 24

(Maniakas & Saliba, 2012). A systematic review of 74 studies that included 5825 patients with vestibular schwannoma treated with stereotactic radiosurgery reported a mean tumor control rate of 94% and overall hearing preservation rate of 57% (Yang, et al., 2009). An evidence-based review of studies comparing tumor control and functional outcomes of stereotactic radiosurgery and microsurgery for vestibular schwannomas less than 3 cm found that although both techniques had comparable tumor control rates, stereotactic radiosurgery was associated with increased hearing and facial nerve preservation (Sarmiento, et al., 2013). Stereotactic radiosurgery is generally not indicated for treatment of vestibular schwannomas larger than 3 cm, which are difficult to control locally, and where there is high risk of radiation damage to surrounding tissues, including the brainstem (Battista, 2009, Conely & Hirsch, 2010). Stereotactic Body Radiation Therapy For liver cancer (primary or metastatic), evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. An evidence-based review article concluded that stereotactic body radiotherapy has effectiveness comparable to that of other local radiation therapies and may have a role in the management of earlystage hepatocellular carcinoma in patients deemed unsuitable for surgical or ablative therapies (Klein & Dawson, 2013). An observational study of 32 patients with inoperable primary liver cancer (21 with hepatocellular carcinoma and 11 with cholangiocarcinoma) reported that, for hepatocellular carcinoma, 63% were free from local progression at a median follow-up of 13 months; median overall survival for hepatocellular carcinoma was 34%, with estimated 1-year and 2-year survival rates of 87% and 55%, respectively. For patients with cholangiocarcinoma, freedom from local progression was 56% at a median follow-up of 8 months; median overall survival for cholangiocarcinoma was 11%, with estimated 6-month and 1-year overall survival rates of 75% and 45%, respectively. Recurrence rates for hepatocellular carcinoma and cholangiocarcinoma were 42% and 67%, respectively (Ibarra, et al., 2012). A study of 47 patients with inoperable hepatocellular carcinoma who had incomplete response after transarterial chemoembolization reported that, after treatment with stereotactic body radiotherapy, 38% achieved complete remission within 6 months and 38% achieved partial remission. The 2-year rates of local control, overall survival, and progression-free survival were 95%, 69%, and 34%, respectively (Kang, et al., 2012). Guidelines developed by an international alliance of cancer centers state that there is growing evidence from nonrandomized clinical trials supporting the use of stereotactic body radiotherapy for patients with unresectable, locally advanced, or recurrent hepatocellular carcinoma, usually in patients with 1 to 3 tumors and minimal or no extrahepatic disease. Stereotactic body radiotherapy may be considered for patients with more extensive disease if there is sufficient uninvolved liver, and liver radiation tolerance can be respected (NCCN, 2014). A study of 36 patients (32 with metastases and 4 with primary cancer) with 54 malignant liver lesions found, at a median follow-up of 21 months, that 40% of patients demonstrated complete response, 30% had a partial response, 16% had stable lesions, and 14% had recurrence, with a median time to local failure of 14.5 months. Actuarial survival was 83% at 1 year and 62% at 2 years (Stintzing, et al., 2010). A study of 18 patients with primary and metastatic liver tumors found, at a median follow-up of 15 months, that the 1-year overall survival and local control rates were 94% and 86%, respectively. The authors noted that additional studies were needed to determine optimal doses and fractionation schedules (Iwata, et al., 2010). Guidelines developed by an international alliance of cancer centers and a specialty society state that stereotactic body radiation therapy may be considered in patients with a limited number of liver metastases, or if the patient is symptomatic, when surgery is not appropriate (NCCN, 2015, Goodman, et al., 2014). Stereotactic Radiosurgery and SBRT.doc Page 11 of 24

For locoregional recurrence, or tumors arising near previously irradiated regions, evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. A review article of re-irradiation with stereotactic body radiotherapy for treatment of local recurrence of non-small cell lung cancer, head and neck cancers, and pelvic tumors concluded that the majority of available data have emerged from small single-institution studies with limited follow-up and that the theoretical advantages of stereotactic body radiotherapy, namely local control with acceptable toxicity, require confirmation in larger prospective studies (Mantel, et al., 2013). Specialty society guidelines state that stereotactic body radiotherapy may be appropriate for tumors of any type arising in or near previously irradiated regions when a high level of precision and accuracy are needed to minimize the risk of injury to surrounding normal tissues or when a high dose per fraction treatment is indicated (ASTRO, 2013). Re-irradiation of the spine with stereotactic body radiotherapy may provide superior tumor control as compared with conventional techniques and dose fractionation plans due to its ability to deliver higher radiation doses to the tumor target while obtaining rapid dose fall-off to spare the spinal cord; in the re-irradiated setting, local control rates between 70% and 100% have been documented (Kirkpatrick, et al., 2014). For lung metastases, evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. A study of 61 patients with lung metastases that were treated with stereotactic body radiotherapy reported 3-year rates of local control, overall survival, and progression-free survival of 84%, 53%, and 22%, respectively. In multivariate analysis, tumor volume was associated with overall, cancer-specific, and progression-free survival. Analysis of registry data for metastasectomy demonstrated a 2-year overall survival of 70% (as compared with 67% in this study) and a 5-year overall survival of 36%. The authors concluded that stereotactic body radiotherapy is an effective and safe local treatment option for selected patients with lung metastases (Ricardi, et al, 2012). Guidelines developed by an international alliance of cancer centers state that stereotactic body radiation therapy may be indicated in patients with a limited number of lung metastases (NCCN, 2014, NCCN, 2015). For non-small cell lung cancer, evidence demonstrates at least moderate certainty of at least moderate net benefit. Multiple studies of stereotactic body radiotherapy for treatment of inoperable non-small cell lung cancer report actuarial 3-year primary tumor control rates of 87% to 98% and overall survival rates up to 56%, as compared with 30% to 40% and 20% to 35%, respectively, for conventional radiotherapy (Palma, et al., 2012, Heinzerling, et al., 2011, Timmer, et al., 2010). Systematic reviews report that actuarial 3-year survival rates for treatment with either stereotactic body radiotherapy or surgical locoregional control are comparable for patients with stage I non-small cell lung cancer with severe chronic obstructive pulmonary disease (Palma, et al., 2012, Chi, et al., 2010). A retrospective multicenter study of 46 patients with a median age of 82 years who were treated with stereotactic body radiotherapy for inoperable stage I non-small cell lung cancer concluded that the same selection criteria should be applied to young and elderly patients alike, citing an overall failure rate of 15% and no toxicities of grade 3 or higher in patients 75 years of age and older (Samuels, et al., 2013). Modified stereotactic body radiotherapy is recommended for tumors within 2 cm of the proximal bronchial tree to reduce toxicity (Donington et al., 2012, Simone, et al., 2013). A systematic review and meta-analysis that compared the efficacy of stereotactic body radiotherapy to surgery for operable stage I non-small cell lung cancer included 6 studies containing 864 matched patients and found that patients treated with stereotactic body radiotherapy had worse 3-year overall survival on a matchedpair analysis as compared with those treated with surgery (Zhang, et al., 2014). Practice guidelines Stereotactic Radiosurgery and SBRT.doc Page 12 of 24

support stereotactic body radiotherapy as definitive treatment in patients with high-risk stage I nonsmall cell lung cancer when the tumor is less than 5 cm and normal tissue dose constraints can be respected (Sahgal, et al., 2012). A specialty society guideline states that stereotactic body radiotherapy offers excellent local control and minimal side effects for stage I medically inoperable patients and is emerging as standard treatment, particularly for peripherally located lesions (Videtic, et al., 2013). Guidelines developed by an international alliance of cancer centers state that patients with medically inoperable non-small cell lung cancer who are node negative or those who refuse surgery may be candidates for stereotactic body radiotherapy (NCCN, 2014). For prostate cancer, evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. A systematic review that included 14 trials and 1472 low-risk to high-risk prostate cancer patients found that, with median follow-up from 11 months to 60 months, stereotactic body radiotherapy had overall biochemical progression-free survival from 81% to 100% (Tan, et al., 2014). A consecutive case series of 41 low-risk prostate cancer patients treated with stereotactic body radiotherapy reported, at a median follow-up of 5 years, a biochemical progression-free survival rate of 93% (Freeman & King, 2011). A study of 67 low-risk prostate cancer patients reported an estimated 4-year biochemical relapse-free survival rate of 94%. Additional studies with longer follow-up were recommended to confirm durable biochemical control rates as well as low rates of late toxicities (King, et al., 2012). A study of stereotactic body radiotherapy in 477 prostate cancer patients (324 low-risk and 153 intermediate-risk) found that actuarial 7-year freedom from biochemical failure was 96% for low-risk patients and 90% for intermediate-risk patients, outcomes that are comparable to those from high-dose brachytherapy (Katz & Kang, 2014). A pooled analysis of 1100 patients with clinically localized prostate cancer from separate phase II clinical trials found a 5-year biochemical relapse-free survival rate of 93% for all patients (95% for low-risk, 84% for intermediate-risk, and 81% for high-risk), which compares favorably with other definitive treatments for low-risk and intermediate-risk patients (King, et al., 2013). Guidelines developed by an international alliance of cancer centers state that stereotactic body radiotherapy can be considered cautiously as an alternative to conventionally fractionated radiation therapy for patients with prostate cancer in clinics with the requisite clinical expertise and technology (NCCN, 2014). A specialty society guideline states that although stereotactic body radiotherapy for treatment of stage T1 and T2 prostate cancer appears to be promising, it should be used with caution, ideally in a clinical trial (Nguyen, et al., 2014). A retrospective study of Medicare beneficiaries treated for prostate cancer with stereotactic body radiotherapy or intensity modulated radiation therapy found that stereotactic body radiotherapy was associated with a significantly higher rate of genitourinary toxicity at 24 months (43.9% vs 36.3%, respectively) (Yu, et al., 2014). For spine metastases, evidence demonstrates a net benefit, but of less than moderate certainty, and may consist of a consensus opinion of experts, case studies, and common standard care. A systematic review identified 31 studies (23 low-quality and 8 very-low-quality) of the role of stereotactic body radiotherapy in the management of spinal metastases; the overall local control rate was approximately 90%, and it was highly effective in reducing pain. Although the quality of the literature was suboptimal, stereotactic radiosurgery appeared to be effective, even in previously irradiated patients (Sohn & Chung, 2012). A study of 149 patients with mechanically stable, non-cord-compressing spinal metastases (166 lesions) found that stereotactic body radiotherapy was associated with significantly decreased pain, significantly reduced opioid use, and progression-free survival of 89% at Stereotactic Radiosurgery and SBRT.doc Page 13 of 24

1 year and 72% at 2 years (Wang, et al., 2012). A specialty society guideline states that stereotactic body radiotherapy has been demonstrated to achieve durable tumor control when treating patients with limited metastatic disease and good performance status who have lesions in vertebral bodies or the paraspinous region. However, for uncomplicated previously untreated bone metastases in a patient with widespread progressive disease in the spine or elsewhere and an unfavorable prognosis, a less technical form of palliative radiotherapy is indicated (ASTRO, 2013). A specialty guideline states that stereotactic body radiotherapy is best used for patients with spinal bone metastases by protocol in a clinical trial (Lo, et al., 2012). Guidelines developed by an international alliance of cancer centers state that stereotactic radiotherapy is an option for treatment of metastatic spine tumors if there is no spinal cord compression, fracture, or spinal instability; it is recommended that treatments be spaced at least 6 months apart (NCCN, 2014). U.S. FOOD AND DRUG ADMINISTRATION (FDA) Devices used for stereotactic radiosurgery or radiation therapy are approved as radionuclide radiation therapy system (product code IWB), medical linear accelerator (product code IYE) and radiation treatment planning system (product code MUJ). For additional information see http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm and enter the specific product codes (Accessed October 2017). The Leksell Gamma Knife Target System received initial FDA 510(k) approval (K984328) on May 21, 1999 (product code IWB), and has received two subsequent 510(k) approvals. In the most recent approval on March 5, 2007 (K063512), for Leksell Perfexion was approved for stereotactic irradiation of head structures ranging from very small target sizes of a few millimeters to several centimeters e.g. metastatic tumors. The CyberKnife Radiosurgery System received initial FDA 510(k) approval (K984563) on July 14, 1999, and has received nine subsequent 510(k) approvals. In the most recent approval on September 21, 2007 (K072504), the CyberKnife Robotic Radiosurgery System (product codes IYE, MUJ) was approved for treatment planning and image-guided radiosurgery of lesions or conditions anywhere in the body provided that radiation therapy is indicated. The CyberKnife Robotic Radiosurgery System is a computer controlled medical system for planning and performing minimally invasive stereotactic radiosurgery and precision radiotherapy using a treatment radiation generator, linear accelerator, manipulator (robot), and a target locating subsystem to accurately deliver radiation to the treatment target. The CyberKnife System uses skull tracking, fiducial tracking, Xsight Spine Tracking, Xsight Lung Tracking, and Synchrony Respiratory Tracking for dynamic positioning and pointing of the linear accelerator. The Trilogy Radiotherapy Delivery System received initial FDA 510(k) approval (K033343) on December 23, 2003, and has received four subsequent 510(k) approvals. In the most recent approval on November 9, 2007 (K072916) the Trilogy System with RapidArc (product code IYE) was approved to provide stereotactic radiosurgery and precision radiotherapy for lesions, tumors and conditions anywhere in the body when radiation treatment is indicated. The Elekta Synergy System received initial FDA 510(k) approval (K032996) on October 23, 2003, and has received one subsequent 510(k) approval on August 12, 2005 (K051932). The Elekta Synergy, Stereotactic Radiosurgery and SBRT.doc Page 14 of 24

Synergy S and XVI R3.5 (product code IYE) were approved be used for radiation therapy treatment of malignant neoplastic diseases, as determined by a licensed physician. The Novalis Shaped Beam Surgery System (product codes IYE, MUJ) received FDA 510(k) approval (K002509) on November 3, 2000 as a dedicated system to plan, to perform and to document radiosurgery or stereotactic radiotherapy for lesions (e.g. arteriovenous malformations), tumors, head and neck targets, functional disorders and extracranial indications. Additional Products Leksell(TM) Gamma Knife Target System (Elekta Instruments AB, San Diego, CA), the Theratron 780C/1000 (MDS Nordion, Kanata, Ontario, Canada), CyberKnife Robotic Radiosurgery System (Accuray Inc., Sunnyvale, CA), X-Knife (Radionics, Burlington, MA), and a number of other commercially available instruments. APPLICABLE CODES The following list(s) of procedure and/or diagnosis codes is provided for reference purposes only and may not be all inclusive. Listing of a code in this policy does not imply that the service described by the code is a covered or non- covered health service. Benefit coverage for health services is determined by the member specific benefit plan document and applicable laws that may require coverage for a specific service. The inclusion of a code does not imply any right to reimbursement or guarantee claim payment. Other Policies and Coverage Determination Guidelines may apply. CPT Code Description Thoracic target(s) delineation for stereotactic body radiation therapy 32701 (SRS/SBRT), (photon or particle beam), entire course of treatment Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); 1 61796 simple cranial lesion Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); each 61797 additional cranial lesion, simple (List separately in addition to code for primary procedure) Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); 1 61798 complex cranial lesion Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); each 61799 additional cranial lesion, complex (List separately in addition to code for primary procedure) Application of stereotactic headframe for stereotactic radiosurgery (List 61800 separately in addition to code for primary procedure) Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); 1 63620 spinal lesion Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); each 63621 additional spinal lesion (List separately in addition to code for primary procedure) Radiation treatment delivery, stereotactic radiosurgery (SRS), complete course of 77371 treatment of cranial lesion(s) consisting of 1 session; multi-source Cobalt 60 based 77295 3-dimensional radiotherapy plan, including dose-volume histograms Stereotactic Radiosurgery and SBRT.doc Page 15 of 24

Radiation treatment delivery, stereotactic radiosurgery (SRS), complete course of 77372 treatment of cranial lesion(s) consisting of 1 session; linear accelerator based Stereotactic body radiation therapy, treatment delivery, per fraction to 1 or more 77373 lesions, including image guidance, entire course not to exceed 5 fractions Stereotactic body radiation therapy, treatment management, per treatment course, 77435 to 1 or more lesions, including image guidance, entire course not to exceed 5 fractions CPT is a registered trademark of the American Medical Association. HCPCS Code G0339 G0340 Description Image guided robotic linear accelerator base stereotactic radiosurgery, complete course of therapy in one session, or first session of fractionated treatment 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 REFERENCES Stereotactic Radiosurgery Kavanagh BD, Timmerman RD. Stereotactic radiosurgery and stereotactic body radiation therapy: an overview of technical considerations and clinical applications. Hematology/Oncology Clinics of North America 2006;20(1):87-95. DOI: 10.1016/j.hoc.2006.01.009. Pannullo SC, Fraser JF, Moliterno J, Cobb W, Stieg PE. Stereotactic radiosurgery: a meta-analysis of current therapeutic applications in neuro-oncologic disease. Journal of Neuro-Oncology 2011;103(1):1-17. DOI: 10.1007/s11060-010-0360-0. Niranjan A, Lunsford LD. Stereotactic radiosurgery guideline for the management of patients with intracranial arteriovenous malformations. Progress in Neurological Surgery 2013;27:130-40. DOI: 10.1159/000341773. Friedman WA, Bova FJ. Radiosurgery for arteriovenous malformations. Neurological Research 2011;33(8):803-19. DOI: 10.1179/1743132811Y.0000000043. Foy AB, Wetjen N, Pollock BE. Stereotactic radiosurgery for pediatric arteriovenous malformations. Neurosurgery Clinics of North America 2010;21(3):457-61. DOI: 10.1016/j.nec.2010.03.002. Buis DR, et al. Radiosurgery of brain arteriovenous malformations in children. Journal of Neurology 2008;255(4):551-60. DOI: 10.1007/s00415-008-0739-4. Douglas JG, Goodkin R. Treatment of arteriovenous malformations using Gamma Knife surgery: the experience at the University of Washington from 2000 to 2005. Journal of Neurosurgery 2008;109 Suppl:51-6. DOI: 10.3171/JNS/2008/109/12/S9. Stereotactic Radiosurgery and SBRT.doc Page 16 of 24