Stereotactic Radiosurgery
Number: 0083
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses stereotactic radiosurgery.
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Medical Necessity
Aetna considers stereotactic radiosurgery medically necessary in certain circumstances.
For medical necessity criteria, see eviCore Healthcare Radiation Therapy Clinical Guidelines.
Note: eviCore guidelines undergo a formal review annually; however, eviCore reserves the right to change and update the guidelines without prior notice. Draft guidelines are posted 90 days prior to implementation. Additional clinical guidelines may be developed as needed or may be withdrawn from use.
Background
With any external beam radiation therapy, the highest dose of radiation develops where multiple beams intersect. Thus, the fewer beams there are, the greater the dose reaching other areas traversed by the beams. For example, if only 2 beams are used, the highest dose would develop at the site where the beams intersect, but a significant portion of the dose would be distributed to fields anterior and posterior to the intersection.
Stereotactic radiosurgery (SRS) uses the above principle to deliver a highly focused ionizing beam so that the desired target is obliterated, leaving adjacent structures nearly unaffected. Guidance is provided by a variety of imaging techniques, including angiography, computerized tomography (CT), and magnetic resonance imaging (MRI). The key to SRS is immobilization of the patient so that targeting can be accurate and precise.
Stereotactic radiation is also used in extra-cranial sites, in a procedure called stereotactic body radiation therapy (SBRT). A body frame has been designed to immobilize patients for such treatment. In addition, frameless methods of administering SBRT to the body have been developed. These frameless systems rely on skeletal landmarks or implanted fiducial markers to locate and guide the therapy beam to treatment targets within the body.
Based upon professional opinion, a coding guide from the American Society for Therapeutic Radiation and Oncology (ASTRO, 2007) stated that SBRT is considered appropriate for the treatment of the following conditions:
- Lung or liver metastases not amenable to surgery
- Medically inoperable early stage lung cancer
- Primary liver cancer not amenable to surgery
- Recurrent lung cancer amenable to salvage therapy
- Recurrent pelvic tumors
- Retroperitoneal tumors
- Spinal and para-spinous tumors
- Other recurrent cancers or tumors.
The radioactive particles used in SRS and SBRT may come from various sources. The Gamma Knife uses Cobalt-60. Over 200 finely focused beams of gamma radiation simultaneously intersect at the precise location of the brain disorder. Proton beam radiosurgery derives its advantage from the so-called "Bragg peak", a term that describes the pattern of deposition of proton beam radiation. Protons decelerate as they travel though tissue, depositing disproportionately more radiation at greater depths. The protons deposit most of their energy at their depth of maximal penetration, resulting in a "peak" of radiation at that tissue depth. The depth of peak radiation can be precisely defined by the energy the cyclotron imparts to the proton beam.
A linear particle accelerator, or LINAC, creates photons by accelerating electrons along a linear path where they collide with a metal target. This produces a single, intense photon beam. To reduce the effect of the radiation on adjacent healthy tissues, a moving frame is used to target the abnormality with "arcs" from different directions. LINAC treatments may be given in multiple sessions over several days, which are referred to as fractionated radiotherapy. With fractionated radiotherapy, radiation is delivered to the tumor or lesion at different points in the cell division cycle. This may be the preferred form of treatment in some circumstances. Fractionated treatments may continue for up to 30 days. "Hypo-fractionated" treatments are given over 5 to 8 treatment days.
Precise stereotactic localization is necessary for treatment of intra-cranial structures, because of their deep location and because of the close proximity of vital structures in the brain. During radiotherapy administration, the cranium can be completely immobilized using a frame.
Fractionated stereotactic radiotherapy (FSRT) involves multiple low-dose radiation treatments. Fractionated stereotactic radiotherapy is used to treat tumors in hard-to-reach locations or with very unusual shapes. Fractionated stereotactic radiotherapy is also used to treat tumors which are located in close proximity to vital structures, such as the optic nerve or hypothalamus, where even a very accurate high-dose single fraction of stereotactic radiosurgery could not be tolerated.
For this procedure, patients are required to wear a special customized fiberglass helmet. (For other stereotactic radiation techniques of the head, the patient's head must be immobilized in a special head-ring frame, which is applied under local anesthetic.) After the patient undergoes the usual stereotactic imaging such as CT or MRI, small doses of radiation are accurately applied each day. The customized fiberglass helmet harnesses the patient while receiving low, daily doses. Fractionated stereotactic radiotherapy is also an excellent way to administer radiation treatments to infants or small children whose fast-growing brains can not tolerate standard radiation. In the past, oncologists were limited to treating infants and small children with chemotherapy alone. This technique also shows great promise in the treatment of benign tumors such as pituitary adenomas or meningiomas. The use of fractionated stereotactic radiotherapy permits excellent control of the tumor but spares the brain from such cognitive side-effects as impaired cognition and memory that commonly occur with standard radiation treatment.
An assessment conducted by the Alberta Heritage Foundation for Medical Research (Hailey, 2002) concluded that there is limited evidence that fractionated stereotactic radiotherapy may have an advantage over stereotactic radiosurgery in treatment of acoustic neuromas and brain tumors.
There are clinical reports of the effectiveness of of SBRT for radiosensitive central nervous system (CNS) tumors invading the spine. SBRT is useful to treat surgically unresectable ependymomas and other radiosensitive primary central nervous system tumors if they are invading the spine and spinal cord. SBRT has not been as successful when used on metastatic tumors to the spine, because these metastatic lesions are not usually radiosensitive. SBRT of the spine has been performed using an immobilizing frame. In addition, frameless methods of administering SBRT to the spine are in development. These frameless systems rely on skeletal landmarks or implanted fiducial markers to locate and guide the therapy beam to treatment targets within the spine or spinal cord.
With the development of a stereotactic body frame analogous to the stereotactic head frames used for intra-cranial targets, stereotactic techniques have been used to treat tumors in extra-cranial sites other than the spine. Available evidence for SBRT is from dose analysis studies showing theoretical advantage to this form of treatment, and phase II studies evaluating local control and toxicity.
A number of studies have examined SBRT of primary lung cancer. Nyman et al (2005) from Finland reported experience of SBRT in 45 patients with stage I non-small cell lung cancer. The investigators reported 80 % 1-year survival and 30 % 5-year survival, and median survival of 39 months. Nagata et al (2005) reported on experience from Japan on SBRT in 45 patients with stage IA and IB lung cancer. Sixteen percent of tumors showed complete response, and 84 % of tumors showed partial response. With a median follow-up of 30 months, no pulmonary complications greater than grade 3 were found and no other vascular, cardiac, esophageal or neurologic toxicities encountered. The investigators reported that, for stage IA lung cancer, the disease-free and overall survival rates after 1 and 3 years were 80 % and 72 %, and 92 % and 83 %, respectively, whereas for stage IB lung cancer, the disease-free survival and overall survival rates were 92 % and 71 %, and 82 % and 72 %, respectively. McGarry et al (2003) from Indiana University reported on a phase I dose escalation study of SBRT in 47 patients with inoperable stage I lung cancer. Dose-limiting toxicity included predominantly bronchitis, pericardial effusion, hypoxia, and pneumonitis. Local failure occurred in 4 of 19 T1 and 6 of 28 T2 patients. Local failures occurred between 3 and 31 months from treatment. Within the T1 group, 5 patients had distant or regional recurrence as an isolated group, whereas 3 patients had both distant and regional recurrence. Within the T2 group, 2 patients had solitary regional recurrences, and the 4 patients who failed distantly also failed regionally.
An earlier report from Indiana University details phase I trial experience with 37 patients with stage I non-small cell lung cancer treated with SBRT (Timmerman et al, 2003). Significant toxicity was limited to 1 case of grade 3 pneumonitis and 1 case of hypoxia. Minor transient pulmonary function changes were commonly seen, and 1 case of asymptomatic pericardial effusion was noted. Twenty-seven patients had a complete response to treatment, and 60 % of patients had a partial response. After a median follow-up period of 15.2 months, 6 patients experienced local failure, all at lower dose levels than currently employed. A 2003 Korean study reported experience using SBRT in 28 patients with primary or metastatic lung tumors (Lee et al, 2003). A hypo-fractionated 3 or 4 treatment regimen was used. Thirty-nine percent complete and 43 % partial response rates were noted. Whyte et al (2003) from Stanford University reported on a phase I clinical trial of SBRT in 23 patients with lung cancer. Complete radiographic responses were seen in 2 patients, partial responses in 15 patients, and no response or progression in 6 patients. Three pneumothoraces resulted from fiducial placement. A 2001 Japanese report detailed a 5-year experience in treating 50 patients with stage I non-small cell lung cancer. In 18 of these patients, SBRT was boost treatment after conventional radiotherapy. With a median 36-month follow-up, 30 patients were alive and disease-free. The 3-year case-specific survival rate was 88 %. The Radiation Therapy Oncology Group has an ongoing clinical study of SBRT in patients with inoperable stage I/II non-small cell lung cancer.
There are studies of SBRT in body sites other than the spine and lung. Schefter et al (2001) reported on a phase I clinical trial of stereotactic body radiotherapy in 18 patients with metastatic liver cancer. The study was limited to patients with 1 to 3 liver metastases, tumor diameter less than 6 cm, and adequate liver function. These investigators reported that no patients experienced acute grade 3 liver or intestinal toxicity or any acute grade 4 toxicity.
Hoyer et al (2005) from Denmark reported on a phase II study of SBRT in pancreatic cancer. A total of 22 patients with locally advanced and surgically non-resectable, histological proven pancreatic carcinoma were included into the trial. The investigators reported that only 2 patients were found to have a partial response, and the remaining patients had no change or progression after treatment. Six patients had local tumor progression, but only 1 patient had an isolated local failure without simultaneous distant metastasis. The investigators reported that median time to local or distant progression was 4.8 months. Median survival time was 5.7 months and only 5 % of patients were alive 1 year after treatment. The investigators noted that acute toxicity reported 14 days after treatment was pronounced. The investigators stated that there was a significant deterioration of performance status, significantly more nausea and significantly more pain after 14 days compared with baseline. However, 8 of 12 patients improved in performance status, scored less nausea, pain, or needed less analgesic drugs at 3 months after treatment. Four patients suffered from severe mucositis or ulceration of the stomach or duodenum and one of the patients had a non-fatal ulcer perforation of the stomach. The investigators concluded that SBRT "was associated with poor outcome, unacceptable toxicity and questionable palliative effect and cannot be recommended for patients with advanced pancreatic carcinoma."
Wersall et al (2005) from Sweden investigated the results of using SBRT in 58 patients with renal cell carcinomas. The investigators reported that tumor lesions regressed totally in 30 % of the patients at 3 to 36 months, whereas 60 % of the patients had a partial volume reduction or no change after a median follow-up of 37 months for censored and 13 months for uncensored patients. The investigators reported that side effects were generally mild. The investigators reported that 3 of 162 treated tumors recurred, yielding a local control rate of 90 to 98 %, considering the 8 % non-evaluable sites.
Hoyer and colleagues (2006) evaluated the effectiveness of SBRT in the treatment of inoperable patients with colorectal cancer metastases. Sixty-four patients with a total number of 141 colorectal cancer metastases in the liver (n = 44), lung (n = 12), lymph nodes (n = 3), suprarenal gland (n = 1) or 2 organs (n = 4) were treated with SBRT. After 2 years, actuarial local control was 86 % and 63 % in tumor and patient based analysis, respectively. Nineteen percent were without local or distant progression after 2 years and overall survival was 67, 38, 22, 13, and 13 % after 1, 2, 3, 4 and 5 years, respectively. The investigators reported that 1 patient died due to hepatic failure, 1 patient was operated for a colonic perforation and 2 patients were conservatively treated for duodenal ulcerations. In addition, moderate toxicities such as nausea, diarrhea and skin reactions were observed.
Tse and colleagues (2008) reported outcomes of a phase I study of individualized SBRT for unresectable hepatocellular carcinoma (HCC) and intra-hepatic cholangiocarcinoma (IHC). Patients with unresectable HCC or IHC, and who are not suitable for standard therapies, were eligible for 6-fraction SBRT during 2 weeks. Radiation dose was dependent on the volume of liver irradiated and the estimated risk of liver toxicity based on a normal tissue complication model. Toxicity risk was escalated from 5 % to 10 % and 20 %, within 3 liver volume-irradiated strata, provided at least 3 patients were without toxicity at 3 months after SBRT. A total of 41 patients with unresectable Child-Pugh A HCC (n = 31) or IHC (n = 10) completed 6-fraction SBRT. Five patients (12 %) had grade 3 liver enzymes at baseline. The median tumor size was 173 ml (9 to 1,913 ml). The median dose was 36.0 Gy (24.0 to 54.0 Gy). No radiation-induced liver disease or treatment-related grade 4/5 toxicity was seen within 3 months after SBRT. Grade 3 liver enzymes were seen in 5 patients (12 %). Two patients (5 %) with IHC developed transient biliary obstruction after the first few fractions. Seven patients (5 HCC, 2 IHC) had decline in liver function from Child-Pugh class A to B within 3 months after SBRT. Median survival of HCC and IHC patients was 11.7 months (95 % confidence interval [CI]: 9.2 to 21.6 months) and 15.0 months (95 % CI: 6.5 to 29.0 months), respectively. The authors concluded that individualized 6-fraction SBRT is a safe treatment for unresectable HCC and IHC.
Goodman et al (2010) performed a phase I dose-escalation study to explore the feasibility and safety of treating primary and metastatic liver tumors with single-fraction SBRT. Between February 2004 and February 2008, a total of 26 patients were treated for 40 identifiable lesions: 19 patients had hepatic metastases, 5 had IHC, and 2 had recurrent HCC. The prescribed radiation dose was escalated from 18 to 30 Gy at 4-Gy increments with a planned maximum dose of 30 Gy. Cumulative incidence functions accounted for competing risks to estimate local failure (LF) incidence over time under the competing risk of death. All patients tolerated the single-fraction SBRT well without developing a dose-limiting toxicity. Nine acute grade 1 toxicities, 1 acute grade 2 toxicity, and 2 late grade 2 gastro-intestinal toxicities were observed. After a median of 17 months follow-up (range of 2 to 55 months), the cumulative risk of LF at 12 months was 23 %. Fifteen patients have died: 11 treated for liver metastases and 4 with primary liver tumors died. The median survival was 28.6 months, and the 2-year actuarial overall survival was 50.4 %. The authors concluded that it is feasible and safe to deliver single-fraction, high-dose SBRT to primary or metastatic liver malignancies measuring less than or equal to 5 cm. Moreover, single-fraction SBRT for liver lesions demonstrated promising local tumor control with minimal acute and long-term toxicity. Single-fraction SBRT appears to be a viable non-surgical option.
Kopek et al (2010) reported outcomes of a single institution study of SBRT for unresectable cholangiocarcinoma. The dose-volume dependency of the observed gastro-intestinal toxicity was explored. A total of 27 patients with unresectable cholangiocarcinoma (IHC, n = 1; Klatskin tumors, n = 26 ) were treated by linac-based SBRT. The dose schedule was 45Gy in 3 fractions prescribed to the isocenter. The median progression-free survival and overall survival were 6.7 and 10.6 months, respectively. With a median follow-up of 5.4 years, 6 patients had severe duodenal/pyloric ulceration and 3 patients developed duodenal stenosis. Duodenal radiation exposure was higher in patients developing moderate- to high-grade gastro-intestinal toxicity with the difference in mean maximum dose to 1cm(3) of duodenum reaching statistical significance. A statistically significant association between grade 2 ulceration and volume of duodenum exposed to selected dose levels was not established. The authors concluded that the outcomes of SBRT for unresectable cholangiocarcinoma appear comparable to conventionally fractionated chemoradiotherapy with or without brachytherapy boost. The practical advantages of SBRT are of particular interest for such poor prognosis patients. Patient selection, however, is key in order to avoid compromising such practical gains with excessive gastrointestinal toxicity.
A structured evidence review by the Alberta Heritage Foundation for Medical Research (Hailey, 2002) concluded that "the place of SRS [stereotactic radiosurgery] in the treatment of Parkinson's disease does not appear to be established." In addition, the review concluded that "[t]he efficacy of SRS in the management of epilepsy appears not to have been established, other than in association with its use in treatment for AVMs or brain tumors."
Bartolomei et al (2008) reported the effectiveness and tolerance of gamma knife (GK) radiosurgery in mesial temporal lobe epilepsy (MTLE) after a follow-up more than 5 years. Patients presenting with MTLE and treated with a marginal dose of 24 Gy were included in the study (n = 15) – 8 were treated on the left side, and 7 were treated on the right. The mean follow-up was 8 years (range of 6 to 10 years). At the last follow-up, 9 of 16 patients (60 %) were considered seizure-free (Engel Class I) (4/16 in Class IA, 5/16 in Class IB). Seizure cessation occurred with a mean delay of 12 months (+/- 3) after GK radiosurgery, often preceded by a period of increasing aura or seizure occurrence (6/15 patients). The mean delay of appearance of the first neuroradiological changes was 12 months (+/- 4). Nine patients (60 %) experienced mild headache and were placed on corticosteroid treatment for a short period. All patients who were initially seizure-free experienced a relapse of isolated aura (10/15, 66 %) or complex partial seizures (10/15, 66 %) during anti-epileptic drug (AED) tapering. Restoration of treatment resulted in good control of seizures. The authors concluded that GK radiosurgery is an effective and safe treatment for MTLE. Results are maintained over time with no additional side effects. Long-term results compare well with those of conventional surgery. The authors also noted that the main disadvantage of this approach is the delay of seizure remission, often preceded by a period of increasing seizure frequency. Patients must also be warned that a long-lasting AED treatment must be maintained (usually at a lower dose) following the procedure.
In an editorial that accompanied the aforementioned article, Spencer (2008) stated that GK treatment in MTLE is still searching for a place; its disadvantages (slightly lower seizure response rate, delayed response, absolute requirement for continued medication, higher mortality) compared to anterior medial temporal resection seem to outweigh its non-invasive status, which so far does not appear to carry any clear benefits in terms of neurological or cognitive function, or seizure response. Furthermore, whether GK treatment should be considered for intractable epilepsy arising in other functional cortical regions that can not be treated with resection remains unexplored.
In a review on the application of SRS to disorders of the brain, Kondziolka et al (2008) noted that radiosurgery has had an impact on the management of patients with vascular malformations, all forms of cerebral neoplasia, and selected functional disorders such as trigeminal neuralgia and tremor. Epilepsy, behavioral disorders, and other novel indications are the topics of current investigation. This is in agreement with the observation of Quigg and Barbaro (2008) who stated that further studies are needed to ascertain if the effectiveness of SRS for treatment of epilepsy attains that of traditional surgery while offering a non-invasive technique with potentially lower morbidity.
Stereotactic radiosurgery is being investigated as a treatment for cluster headache. In a prospective open trial, Donnet et al (2005) examined the effectiveness of gamma knife radiosurgery of the trigeminal nerve in the treatment of patients with chronic cluster headache (CCH). A total of 10 patients (9 men, 1 woman; mean age of 49.8 years) were enrolled. They presented with severe and drug resistant CCH (mean duration of 9 years). The cisternal segment of the trigeminal nerve was targeted with a single 4-mm collimator (80 to 85 Gy max). The mean follow-up was 13.2 months. No improvement was observed in 2 patients, while 3 patients had no further attacks. Three patients showed dramatic improvement with a few attacks per month or very few attacks over the last 6 months. Two patients were pain-free for only 1 week and 2 weeks, respectively, and their headaches recurred with the same severity as before. Three patients developed paresthesia with no hypoesthesia, 1 developed hypoesthesia, and 1 developed de-afferentation pain. These investigators considered the morbidity to be significant for the low rate of pain cessation, making this procedure less attractive even for the more severely affected subgroup of patients.
In a phase I clinical trial, Boike et al (2011) evaluated the tolerability of escalating doses of stereotactic body radiation therapy in the treatment of localized prostate cancer. Eligible patients included those with Gleason score 2 to 6 with prostate-specific antigen (PSA) less than or equal to 20, Gleason score 7 with PSA less than or equal to 15, less than or equal to T2b, prostate size less than or equal to 60 cm(3), and American Urological Association (AUA) score less than or equal to 15. Pre-treatment preparation required an enema and placement of a rectal balloon. Dose-limiting toxicity (DLT) was defined as grade 3 or worse GI/genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 3). Patients completed quality-of-life questionnaires at defined intervals. Groups of 15 patients received 45 Gy, 47.5 Gy, and 50 Gy in 5 fractions (45 total patients). The median follow-up is 30 months (range of 3 to 36 months), 18 months (range of 0 to 30 months), and 12 months (range of 3 to 18 months) for the 45 Gy, 47.5 Gy, and 50 Gy groups, respectively. For all patients, GI greater than or equal to 2 and grade greater than or equal to 3 toxicity occurred in 18 % and 2 %, respectively, and GU grade greater than or equal to 2 and grade greater than or equal to 3 toxicity occurred in 31 % and 4 %, respectively. Mean AUA scores increased significantly from baseline in the 47.5-Gy dose level (p = 0.002) as compared with the other dose levels, where mean values returned to baseline. Rectal quality-of-life scores (Expanded Prostate Cancer Index Composite) fell from baseline up to 12 months but trended back at 18 months. In all patients, PSA control is 100 % by the nadir + 2 ng/ml failure definition. The authors concluded that dose escalation to 50 Gy has been completed without DLT. They stated that a multi-center phase II trial is underway treating patients to 50 Gy in 5 fractions to further evaluate this experimental therapy.
The Agency for Healthcare Research and Quality (AHRQ)'s Effective Health Care Program released a new technical brief (2011) that provides a broad overview of the current state of evidence on the use of stereotactic body radiation therapy for targeting solid malignant tumors. The brief, Stereotactic Body Radiation Therapy, identifies gaps in the scientific data regarding the theoretical advantages of stereotactic body radiation therapy over other radiotherapies in actual clinical use. While stereotactic body radiation therapy appears to be widely used for treatment of a variety of cancer types, none of the currently available studies includes comparison groups. The researchers noted that in order to assess fully the benefits and risks of stereotactic body radiation therapy, comparative studies are needed. These studies should preferably be randomized trials but, at a minimum, there is a need for trials with concurrent controls. The technical brief also provides a review of key research questions that remain unanswered and may be helpful to radiology researchers in prioritizing future research.
The Expert Panel on Radiation Oncology-Gynecology/American College of Radiology‘s Appropriateness Criteria on "Definitive therapy for early stage cervical cancer" (Small et al, 2012) stated that "Stereotactic body RT (SBRT) has been shown to be a useful treatment option in other tumor sites, especially in early stage lung cancer. There are preliminary data on its use in treating cervical cancer, but, given target definition, tumor motion, and the proven track record of brachytherapy, SBRT should not be considered a substitute for brachytherapy".
Yamada et al (2013) stated that en bloc wide-margin excision significantly decreases the risk of chordoma recurrence. However, a wide surgical margin cannot be obtained in many chordomas because they arise primarily in the sacrum, clivus, and mobile spine. Furthermore, these tumors have shown resistance to fractionated photon radiation at conventional doses and numerous chemotherapies. These researchers analyzed the outcomes of single-fraction SRS in the treatment of chordomas of the mobile spine and sacrum. A total of 24 patients with chordoma of the sacrum and mobile spine were treated with high-dose single-fraction SRS (median dose of 2,400 cGy); 21 primary and 3 metastatic tumors were treated; 7 patients were treated for post-operative tumor recurrence. In 7 patients, SRS was administered as planned adjuvant therapy, and in 13 patients, SRS was administered as neoadjuvant therapy. All patients had serial magnetic resonance imaging follow-up. The overall median follow-up was 24 months. Of the 24 patients, 23 (95 %) demonstrated stable or reduced tumor burden based on serial magnetic resonance imaging. One patient had radiographic progression of tumor 11 months after SRS; 6 of 13 patients who underwent neoadjuvant SRS proceeded to surgery. This decision was based on the lack of radiographic progression and the patient's preference. Complications were limited to 1 patient in whom sciatic neuropathy developed and 1 with vocal cord paralysis. The authors concluded that high-dose single-fraction SRS provides good tumor control with low treatment-related morbidity. Moreover, they stated that additional follow-up is needed to determine the long-term recurrence risk.
Hepatocellular Carcinoma
Klein et al (2014) stated that although liver-directed therapies such as surgery or ablation can cure hepato-cellular carcinoma (HCC), few patients are eligible due to advanced disease or medical co-morbidities. In advanced disease, systemic therapies have yielded only incremental survival benefits. Historically, RT for liver cancer was dismissed due to concerns over unacceptable toxicities from even moderate doses. Although implementation requires more resources than standard RT, SBRT can deliver reproducible, highly conformal ablative radiotherapy to tumors while minimizing doses to nearby critical structures. Trials of SBRT for HCC have demonstrated promising local control and survival results with low levels of toxicity in Child-Pugh class A patients. The authors reviewed the published literature and made recommendations for the future of this emerging modality.
Van De Voorde et al (2015) noted that stereotactic ablative body radiotherapy (SABR) is a non-invasive treatment option for inoperable patients or patients with unresectable liver tumors. Outcome and toxicity were evaluated retrospectively in this single-institution patient cohort. Between 2010 and 2014, a total of 39 lesions were irradiated in 33 consecutive patients (18 males, 15 females, median age of 68 years). All the lesions were liver metastases (n = 34) or primary HCC (n = 5). The patients had undergone 4-dimensional respiration-correlated PET-CT for treatment simulation to capture tumor motion. These researchers analyzed local control with a focus on CT-based response at 3 months, 1 year and 2 years after treatment, looking at overall survival (OS) and the progression pattern. All patients were treated with hypo-fractionated image-guided SRS. The equivalent dose in 2 Gy fractions varied from 62.5 Gy to 150 Gy, delivered in 3 to 10 fractions (median dose of 93.8 Gy, alpha/beta = 10). The CT-based regression pattern 3 months after radiotherapy revealed partial regression in 72.7 % of patients with a complete remission in 27.3 % of the cases. The site of first progression was predominantly distant; 1-and 2-year OS rates were 85.4 % and 68.8 %, respectively. No toxicity of grade 2 or higher according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v4.0 was observed. The authors concluded that SABR is a safe and efficient treatment for selected inoperable patients or unresectable tumors of the liver. Moreover, they stated that future studies should combine SABR with systemic treatment acting in synergy with radiation, such as immunological interventions or hypoxic cell radio-sensitizers to prevent distant relapse.
Furthermore, National Comprehensive Cancer Network (NCCN)’s clinical practice guideline on "Hepatobiliary cancers" (Version 2.2015) does not mention SRS as a therapeutic option.
Intramedullary Spinal Cord Tumors
Park and Chang (2013) stated that SRS represents an increasingly utilized modality in the treatment of intra-cranial and extra-cranial pathologies. Stereotactic spine radiosurgery (SSR) uses an alternative strategy to increase the probability of local control by delivering large cumulative doses of RT in only a few fractions. Stereotactic spine radiosurgery in the treatment of intramedullary lesions remains in its infancy. This review summarized the current literature regarding the use of SSR for treating intramedullary spinal lesions. Several studies have suggested that SSR should be guided by the principles of intra-cranial radiosurgery with radiation doses placed no further than 1 to 2 mm apart, thereby minimizing exposure to the surrounding spinal cord and allowing for delivery of higher radiation doses to target areas. Maximum dose-volume relationships and single-point doses with SSR for the spinal cord are currently under debate. Prior reports of SRS for intramedullary metastases, AVMs, ependymomas, and hemangioblastomas demonstrated favorable outcomes. The authors concluded that in the management of intramedullary spinal lesions, SSR appeared to provide a safe and effective treatment compared to conventional RT. They stated that SSR should likely be utilized for select patient-scenarios given the potential for radiation-induced myelopathy, though high-quality literature on SSR for intramedullary lesions remains limited.
Hernandez-Duran et al (2016) noted that advances in imaging technology and microsurgical techniques have made microsurgical resection the treatment of choice in cases of symptomatic intramedullary tumors. The use of SRS for spinal tumors is a recent development, and its application to intramedullary lesions is debated. These researchers conducted a literature search through PubMed's MeSH system, compiling information regarding intramedullary neoplasms treated by SRS. They compiled histology, tumor location and size, treatment modality, radiation dose, fractionation, radiation-induced complications, follow-up, and survival. A total of 10 papers reporting on 52 patients with 70 tumors were identified. Metastatic lesions accounted for 33 %, while 67 % were primary ones. Tumor location was predominantly cervical (53 %), followed by thoracic (33 %). Mean volume was 0.55 cm3 (95 % CI: 0.26 to 0.83). Preferred treatment modality was CyberKnife (87 %), followed by Novalis (7 %) and LINAC (6 %). Mean radiation dose was 22.14 Gy (95 % CI: 20.75 to 23.53), with mean fractionation of 4 (95 % CI: 3 to 5); 3 hemangioblastomas showed cyst enlargement. Symptom improvement or stabilization was seen in all but 2 cases. Radionecrotic spots adjacent to treated areas were seen at autopsy in 4 lesions, without clinical manifestations. Overall, clinical and radiological outcomes were favorable. Although surgery remains the treatment of choice for symptomatic intramedullary lesions, SRS can be a safe and effective option in selected cases. The authors concluded that while the findings of this review suggested the overall safety and effectiveness of SRS in the management of intramedullary tumors, future studies need randomized, homogeneous patient populations followed over a longer period to provide more robust evidence in its favor.
Operable Non-Small-Cell Lung Cancer
The American College of Chest Physicians’ evidence-based clinical practice guidelines on "Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer" (Howington et al, 2013) noted that surgical resection remains the primary and preferred approach to the treatment of stage I and II non-small-cell lung cancer (NSCLC). Lobectomy or greater resection remains the preferred approach to T1b and larger tumors. The use of sublobar resection for T1a tumors and the application of adjuvant radiation therapy in this group are being actively studied in large clinical trials. Every patient should have systematic mediastinal lymph node sampling at the time of curative intent surgical resection, and mediastinal lymphadenectomy can be performed without increased morbidity. Peri-operative morbidity and mortality are reduced and long-term survival is improved when surgical resection is performed by a board-certified thoracic surgeon. The use of adjuvant chemotherapy for stage II NSCLC is recommended and has shown benefit. The use of adjuvant radiation or chemotherapy for stage I NSCLC is of unproven benefit. Primary radiation therapy remains the primary curative intent approach for patients who refuse surgical resection or are determined by a multi-disciplinary team to be inoperable. There is growing evidence that SBRT provides greater local control than standard RT for high-risk and medically inoperable patients with NSCLC. The authors concluded that the role of ablative therapies in the treatment of high-risk patients with stage I NSCLC is evolving. Radiofrequency ablation, the most studied of the ablative modalities, has been used effectively in medically inoperable patients with small (less than 3 cm) peripheral NSCLC that are clinical stage I.
In a systematic review and meta-analysis, Zhang et al (2014) compared the effectiveness of SBRT versus surgery for early-stage NSCLC. All the eligible studies were searched by PubMed, Medline, Embase, and the Cochrane Library. The meta-analysis was performed to compare odds ratios (OR) for OS, cancer-specific survival (CSS), disease-free survival (DFS), local control (LC), and distant control (DC). A total of 6 studies containing 864 matched patients were included in the meta-analysis. The surgery was associated with a better long-term OS in patients with early-stage NSCLC. The pooled OR and 95 % CI for 1-year, 3-year OS were 1.31 [0.90 to 1.91] and 1.82 [1.38 to 2.40], respectively. However, the differences in 1-year and 3-year CSS, DFS, LC and DC were not significant. The authors concluded that the findings of this systematic review revealed a superior 3-year OS after surgery compared with SBRT, which supports the need to compare both treatments in large prospective, randomized, controlled clinical trials.
In a meta-analysis, Zheng et al (2014) compared treatment outcomes of SBRT with those of surgery in stage I NSCLC. Eligible studies of SBRT and surgery were retrieved through extensive searches of the PubMed, Medline, Embase, and Cochrane library databases from 2000 to 2012. Original English publications of stage I NSCLC with adequate sample sizes and adequate SBRT doses were included. A multi-variate random effects model was used to perform a meta-analysis to compare survival between treatments while adjusting for differences in patient characteristics. A total of 40 SBRT studies (4,850 patients) and 23 surgery studies (7,071 patients) published in the same period were eligible. The median age and follow-up duration were 74 years and 28.0 months for SBRT patients and 66 years and 37 months for surgery patients, respectively. The mean unadjusted OS rates at 1, 3, and 5 years with SBRT were 83.4 %, 56.6 %, and 41.2 % compared to 92.5 %, 77.9 %, and 66.1 % with lobectomy and 93.2 %, 80.7 %, and 71.7 % with limited lung resections. In SBRT studies, OS improved with increasing proportion of operable patients. After these researchers adjusted for proportion of operable patients and age, SBRT and surgery had similar estimated OS and DFS. The authors concluded that patients treated with SBRT differed substantially from patients treated with surgery in age and operability. After adjustment for these differences, OS and DFS did not differ significantly between SBRT and surgery in patients with operable stage I NSCLC. They stated that a randomized prospective trial is needed to compare the effectiveness of SBRT and surgery.
Chang et al (2015) stated that the standard of care for operable, stage I NSCLC is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but 2 independent, randomized, phase III clinical trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. These investigators evaluated OS for SABR versus surgery by pooling data from these trials. Eligible patients in the STARS and ROSEL studies were those with clinical T1-2a (less than 4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. These investigators performed a pooled analysis in the intention-to-treat population using OS as the primary end-point. Both trials are registered with ClinicalTrials.gov (STARS: NCT00840749; ROSEL: NCT00687986). A total of 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40.2 months (IQR 23.0 to 47.3) for the SABR group and 35.4 months (18.9 to 40.7) for the surgery group; 6 patients in the surgery group died compared with 1 patient in the SABR group. Estimated OS at 3 years was 95 % (95 % CI: 85 to 100) in the SABR group compared with 79 % (64 to 97) in the surgery group (hazard ratio [HR] 0.14 [95 % CI: 0.017 to 1.190], log-rank p = 0.037). Recurrence-free survival at 3 years was 86 % (95 % CI: 74 to 100) in the SABR group and 80 % (65 to 97) in the surgery group (HR 0.69 [95 % CI: 0.21 to 2.29], log-rank p = 0.54). In the surgery group, 1 patient had regional nodal recurrence and 2 had distant metastases; in the SABR group, 1 patient had local recurrence, 4 had regional nodal recurrence, and 1 had distant metastases. Three (10 %) patients in the SABR group had grade 3 treatment-related adverse events (3 [10 %] chest wall pain, 2 [6 %] dyspnea or cough, and 1 [3 %] fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, 1 (4 %) patient died of surgical complications and 12 (44 %) patients had grade 3 to 4 treatment-related adverse events. Grade 3 events occurring in more than 1 patient in the surgery group were dyspnea (4 [15 %] patients), chest pain (4 [15 %] patients), and lung infections (2 [7 %]). The authors concluded that SABR could be an option for treating operable stage I NSCLC. Moreover, they stated that because of the small patient sample size and short follow-up, additional randomized studies comparing SABR with surgery in operable patients are needed.
Furthermore, NCCN’s clinical practice guideline on "Non-small cell lung cancer" (Version 1.2016) lists SRS only as a therapeutic option of brain metastases of NSCLC.
Syed et al (2022) noted that patients undergoing surgery for early-stage NSCLC may be at high risk for post-operative mortality. Access to SBRT may facilitate more appropriate patient selection for surgery. These researchers examined if post-operative mortality associated with early-stage NSCLC is lower at facilities with higher use of SBRT? Patients with early-stage NSCLC reported to the National Cancer Database between 2004 and 2015 were included. Use of SBRT was defined by each facility's SBRT experience (in years) and SBRT to surgery volume ratios. Multi-variate logistic regression was used to test for the associations between SBRT use and post-operative mortality. The study cohort consisted of 202,542 patients who underwent surgical resection of cT1-T2N0M0 NSCLC tumors. The 90-day post-operative mortality rate declined during the study period from 4.6 % to 2.6 % (p < 0.001), the proportion of facilities that used SBRT increased from 4.6 % to 77.5 % (p < 0.001), and the proportion of patients treated with SBRT increased from 0.7 % to 15.4 % (p < 0.001). On multi-variate analysis, lower 90-day post-operative mortality rates were observed at facilities with less than 6 years of SBRT experience (OR, 0.84; 95 % CI: 0.76 to 0.94; p = 0.003) and SBRT to surgery volume ratios of more than 17 % (OR, 0.85; 95 % CI: 0.79 to 0.92; p < 0.001); 90-day mortality also was associated with surgical volume, region, year, age, sex, and race, among other co-variates. Interaction testing between these co-variates showed negative results. The authors concluded that patients who underwent resection for early-stage NSCLC at facilities with higher SBRT use showed lower rates of post-operative mortality. These researchers stated that these findings suggested that the availability and use of SBRT may improve the selection of patients for surgery who are predicted to be at high risk of post-operative mortality.
Pancreatic Adenocarcinoma
In a phase II, multi-institutional, clinical trial, Herman et al (2015) examined if gemcitabine (GEM) with fractionated SBRT results in acceptable late grade 2 to 4 gastro-intestinal (GI) toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC). A total of 49 patients with LAPC received up to 3 doses of GEM (1,000 mg/m(2)) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the NCI Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT. The median follow-up was 13.9 months (range of 3.9 to 45.2 months). The median age of the patients was 67 years and 84 % had tumors of the pancreatic head. Rates of acute and late (primary end-point) grade greater than or equal to 2 gastritis, fistula, enteritis, or ulcer toxicities were 2 % and 11 %, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; p > 0.05 for both). Patients reported a significant improvement in pancreatic pain (p = 0.001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/ml versus 62 U/ml [p < 0.001]). The median OS was 13.9 months (95 % CI: 10.2 months to 16.7 months). Freedom from local disease progression at 1 year was 78 %; 4 patients (8 %) underwent margin-negative and lymph node-negative surgical resections. The authors concluded that fractionated SBRT with GEM resulted in minimal acute and late GI toxicity. They stated that future studies should incorporate SBRT with more aggressive multi-agent chemotherapy.
Furthermore, NCCN’s clinical practice guideline on "Pancreatic adenocarcinoma" (Version 2.2015) does not mention SRS as a therapeutic option.
Buwenge et al (2022) noted that severe pain is frequent in patients with locally advanced pancreatic ductal adenocarcinoma (PDCA); SBRT provides high local control rates in these patients. In a systematic review, these investigators examined available evidence on pain relief in patients with PDCA. They updated their previous systematic review via a search on PubMed of studies published from January 1, 2018 to June 30, 2021. Studies with full available text, published in English, and reporting pain relief after SBRT on PDCA were included in this analysis. Statistical analysis was performed using the MEDCALC statistical software; all tests were t2-sided. The I2 statistic was used to quantify statistical heterogeneity. A total of 19 studies were included in this updated literature review. None of them specifically aimed at examining pain and/or QOL. The rate of analgesics reduction or suspension ranged between 40.0 % and 100.0 % (median of 60.3 %) in 6 studies. The pooled rate was 71.5 % (95 % CI: 61.6 % to 80.0 %), with high heterogeneity between studies (Q2 test: p < 0.0001; I2 = 83.8 %). The rate of complete response of pain following SBRT ranged between 30.0 % and 81.3 % (median of 48.4 %) in 3 studies. The pooled rate was 51.9 % (95 % CI: 39.3 % to 64.3 %), with high heterogeneity (Q2 test: p < 0.008; I2 = 79.1 %). The rate of partial plus complete pain response ranged between 44.4 % and 100 % (median of 78.6 %) in 9 studies. The pooled rate was 78.3 % (95 % CI: 71.0 % to 84.5 %), with high heterogeneity (Q2 test: p < 0.0001; I2 = 79.4 %). A linear regression with sensitivity analysis showed significantly improved overall pain response as the EQD2α/β:10 increases (p: 0.005). A total of 8 studies did not report any side effect during and after SBRT. In 3 studies only transient acute effects were recorded. The results of the included studies showed high heterogeneity; however, SBRT of PDCA resulted reasonably effective in producing pain relief in these patients. The authors concluded that further studies are needed to examine the impact of SBRT in this setting based on patient-reported outcomes.
Stereotactic Radiosurgery for Epilepsy
Chang et al (2015) stated that surgery can be a highly effective treatment for medically refractory temporal lobe epilepsy (TLE). The emergence of minimally invasive resective and non-resective treatment options has led to interest in epilepsy surgery among patients and providers. Nevertheless, not all procedures are appropriate for all patients, and it is critical to consider seizure outcomes with each of these approaches, as seizure freedom is the greatest predictor of patient quality of life. Standard anterior temporal lobectomy (ATL) remains the gold standard in the treatment of TLE, with seizure freedom resulting in 60 to 80 % of patients. It is currently the only resective epilepsy surgery supported by randomized controlled trials (RCTs) and offers the best protection against lateral temporal seizure onset. Selective amygdalohippocampectomy techniques preserve the lateral cortex and temporal stem to varying degrees and can result in favorable rates of seizure freedom but the risk of recurrent seizures appears slightly greater than with ATL, and it is not clear whether neuropsychological outcomes are improved with selective approaches. Stereotactic radiosurgery presents an opportunity to avoid surgery altogether, with seizure outcomes now under investigation. Stereotactic laser thermo-ablation allows destruction of the mesial temporal structures with low complication rates and minimal recovery time, and outcomes are also under study. Finally, while neuromodulatory devices such as responsive neurostimulation, vagus nerve stimulation, and deep brain stimulation have a role in the treatment of certain patients, these remain palliative procedures for those who are not candidates for resection or ablation, as complete seizure freedom rates are low. The authors concluded that further development and investigation of both established and novel strategies for the surgical treatment of TLE will be critical moving forward, given the significant burden of this disease.
Mathon et al (2015) evaluated the published literature related to the outcome of the surgical treatment of mesial temporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS) and described the future prospects in this field. Surgery of MTLE associated with HS achieves long-term seizure freedom in about 70 % (62 to 83 %) of cases. Seizure outcome is similar in the pediatric population. Mortality following temporal resection is very rare (less than 1 %) and the rate of definitive neurological complication is low (1 %). Gamma knife stereotactic radiosurgery used as a treatment for MTLE would have a slightly worse outcome to that of surgical resection, but would provide neuropsychological advantage. However, the average latency before reducing or stopping seizures is at least 9 months with radiosurgery. Regarding palliative surgery, amygdalohippocampal stimulation has been demonstrated to improve the control of epilepsy in carefully selected patients with intractable MTLE who are not candidates for resective surgery. Recent progress in the field of imaging and image-guidance should allow to elaborate tailored surgical strategies for each patient in order to achieve seizure freedom. Concerning therapeutics, closed-loop stimulation strategies allow early seizure detection and responsive stimulation. It may be less toxic and more effective than intermittent and continuous neurostimulation. Moreover, stereotactic radiofrequency amygdalohippocampectomy is a recent approach leading to hopeful results. Closed-loop stimulation and stereotactic radiofrequency amygdalohippocampectomy may provide a new treatment option for patients with pharmaco-resistant MTLE. The authors concluded that mesial temporal lobe surgery has been widely evaluated and has become the standard treatment for MTLE associated with HS. Alternative surgical procedures like gamma knife stereotactic radiosurgery and amygdalohippocampal stimulation are currently under assessment, with promising results.
Feng et al (2016) noted that stereotactic radiosurgery (RS) is a potential option for some patients with TLE. These researchers determined the pooled seizure-free rate and the time interval to seizure cessation in patients with lesions in the mesial temporal lobe, and who were eligible for either stereotactic or gamma knife RS. They searched the Medline, Cochrane, Embase, and Google Scholar databases using combinations of the following terms: RS, stereotactic radiosurgery, gamma knife, and TLE. These investigators screened 103 articles and selected 13 for inclusion in the meta-analysis. Significant study heterogeneity was detected; however, the included studies displayed an acceptable level of quality. They showed that approximately 50 % of the patients were seizure-free over a follow-up period that ranged from 6 months to 9 years [pooled estimate: 50.9 % (95 % confidence interval [CI]: 0.381 to 0.636)], with an average of 14 months to seizure cessation [pooled estimate: 14.08 months (95 % CI: 11.95 to 12.22 months)]; 9 of 13 included studies reported data for adverse events (AEs), which included visual field deficits and headache (the 2 most common AEs), verbal memory impairment, psychosis, psychogenic non-epileptic seizures, and dysphasia. Patients in the individual studies experienced AEs at rates that ranged from 8 %, for non-epileptic seizures, to 85 %, for headache. The authors concluded that the findings of this meta-analysis indicated that RS may have similar or slightly less efficacy in some patients compared with invasive surgery. They stated that RCTs of both treatment regimens should be undertaken to generate an evidence base for patient decision-making.
Park et al (2016) reported the findings of an 18-year old left-handed male harbored intractable medial temporal lobe epilepsy (MTLE) who underwent fractionated gamma knife surgery (GKS) instead of open surgery, considering the mental retardation and diffuse cerebral dysfunction. GKS treatment parameters were: target volume, 8.8 cm(3); total marginal dose, 24 Gy in 3 fractionations at the 50 % isodose line. The patient has been free from seizures since 9 months after GKS, with notable improvement in cognitive outcome. The authors concluded that fractionated GKS could be considered as a safe tool for seizure control and neuropsychological improvement in patients with MTLE. Moreover, they stated that further long-term prospective studies with a larger numbers of patients are needed to determine the optimal doses and fraction schedules of fractionated GKS for MTLE.
Bostrom et al (2016) stated that the eradication of epileptogenic lesions (e.g., focal cortical dysplasia) can be used for treatment of drug-resistant focal epilepsy, but in highly eloquent cortex areas it can also lead to a permanent neurological deficit. In such cases the neuromodulation effect of low-dose high-precision irradiation of circumscribed lesions may represent an alternative therapy. A total of 10 patients with eloquent localized lesions causing pharmaco-resistant focal epilepsy were prospectively identified. After informed consent, 6 patients agreed and were treated with risk adapted low-dose radiosurgery (SRS) or hypo-fractionated stereotactic radiotherapy (hfSRT). Comprehensive data concerning treatment modalities and outcome after short-term follow-up (mean of 16.3 months) were prospectively collected and evaluated. From the 6 patients, 2 patients were treated with hfSRT (marginal dose 36 Gy) and 4 with SRS (marginal dose 13 Gy). Clinical target volume (CTV) ranged from 0.70 ccm to 4.32 ccm. The short-term follow-up ranged from 6 to 27 months. There were no side effects or neurological deficits after treatment. At last available follow-up, 2 patients were seizure-free, 1 of them being off anti-epileptic drugs. The seizure frequency improved in 1 and remained unchanged in 3 patients. The authors concluded that treatment of eloquent localized epileptogenic lesions by SRS and hfSRT showed no adverse events and an acceptable seizure outcome in this small prospective patient series. The relatively short-term follow-up comprised one of the study's drawbacks and therefore a longer follow-up should be awaited in order to evaluate the neuromodulation effect of the treatment. They stated that these preliminary results may however justify the initiation of a larger prospective trial investigating whether focused low-dose stereotactic irradiation could be an option for lesions in eloquent brain areas.
McGonigal et al (2017) noted that while there are many reports of radiosurgery for treatment of drug-resistant epilepsy, a literature review is lacking. In this systematic review, these researchers summarized current literature on the use of stereotactic radiosurgery (RS) for treatment of epilepsy. Literature search was performed using various combinations of the search terms "radiosurgery", "stereotactic radiosurgery", "Gamma Knife", "epilepsy" and "seizure", from 1990 until October 2015. Level of evidence was assessed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. A total of 55 articles fulfilled inclusion criteria. Level 2 evidence (prospective studies) was available for the clinical indications of MTLE and hypothalamic hamartoma (HH) treated by Gamma Knife (GK) RS. For remaining indications including corpus callosotomy as palliative treatment, epilepsy related to cavernous malformation and extra-temporal epilepsy, only Level 4 data was available (case report, prospective observational study, or retrospective case series). No Level 1 evidence was available. The authors concluded that based on level 2 evidence, RS is an effective treatment to control seizures in MTLE, possibly resulting in superior neuropsychological outcomes and quality of life (QOL) metrics in selected subjects compared to microsurgery; RS had a better risk-benefit ratio for small HHs compared to surgical methods. Moreover, they stated that the lack of level 1 evidence precluded the formation of guidelines at present.
Furthermore, an UpToDate review on "Seizures and epilepsy in children: Refractory seizures and prognosis" (Wilfong, 2017) states that "Stereotactic radiosurgery may be helpful for selected cases when the lesion is located where a conventional surgical approach is technically difficult or excessively risky. More information is needed on long-term outcome before wider application of this procedure".
Fractionated Stereotactic Radiotherapy for Pancreatic Adenocarcinoma
Zhong and co-workers (2017) stated that as systemic therapy has improved for locally advanced pancreatic cancer (LAPC), efforts to improve local control (LC) with optimal radiotherapy may be critical. Although conventionally fractionated radiation therapy (CFRT) has more recently shown a limited role in LAPC, SBRT is an emerging approach with promising results. With no studies to-date comparing SBRT with CFRT for LAPC, this study used the National Cancer Data Base (NCDB) to evaluate these 2 modalities. With the NCDB, patients with American Joint Committee on Cancer cT2-4/N0-1/M0 adenocarcinoma of the pancreas diagnosed from 2004 to 2013 were analyzed. Radiation therapy delivered at less than or equal to 2 Gy was deemed CFRT, and radiation therapy delivered at greater than or equal to 4 Gy per fraction was considered SBRT. Kaplan-Meier analysis, log-rank testing, and multi-variate Cox proportional hazards regression were performed with OS as the primary outcome; propensity score matching was used. Among 8,450 patients, 7,819 (92.5 %) were treated with CFRT, and 631 (7.5 %) underwent SBRT. Receipt of SBRT was associated with superior OS in the multi-variate analysis (HR, 0.84; 95 % CI: 0.75 to 0.93; p < 0.001). With propensity score matching, 988 patients in all were matched, with 494 patients in each cohort. Within the propensity-matched cohorts, the median OS (13.9 versus 11.6 months) and the 2-year OS rate (21.7 % versus 16.5 %) were significantly higher with SBRT versus CFRT (p = 0.0014). The authors concluded that in this retrospective review using a large national database, SBRT was associated with superior OS in comparison with CFRT for LAPC, and these findings remained significant in a propensity-matched analysis. Moreover, they stated that further prospective studies investigating these hypothesis-generating results are needed.
This study had several drawbacks inherent in the structure of the NCDB. A major drawback of this analysis was that these researchers could not control for the specific type of chemotherapy (type of agent or agents and number of cycles) in propensity matching because this information was not captured by the NCDB. This limitation presented a potential confounder in that SBRT patients tended to be treated more recently and potentially received more effective systemic therapy. These investigators attempted to address this confounder by controlling for the year of treatment, which can be viewed as a surrogate for the dominant type of chemotherapy regimen administered. Even after the year of treatment was included in the propensity-matched analysis, SBRT treatment remained superior with respect to OS. In addition, data regarding LC and the cause of death were not captured by the NCDB, and this presented a further drawback.
Stereotactic Radiosurgery for Central Neurocytoma
Bui and associates (2017) noted that central neurocytoma (CN) typically presents as an intra-ventricular mass causing obstructive hydrocephalus. The 1st-line of therapy is surgical resection with adjuvant conventional radiotherapy; SRS was proposed as an alternative therapy for CN because of its lower risk profile. In a systematic analysis, these investigators evaluated the effectiveness of SRS for CN. A systematic analysis for CN treated with SRS was conducted in PubMed. Baseline patient characteristics and outcomes data were extracted. Heterogeneity and publication bias were also assessed. Uni-variate and multi-variate linear regressions were used to test for correlations to the primary outcome: LC. The estimated cumulative rate of LC was 92.2 % (95 % CI: 86.5 to 95.7 %, p < 0.001). Mean follow-up time was 62.4 months (range of 3 to 149 months). Heterogeneity and publication bias were insignificant. The uni-variate linear regression models for both mean tumor volume and mean dose were significantly correlated with improved LC (p < 0.001). The authors concluded that these findings suggested that SRS may be a safe and effective treatment for CN. However, they noted that the rarity of CN still limits the efficacy of a quantitative analysis; future multi-institutional, randomized trials of CN patients should be considered to further elucidate this therapy.
Stereotactic Radiosurgery for Meningiomas in Neurofibromatosis Type 2
Nguyen and colleagues (2019) stated that neurofibromatosis type 2 (NF2) is a genetic neoplastic disorder that presents with hallmark bilateral vestibular schwannomas and multiple meningiomas. Although the current standard of care for meningiomas includes surgery, the multiplicity of meningiomas in NF2 patients renders complete resection of all developing lesions infeasible; SRS may be a viable non-invasive alternative to surgery. These researchers described a particularly challenging case in a 39-year old male with over 120 lesions who underwent more than 30 surgical procedures, and reviewed the literature. They also searched 3 popular databases and compared outcomes of SRS versus surgery for the treatment of multiple meningiomas in patients with NF2. A total of 50 patients (27 radio-surgical and 23 surgical) were identified. For patients treated with SRS, local tumor control was achieved in 22 patients (81.5 %) and distal control was achieved in 14 patients (51.8 %). No malignant inductions were observed at an average follow-up duration of 90 months. Complications in the SRS-treated cohort were reported in 9 patients (33 %); 8 patients (29.6 %) died due to disease progression; 6 patients experienced treatment failure and needed further management. For NF2 patients treated with surgery, 11 patients (48 %) showed tumor recurrence and 10 patients (43.5 %) died due to neurological complications. The authors concluded that SRS may be a safe and effective alternative for NF2-associated meningiomas; however, further studies are needed to identify the ideal candidate.
Stereotactic Radiosurgery for Brain Metastases / Repeat Stereotactic Radiosurgery for Locally Recurrent Brain Metastases
Chen and associates (2018) characterized the effect of concurrent SRS-SRT and immune checkpoint inhibitors (ICI) on patient outcomes and safety in patients with brain metastases (BM). These researchers retrospectively identified metastatic non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) patients who had BMs treated with SRS-SRT from 2010 to 2016 without prior whole-brain radiation therapy (RT). They included SRS-SRT patients who were treated with ipilimumab, nivolumab, and pembrolizumab. Patients who were given ICI on active or unreported clinical trials were excluded, and concurrent ICI was defined as ICI given within 2 weeks of SRS-SRT. Patients were managed with SRS-SRT, SRS-SRT with non-concurrent ICI, or SRS-SRT with concurrent ICI. Progression-free survival (PFS) and OS were estimated using Kaplan-Meier survival curves, and Cox proportional hazards models were used for multi-variate analysis. Logistic regression was used to identify predictors of acute neurologic toxicity, immune-related AEs, and new BM. A total of 260 patients were treated with SRS-SRT to 623 BM. Of these patients, 181 were treated with SRS-SRT alone, whereas 79 received SRS-SRT and ICI, 35 % of whom were treated with concurrent SRS-SRT and ICI. Concurrent ICI was not associated with increased rates of immune-related AEs or acute neurologic toxicity and predicted for a decreased likelihood of the development of greater than or equal to 3 new BM after SRS-SRT (p = 0.045; OR, 0.337). Median OS for patients treated with SRS-SRT, SRS-SRT with non-concurrent ICI, and SRS-SRT with concurrent ICI was 12.9 months, 14.5 months, and 24.7 months, respectively. SRS-SRT with concurrent ICI was associated with improved OS compared with SRS-SRT alone (p = 0.002; HR, 2.69) and compared with non-concurrent SRS-SRT and ICI (p = 0.006; HR, 2.40) on multi-variate analysis. The OS benefit of concurrent SRS-SRT and ICI was significant in comparison with patients treated with SRS-SRT before ICI (p = 0.002; HR, 3.82) or after ICI (p = 0.021; HR, 2.64). The authors concluded that delivering SRS-SRT with concurrent ICI may be associated with a decreased incidence of new BM and favorable survival outcomes without increased rates of AEs. These findings need to be validated by well-designed studies.
Lehrer and colleagues (2019) stated that while the combination of SRS and ICI is becoming more widely used in the treatment of BM, there is a paucity of prospective data to validate both the safety and efficacy, as well as the optimal timing of these 2 therapies relative to one another. A population, intervention, comparison, outcomes (PICOS) / PRISMA / meta-analysis of observational studies in epidemiology (MOOSE) selection protocol was used to identify 17 studies across 15 institutions in 3 countries. Inclusion criteria were patients: diagnosed with BMs; treated with SRS/ICI, either concurrently or non-concurrently; with at least 1 of the primary or secondary outcomes measures reported. Weighted random effects meta-analyses using the DerSimonian and Laird method was performed. The primary outcome was 1-year OS; secondary outcomes were 1-year LC, 1-year regional brain control (RBC), and radio-necrosis incidence. A total of 534 patients with 1,570 BM were included. The 1-year OS was 64.6 % and 51.6 % for concurrent and non-concurrent therapy, respectively (p < 0.001); LC at 1-year was 89.2 % and 67.8 % for concurrent and non-concurrent therapy, respectively (p = 0.09). The RBC at 1-year was 38.1 % and 12.3 % for concurrent and ICI administration prior to SRS, respectively (p = 0.049). The overall incidence of radio-necrosis for all studies was 5.3 %. The authors concluded that concurrent administration of SRS/ICI may be associated with improved safety and efficacy versus sequential therapy. Moreover, they stated that these findings are hypothesis-generating; and require further validation by ongoing and planned prospective studies.In a systematic review and meta-analysis, Singh et al (2022) examined outcomes for patients with locally recurrent BMs treated with a repeat course of SRS (rSRS). Primary outcomes were 1-year LBC and radio-necrosis (RN); secondary outcomes were 1-year OS and 1-year DBC. Weighted random effects meta-analyses by means of the DerSimonian and Laird methods were carried out to characterize summary effect sizes. Mixed effects regression models were employed to analyze potential correlations between prognostic factors and outcomes. A total of 347 patients with 462 BMs treated with rSRS were included. Estimated 1-year LC, OS, and DBC rates were 69.0 % (95 % CI: 61.0 % to 77.0 %), 49.7 % (95 % CI: 28.9 % to 70.6 %), and 41.6 % (95 % CI: 33.0 % to 50.4 %), respectively. The estimated RN rate was 16.1 % (95 % CI: 6.3 % to 25.9 %). Every 1 Gy increase in prescription dose was estimated to result in roughly 5 % increase in 1-year LC (p = 0.14). The authors concluded that rSRS was well-tolerated with reasonable 1-year LC and OS; dose escalation may result in improved LC.
Stereotactic Radiosurgery for Central Nervous System Hemangioblastoma
Pan and colleagues (2018) noted that hemangioblastomas are rare, benign, vascular tumors of the CNS, often associated with von Hippel-Lindau (VHL) disease. Current therapeutic options include microsurgical resection or SRS. With no RCTs and minimal data beyond single-institution reviews, the optimal management approach for patients with CNS hemangioblastomas is unclear. These investigators completed a PubMed/SCOPUS literature search from January 1990 to January 2017 for eligible studies on SRS for CNS hemangioblastomas. Relevant articles were identified and reviewed in accordance to the PRISMA guidelines. A total of 26 studies met eligibility criteria for qualitative synthesis, representing 596 subjects and 1.535 tumors. The Gamma Knife was the most published SRS method for CNS hemangioblastomas. After critical study appraisal for intra-study bias, 14 studies were used for quantitative meta-analysis of 5-year PFS. The pooled 5-year PFS across all eligible studies was 88.4 %; no difference was observed between spine versus intracranial studies. Individual patient data (IPD) was extracted from 14 studies, representing 322 tumors. Univariate analysis of IPD revealed that VHL patients were younger, and had smaller tumors compared to those with sporadic disease; AEs were associated with increasing marginal dose, independent of tumor volume. von-hippel lindau status, sex, radio-surgical method, tumor location, and tumor volume were not found to be significantly associated with tumor progression. The authors concluded that multiple studies showed excellent tumor control at 5-year follow-up, however, the long-term efficacy of SRS for CNS hemangioblastomas still needs to be investigated, and the studies exploring the role of SRS for early treatment of asymptomatic lesions is wanting.
Stereotactic Radiosurgery for Dural Glioblastoma Multiforme Metastasis
Hintenlang and co-workers (2018) noted that glioblastoma multiforme (GBM) is a primary brain neoplasm accounting for approximately 75 % of all high-grade gliomas. It is diffusely infiltrative and exhibits rapid proliferation with a poor overall prognosis. Maximum surgical resection and post-operative RT, accompanied by concurrent and adjuvant temozolomide chemotherapy, remain the standard of care without major therapeutic advances over the past 10 years. These researchers presented the case of a 64-year old man with a GBM who subsequently developed a left frontal dural metastasis, subsequently treated with SRS (20 Gy in 1 fraction). With 6 month follow-up, the patient showed near complete resolution of his dural metastases and no overall change in neurological symptoms or side effects following radiosurgery. Due to the paucity of clinical literature regarding dural metastases from GBM, its optimal treatment remains unknown. The authors concluded that while the role of SRS has yet to be defined in this setting, they provided evidence suggesting its overall efficacy in the treatment of select dural GBM metastases.
Stereotactic Radiosurgery for Oligometastatic Colorectal Cancer
Kobiela and associates (2018) stated that SBRT is a novel modality in treatment for oligometastatic colorectal cancer (CRC). These investigators performed a systematic review of results of SBRT in maintaining LC for CRC liver and lung oligometastases. The review was performed according to PRISMA and PICO guidelines. Database search using keywords stereotactic, colon, colorectal, cancer, sbrt, and sabr returned 457 results; 15 were included in the study. Only cohorts with CRC histology and reported LC were included. For liver, LC rates ranged from 50 % to 100 % after 1 year, and 32 % to 91 % after 2 years; biologically effective dose (BED) range of 40.5 to 262.5 Gy (Gray). For lung, LC rates ranged from 62 % to 92 % after 1 year, and from 53 % to 92 % after 2 years; BED range of 51.3 to 262.5 Gy. The authors concluded that SBRT of oligometastatic CRC offered high LC with low morbidity and toxicity. These researchers stated that more observational studies and randomized trials are needed; but available data on clinical efficacy are promising, however not yet matured.
Stereotactic Radiosurgery for Cerebral Cavernous Malformations
Poorthuis and colleagues (2019) noted that the efficacy of stereotactic radiosurgery (SRS) for the treatment of cerebral cavernous malformations (CCMs) is uncertain. These researchers examined clinical outcomes following SRS for CCM and compared them to microsurgical excision or conservative management. They searched Ovid Medline and Ovid Embase from inception until June 1, 2018, for peer-reviewed publications describing clinical outcomes after SRS for more than 10 individuals with CCM in cohorts with or without a comparison group treated with neurosurgical excision or conservative management; 2 reviewers independently extracted data from the included studies to quantify cohort characteristics and the incidence of the primary outcome (death attributable to CCM or its treatment) and secondary outcomes (incident non-fatal symptomatic intra-cerebral hemorrhage [ICH] and incident non-hemorrhagic persistent focal neurologic deficit [FND]). These investigators examined if comparative studies showed a dramatic association (meaning the conventionally calculated probability comparing 2 differently-managed patient groups from the same population was < 0.01 with a rate ratio greater than 10). A total of 30 cohort studies involving a total of 1,576 patients undergoing SRS for CCM were included; 4 non-randomized studies compared SRS to other treatment strategies, but did not demonstrate dramatic associations. During a median follow-up of 48 months (inter-quartile range [IQR] of 35 to 62 months) after SRS, the annual incidences (95 % confidence interval [CI]) of outcomes were death 0.18 % (0.10 to 0.31), ICH 2.40 % (2.05 to 2.80), FND 0.71 % (0.53 to 0.96), and the composite of death, ICH, or FND 3.63 % (3.17 to 4.16). Outcomes did not differ by CCM location or type of SRS. The authors concluded that after SRS for CCM, the annual incidences of death, ICH, and FND were less than 5 % and appeared comparable to outcomes without SRS. These researchers stated that a randomized trial of SRS for CCM is needed.Furthermore, an UpToDate review on "Vascular malformations of the central nervous system" (Singer et al, 2020) states that "Role of stereotactic radiosurgery – We suggest not using stereotactic radiosurgery as the primary treatment for CMs. Stereotactic radiosurgery is a potential alternative to conservative therapy in patients with such surgically inaccessible lesions, and the available evidence suggests that it does lead to a reduction in hemorrhage, especially two years or more after radiosurgery. Nevertheless, high complication rates in available published series coupled with clinical experience has dissuaded many from using stereotactic radiosurgery for the treatment of CMs. In addition, there is concern that radiation exposure may promote the development of new CMs in familial cases … data regarding the long-term safety and adverse effects of stereotactic radiosurgery remain sparse".
Medial Thalamotomy Using Stereotactic Radiosurgery for Intractable Pain
Franzini and colleagues (2022) stated that medial thalamotomy using SRS is a potential treatment for intractable pain; however, the ideal treatment parameters and expected outcomes from this procedure remain unclear. In a systematic review, these investigators provided further insights on medial thalamotomy using SRS, specifically for intractable pain. They identified all clinical articles discussing medial thalamotomy using SRS for intractable pain. Only studies in which SRS was used to target the medial thalamus for pain were included. For centers with multiple publications, care was taken to avoid recounting individual patients. The literature review revealed 6 studies describing outcomes of medial thalamotomy using SRS for a total of 125 patients (118 included in the outcome analysis); 52 patients were treated for cancer pain across 3 studies, whereas 5 studies included 73 patients who were treated for non-malignant pain. The individual studies demonstrated initial meaningful pain reduction in 43.3 % to 100 % of patients, with an aggregate initial meaningful pain reduction in 65 patients (55 %) following SRS medial thalamotomy. This effect persisted in 45 patients (38 %) at the last follow-up; AEs were observed in 6 patients (5 %), which were related to radiation in 5 patients (4 %). The authors concluded that medial thalamotomy using SRS was effective for select patients with treatment-resistant pain and was remarkably safe when modern radiation delivery platforms were used; and more posteriorly placed lesions within the medial thalamus were associated with better pain relief. Moreover, these researchers stated that further investigation is needed to shed light on differences in patient responses.
Stereotactic Radiosurgery for Incidental Meningiomas
In a systematic review and meta-analysis, Zhang and Zhang (2021) examined the clinical outcomes of incidental meningiomas (IM) treated with SRS or observation. PubMed, Cochrane Library and Medline(Ovid) databases were comprehensively searched for eligible studies about IM that were managed with serial imaging follow-up or SRS. These researchers performed a systematic review and meta-analysis of the tumor progression rate between these 2 groups. The SRS-related morbidity was qualitatively analyzed. To predict potential tumor growth, the correlation between rapid tumor growth and the following factors, MRI T2 hyperintensity, initial tumor diameter and age were also analyzed by meta-analysis. A total of 16 studies were included. The SRS treatment group had significantly higher tumor control than the observation group in a mean follow-up of more than 3 years (pooled OR: 0.06, 95 % CI: 0.01 to 0.20, p < 0.0001; random effects model). Furthermore, there was an acceptable level of SRS-associated morbidity. Tumor progression was positively associated with MRI T2 hyperintensity (pooled OR: 1.93, 95 % CI: 1.30 to 2.87, p < 0.05, fixed effects model), initial large tumor diameter (pooled OR: 3.19, 95 % CI: 0.94 to 5.44, p < 0.05, fixed effects model) and younger age to some extent (pooled OR: -3.80, 95 % CI: -9.13 to 1.53, p > 0.05, random effects model). Absence of calcification was consistently shown to be a risk factor for progressive IM based on the existing literature. The authors concluded that SRS is a rational treatment for incidental meningioma in consideration of the higher tumor control rate and acceptable complications compared with treatment via observation. The integration of risk factors such as absence of calcification, MRI T2 hyperintensity and initial large tumor size may contribute to accurately predicting rapid tumor growth.
Stereotactic Radiosurgery for Intra-Cranial Histiocytosis
Tripathi and colleagues (2021) stated that histiocytosis is a group of immunoproliferative disorders of clonal cells. The management protocols are still evolving, with chemotherapy as the mainstay of treatment. In a systematic review, these researchers examined the feasibility, safety, effectiveness, and complication profile of SRS for the treatment of patients with intra-cranial histiocytosis. They reviewed PubMed, Scopus, Web of Science, and Embase for "radiosurgery" and "histiocytosis" in the English/Japanese language following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The patient profile, radio-surgical parameters (dose and isodose), target volume, and mode of radiosurgery (Gamma knife, LINAC radiosurgery, etc.) were collected. Its use as primary or adjuvant therapy, clinical and radiological outcome was also evaluated. These investigators identified 7 studies (9 patients); mean age of 41.9 years (24 to 57 years); 6 patients received Gamma-knife radiosurgery, whereas 3 received CyberKnife radiosurgery. The Langerhans cell histiocytosis variants were eosinophilic granuloma in 3, whereas 4 were not defined. Two cases had Rosai-Dorfman disease, and 2 different yet pathogenetically related histiocytic disorders; 4 patients harbored lesions in the pituitary stalk and posterior pituitary, 2 patients in the petrous region, 1 patient had a pontine lesion, and 2 patients had multiple lesions. The dose delivered ranged from 8 to 28 Gy. A total of 18 lesions (9 patients) were followed for 81.67 patient-years: 7 (39 %) disappeared, 8 (44.4 %) showed radiological reduction, and 2 (11 %) remained stable; 1 lesion (5 %) showed an increase in size, which required surgical excision. There were no AEs. The authors concluded that the role of SRS needs to be further examined as the current cohort study had only 9 cases (2 are Rosai-Dorfman disease), which were insufficient to make conclusions. These researchers stated that SRS may be a viable alternative in localized disease, along with chemotherapy and targeted surgery.
Stereotactic Radiosurgery for Intra-Cranial Non-Cavernous Sinus Benign Meningioma
In a systematic review and meta-analysis, Marchetti and colleagues (2020) examined the literature and provided evidence-based practice guidelines on behalf of the International Stereotactic Radiosurgery Society (ISRS). Articles in English specific to SRS for benign intra-cranial meningioma, published from January 1964 to April 2018, were reviewed; 3 electronic databases (PubMed, Embase, and the Cochrane Central Register) were searched. Of the 2,844 studies identified, 305 had a full text evaluation and 27 studies met the criteria to be included in this analysis. All but 1 were retrospective studies. The 10-year LC rate ranged from 71 % to 100 %; and the 10-year PFS rate ranged from 55 % to 97 %. The prescription dose ranged typically between 12 and 15 Gy, delivered in a single fraction. Toxicity rate was generally low. The authors concluded that the current literature supporting SRS for benign intra-cranial meningioma lacked level I and II evidence. However, when summarizing the large number of level III studies, it is clear that SRS can be recommended as an effective evidence-based therapeutic option (recommendation level = II) for grade-1 meningioma. Tumor control rates are generally high, with rare events of post-SRS deterioration. Moreover, these researchers stated that due to the lack of class level I and II evidence, further investigation with longer periods of observation and larger, multi-institutional series are needed. They stated that RCTs would be recommended; on the other hand, such studies are unlikely to be performed given current practice patterns, funding constraints, and clinical equipoise.
Stereotactic Radiosurgery for Pituitary Adenomas
In a systematic review, Mathieu and colleagues (2021) provided objective evidence on the use of SRS in the management of patients with secretory pituitary adenomas and developed consensus recommendations. These investigators reviewed the English-language literature up until June 2018 using the PRISMA guidelines. The PubMed (Medline), Embase, and Cochrane databases were searched. A total of 45 articles reporting single-center outcomes of SRS for acromegaly, Cushing's disease, and prolactinomas were selected and included in the analysis. For acromegaly, random effects meta-analysis estimates for crude tumor control rate, crude endocrine remission rate, and any new hypopituitarism rates were 97.0 % (95 % CI: 96.0 % to 98.0%), 44.0 % (95 % CI: 35.0 % to 53.0 %), and 17.0 % (95 % CI: 13.0 % to 23.0 %), respectively. For Cushing's disease, random effects estimate for crude tumor control rate, crude endocrine remission rate, and any new hypopituitarism rate were 92.0 % (95 % CI: 87.0 % to 95.0 %), 48.0 % (95 % CI: 35.0 % to 61.0 %), and 21.0 % (95 % CI: 13.0 % to 31.0 %), respectively. For prolactinomas, random effects estimate for crude tumor control rate, crude endocrine remission rate, and any new hypopituitarism rate were 93.0 % (95 % CI: 90.0 % to 95.0 %), 28.0 % (95 % CI: 19.0 % to 39.0 %), and 12.0 % (95 % CI: 6.0 % to 24.0 %), respectively. Meta-regression analysis did not show a statistically significant association between mean margin dose with crude endocrine remission rate or mean margin dose with development of any new hypopituitarism rate for any of the secretory subtypes. The authors concluded that SRS offered effective tumor control of hormone-producing pituitary adenomas in the majority of patients but a lower rate of endocrine improvement or remission.
Stereotactic Radiosurgery for Small Cell Lung Cancer
Safavi and colleagues (2021) noted that SABR is used to treat inoperable early-stage, node-negative small cell lung cancer (SCLC). These investigators carried out a systematic review and meta-analysis of the literature on SABR for T1-2N0M0 SCLC to examine outcomes including LC, OS, recurrence rates, and toxicity. This study was performed in accordance with PRISMA and MOOSE guidelines; a systematic review of PubMed and Embase (inception to April 2021) was carried out. Two authors independently reviewed articles for inclusion and extracted study-level data. Random-effects meta-analysis was performed using R (version 3.6.2) at a significance threshold of 0.05. A total of 11 studies were identified in the systematic review and 7 (399 patients) were selected for meta-analysis. Inoperability was noted as the indication for SABR in 94 % (75 % to 100 %) of patients. Median follow-up and tumor size were 19.5 months (11.9 to 32) and 24 mm (19 to 29), respectively. Chemotherapy and prophylactic cranial irradiation (PCI) use rates were 44.1 % (95 % CI: 27.0 % to 61.9 %) and 13.8 % (95 % CI: 0.4 % to 41.2 %), respectively. Local control was 97.3 % (95 % CI: 92.3 % to 99.8 %) at 1 year and 95.7 % (95 % CI: 74.2 % to 100.0 %) at 2 years. Overall survival was 86.3 % (95 % CI: 74.4% to 94.9 %) at 1 year and 63.7 % (95 % CI: 45.7 % to 79.9 %) at 2 years. Nodal and distant recurrence rates were 17.8 % (95 % CI: 7.5 % to 31.2 %) and 26.9 % (95 % CI: 7.4 % to 53.0 %), respectively. The rates of grade-1, grade-2, and grade-3 toxicity (CTCAE) were 12.6 % (95 % CI: 6.7 % to 19.9 %), 6.7 % (95 % CI: 3.3 % to 11.2 %), and 1.4 % (95 % CI: 0.0 % to 5.3 %), respectively. No grade-4 or grade-5 events were observed across the studies. The authors concluded that SABR for inoperable early-stage, node-negative SCLC was locally effective with limited toxicity. Moreover, these researchers stated that prospective studies are needed to further examine the role of SABR for patients at higher risk of toxicity with surgery or combined chemoradiation.
Stereotactic Radiosurgery for Vestibular Schwannomas
Tosi and colleagues (2021) noted that large vestibular schwannomas (VS) pose a treatment challenge for both microsurgery (MS) and SRS. Technical developments have allowed for safer irradiation of large tumors. It remains unclear if SRS could achieve appropriate tumor control and acceptable cranial nerve toxicities. In a systematic review and meta-analysis, these researchers examined outcomes of irradiation for large VS. PubMed Medline, Embase, Web of Science, and Cochrane were searched for all the studies evaluating SRS outcome in large VS. Primary endpoints included clinical and radiographic tumor control, need for salvage surgery, serviceable hearing, cranial nerve V and VII impairment, presence of hydrocephalus requiring shunting, and presence of vertigo/dizziness. A total of 22 studies were identified that met selection criteria for analysis from an initial pool of 1,272 reports. They were examined according to treatment protocol: single-dose SRS (13 studies, 483 patients); combination of MS and SRS (7 studies, 182 patients); and fractionated SRS (3 studies, 82 patients). Tumor control was achieved in 89 %, 94 %, and 91 % of patients, respectively; ORs of post- over pre-treatment serviceable hearing were 0.42 (p < 0.01), 0.47 (p = 0.05), and 0.60 (p = 0.22); for facial nerve impairment, these ORs were 1.08 (p = 0.69), 3.45 (p = 0.28), and 0.87 (p = 0.71), respectively. The authors concluded that the management of large VS remains challenging. All treatment modalities resulted in high tumor control rates and worsening of pre-treatment hearing; however, none caused significant facial nerve impairment, suggesting that management strategies incorporating focal irradiation could be successful.Dumot et al (2022) stated that although SRS is an established treatment for small- and medium-sized VS, its role in the management of Koos grade-IV VS is still unclear. In a retrospective, multi-center study, these researchers examined tumor control and patient outcomes of primary, single-session SRS treatment for patients with Koos grade-IV VS. This trial included patients treated with primary, single-session SRS for Koos grade-IV VS at 10 participating centers. Only those patients presenting with non-life-threatening or incapacitating symptoms and at least 12 months of clinical and neuroimaging follow-up were eligible for inclusion. Relevant data were collected, and the Kaplan-Meier method was used to carry out time-dependent analysis for post-SRS tumor control, hearing preservation, and facial nerve function preservation. Univariate and multivariate analyses were carried out for outcome measures using Cox regression analysis. A total of 627 patients (344 females, median patient age of 54 [inter-quartile range [IQR] 22] years) treated with primary SRS were included in this study. The median tumor volume was 8.7 (IQR 5) cm3. Before SRS, serviceable hearing, facial nerve weakness (House-Brackmann grade of greater than I), and trigeminal neuropathy were present in 205 (33 %), 48 (7.7 %), and 203 (32.4 %) patients, respectively. The median prescription dose was 12 (IQR 1) Gy. At a median radiological follow-up of 38 (IQR 54) months, tumor control was achieved in 94.1 % of patients. Early tumor expansion occurred in 67 (10.7 %) patients and was associated with a loss of tumor control at the last follow-up (p = 0.001). Serviceable hearing preservation rates at the 5- and 10-year follow-ups were 65 % and 44.6 %, respectively. Gardner-Robertson class of greater than 1 (p = 0.003) and cochlear dose of 4 or higher Gy (p = 0.02) were risk factors for hearing loss. Facial nerve function deterioration occurred in 19 (3.0 %) patients at the last follow-up and was associated with margin doses of 13 or higher Gy (p = 0.03) and early tumor expansion (p = 0.04). Post-SRS, 33 patients developed hydrocephalus requiring shunting. Adverse radiation effects occurred in 92 patients and were managed medically or surgically in 34 and 18 cases, respectively. The authors concluded that SRS was a safe and effective approach of obtaining tumor control in patients with Koos grade-IV VS presenting with non-life-threatening or debilitating symptoms, especially those with surgical co-morbidities that contraindicated resection. To decrease the incidence of post-SRS facial palsy, a prescription dose < of less than 13 Gy is recommended.
Gamma Knife Radiosurgery for the Newly Diagnosed Glioblastoma
Gallitto et al (2022) noted that GBM is the most common primary malignant brain tumor in adults, with OS remaining poor despite ongoing efforts to explore new therapeutic options. Given these outcomes, efforts have been made to shorten treatment time. Recent data reported on the safety of CyberKnife (CK) fractionated SRS in the management of GBM using a 5-fraction regimen. The latest GK model also supports frameless SRS, and outcomes using GK-SRS in the management of primary GBM have not yet been reported. In a retrospective, single-center study, these researchers reported on the feasibility of 5-fraction SRS with the GK ICON in the management of newly diagnosed GBM. They reviewed all patients from their medical center from January 2017 through December 2021 who received fractionated SRS with GK ICON for newly diagnosed GBM. Patient demographics, upfront surgical margins, molecular subtyping, radiation treatment volumes, systemic therapies, and follow-up imaging findings were extracted to report on oncologic outcomes. These researchers identified 6 patients treated within the afore-mentioned time frame. Median age at diagnosis was 73.5 years, 66 % were men, and had a median Karnofsky Performance Status (KPS) of 70. All tumors were IDH wild-type, and all but 1 were MGMT methylated and received concurrent temozolomide (TMZ). Within this group, PFS was comparable to that of historical data without significant radiation-induced toxicities. The authors concluded that GK ICON may be discussed as a potential therapeutic option for select GBM patients and further prospective, randomized trials are needed to provide more robust data. The authors stated that in addition to short interval follow-up time, they recognized the other limitations of this small (n = 6), retrospective, single-center study including selection bias.
Stereotactic Body Radiation Therapy for Lung and Liver Oligometastases from Breast Cancer
Franceschini et al (2022) reported the mature toxicity data of a non-randomized, phase-II clinical trial on the use of SBRT for lung and liver oligometastases. Oligometastatic patients from breast cancer were treated with SBRT for up to 5 lung and/or liver lesions. Inclusion criteria included age of greater than 18 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, diagnosis of breast cancer, less than 5 lung/liver lesions (with a maximum diameter of 5 cm), metastatic disease confined to the lungs and liver or extra-pulmonary or extra-hepatic disease stable or responding to systemic therapy. Various dose-fractionation schedules were used. Then, a 4D-CT scan and FDG-CTPET were acquired for simulation and fused for target definition. From 2015 to 2021, a total of 64 patients (90 lesions) were irradiated; treatment was well-tolerated, with no grade 3 to 4 toxicities. No grade 3 or higher toxicities were registered; and the co-primary endpoint of the study was met. Median follow-up was 19.4 months (range of 2.6 to 73.1). The authors concluded that the co-primary endpoint of this phase-II clinical trial was met, showing excellent tolerability of SBRT for lung and liver oligometastatic in breast cancer patients. Moreover, these researchers stated that until effectiveness data will mature with longer follow-up, SBRT should be regarded as an opportunity for oligometastatic breast cancer patients.
Stereotactic Ablative Radiotherapy for Oligometastatic Renal Cell Cancer
Ma et al (2022) noted that SABR is one of the therapeutic options for oligometastatic RCC but is limited by a lack of data to examine high-dose SABR to all/multiple sites. In a retrospective study, these investigators examined the effectiveness and prognostic factors of high-dose SABR for oligometastatic RCC patients. Patients with oligometastatic RCC on systemic therapy were collected. All patients were treated with SABR (40 to 50 Gy/5 fractions) for small tumors or partial-SABR (tumor center boosted with 6 to 8 Gy/3 to 5 fractions with 50 to 60 Gy/20 to 25 fractions to the whole tumor volume) for bulky tumors or tumors adjacent to critical organs; PFS and OS were calculated. A total of 35 patients were enrolled, of which 88.5 % had intermediate- or high-risk disease, with 60 % on 2nd- to 4th-line systemic therapy. The median follow-up time was 17 months. The median PFS and OS times were 11.3 and 29.7 months, respectively. Univariate analysis showed that an OS benefit was found in patients who received radiation before tyrosine kinase inhibitor (TKI) failure (p = 0.006) and where there was a short time interval less than 6 months) from being diagnosed with metastatic disease to undergoing radiotherapy (p = 0.046). Similar results were also found in PFS in patients who received radiation before TKI failure (p = 0.049) or within 8 months (p = 0.047). There were certain differences in PFS (p = 0.033) between patients receiving radiotherapy with all lesions and those with selected tumors. In multi-variate analysis, OS benefits were found in patients who received radiotherapy before TKI failure (p = 0.028). The authors concluded that the early use of high-dose SABR to multi-lesions may improve survival. Partial-SABR for bulky lesions close to critical organs could be safely and effectively applied under certain circumstances. These researchers stated that the limitations of this study included its retrospective design and the small patient cohort (n = 35).
Stereotactic Radiosurgery Combined with Immune Checkpoint Inhibitors for Brain Metastasis
Deng et al (2022) stated that many studies have reported the combination of radiosurgery and immune checkpoint inhibitors (ICI) in the treatment of brain metastasis (BMs); however, these studies have not reached a consistent conclusion. In a systematic review and meta-analysis, these investigators examined the effect of combination therapy compared with radiosurgery alone on the prognosis of patients with BMs. The PubMed-Medline and Ovid-Embase databases were searched to identify relevant studies until May 5, 2022. The search results were filtered by the inclusion and exclusion criteria described in this paper. The pooled HR with 95 % CI were presented as estimates effect to reflect the effect of combined therapy on each outcome. A total of 17 eligible studies covering 2,079 patients were included in this meta-analysis. The pooled results showed that the use of targeted drugs could significantly improve the OS (HR = 0.62, 95 % CI: 0.51 to 0.76; p < 0.01), reduce the risk of local recurrence (HR = 0.48, 95 % CI: 0.38 to 0.62; p < 0.01) and distant brain recurrence (HR = 0.70, 95 % CI: 0.50 to 0.97; p < 0.05). Overall, SRS combined with ICIs could significantly improve OS, local control, and distant brain control of patients with BMs compared to SRS alone; however, the effect varied for different pathological types. The authors concluded that these findings verified the rationale of the current treatment strategy for BMs that emphasizes the combination of local and systematic therapy.
Badrigilan et al (2022) noted that ICIs are an emerging tool in the treatment of BMs; SRS, traditionally used for BMs, elicits an immune brain response and can act synergistically with ICIs. In a meta-analysis, these investigators examined the effectiveness of ICI administered with SRS and determined the impact of timing on BM response. They carried out a systematical search to identify potential studies concerning BMs managed with SRS alone or with SRS + ICI with relative timing administration (ICI concurrent with SRS, ICI non-concurrent with SRS, SRS before ICI, SRS after ICI). The OS, 12-month OS, local PFS (LPFS), 12-month local brain control (LBC), distant PFS (DPFS), 12-month distant brain control (DBC), and AEs (intra-cranial hemorrhage, radio-necrosis) were analyzed using the random-effects model. A total of 16 retrospective studies with 1,356 BM patients were included. Compared to non-concurrent therapy, concurrent therapy revealed a significantly longer OS (HR = 1.43; p = 0.008) and 12-months LBC (HR = 1.91; p = 0.04), a similar 12-months DBC (HR = 1.12; p = 0.547) and higher complication rate (R = 0.77; p = 0.346). Concurrent therapy resulted in a significantly higher OS compared to ICI before SRS (HR = 2.55; p = 0.0003). The authors concluded that the combination of SRS with ICI improved patients' clinical and radiological outcomes. The effectiveness of the combination is subject to the identification of an optimal therapeutic window.
Stereotactic Body Radiotherapy Versus Conventional Radiotherapy for Painful Bone Metastases
Ito et al (2022) noted that SBRT is a promising approach in the treatment of patients with painful bone metastases; however, the superiority of SBRT over conventional external beam radiotherapy (cEBRT) remains controversial. In a systematic review and meta-analysis, these researchers compared SBRT and cEBRT for the treatment of bone metastases. They carried out a literature search using PubMed on January 22, 2022, with the following inclusion criteria: randomized controlled trials comparing SBRT with cEBRT for bone metastases as well as endpoint including pain response. Effect sizes across studies were pooled using random-effects models in a meta-analysis of risk ratios. A total of 1,246 articles were screened, with 7 articles comprising 964 patients (522 and 442 patients in the SBRT and cEBRT arms, respectively) meeting the inclusion criteria. The overall pain response (OR) rates of bone metastases at 3 months were 45 % and 36 % in the SBRT and cEBRT arms, respectively. The present analyses showed no significant difference between the 2 groups. In 4 studies included for the calculation of OR rates of spinal metastases at 3 months, the OR rates were 40 % and 35 % in the SBRT and cEBRT arms, respectively, with no significant difference between the 2 groups. The incidence of severe adverse effects and health-related QOL (HR-QOL) outcomes were comparable between the 2 arms. The authors concluded that the superiority of SBRT over cEBRT for pain palliation in bone metastases was not confirmed in this meta-analysis. These investigators stated that although SBRT is a standard of care (SOC) for bone metastases, patients receiving SBRT should be selected appropriately. Moreover, these researchers stated that further prospective, high-quality studies (e.g., phase-III clinical trials) are needed to examine if SBRT is a better clinical choice than cEBRT.
The authors stated that this review had several drawbacks. First, there was no access to the individual patient data; thus, the heterogeneous population was analyzed as a single population. If the population is analyzed separately according to performance status, relative radiosensitivity, and severe or mild pain at baseline, patients who will benefit from SBRT may be identified. Second, moderate-to-strong heterogeneity was observed in the main analyses. This heterogeneity might be due to inter-trial differences in the patient cohort, SBRT dose, or SBRT planning. Third, only 2 phase-III clinical trials were included in this study. Since the results of these 2 studies were definitely conflicting, the present synthetic analysis could not find a significant difference.
Appendix
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Cranial stereotactic radiosurgery with a Cyberknife, gamma knife, or linear accelerator (LINAC) is considered medically necessary when used for any of the following indications:
- For treatment of members with symptomatic, small (less than 3 cm) arterio-venous (AV) malformations, aneurysms, and benign tumors (acoustic neuromas (vestibular schwannomas), craniopharyngiomas, hemangiomas, hemangioblastomas, meningiomas, pituitary adenomas, and neoplasms of the pineal gland) if the lesion is unresectable due to its deep intracranial location or if the member is unable to tolerate conventional operative intervention; or
- For members with trigeminal neuralgia that has not responded to other more conservative treatments (see CPB 0374 - Trigeminal Neuralgia: Treatments); or
- Severe essential tremor not adequately responsive to standard medical therapy (see CPB 0153 - Thalamotomy); or
- Disabling tremor in individuals with Parkinson’s disease (eg, thalamotomy) who meet medical necessity criteria for thalamotomy (see CPB 0153 - Thalamotomy) but are not candidates for surgery; or
- For treatment of brain malignancies (primary tumors and/or metastatic lesions) in members with a good performance status (a score between 80 and 100 on the Karnofsky Performance Scale;1 [ie, at a minimum, able to perform normal activity with effort]), controlled systemic disease (defined as extracranial disease that is stable or in remission), and no more than 4 metastatic lesions. For treatment to additional lesions, further clinical justification may be needed.
- For ocular melanomas that are not amenable to surgical excision or other conventional forms of treatment.
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Stereotactic body radiation therapy with a Cyberknife, gamma knife, or linear accelerator (LINAC) is considered medically necessary for localized malignant conditions within the body where highly precise application of high-dose radiotherapy is required and clinically appropriate, including:
- Hepatocellular carcinoma in individuals with unresectable disease that is considered to be extensive and not suitable for liver transplantation or for individuals with local disease only with a good performance status (a score between 80 and 100 on the Karnofsky Performance Scale) but who are not amenable to surgery due to comorbidities;
- Prostate cancer in individuals with organ-confined prostate cancer with Gleason score less than or equal to eight and prostate-specific antigen (PSA) less than 20;
- Non-small cell lung cancer for inoperable stage I or II tumors;
- Oligometastatic colorectal cancer (1 to 3 metastases to the lung or liver) not amenable to surgery;
- Inoperable primary spinal tumors with compression or intractable pain;
- Recurrent metastatic disease in a previously irradiated area;
- Recurrent localized head and neck cancer;
- Metastatic lesions to the liver when they are the sole site of disease and cannot be surgically resected or undergo accepted ablation techniques;
- Metastatic disease to the lung when clinically appropriate and on a case-by-case basis.
All other clinical sites or indications are considered experimental and investigational but will be considered on a case-by-case basis.
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Fractionated stereotactic radiotherapy is considered medically necessary when criteria for stereotactic radiosurgery are met. Fractionated stereotactic radiotherapy is useful for treatment of tumors in hard-to-reach locations, tumors with very unusual shapes, or for tumors located in such close proximity to a vital structure (e.g., optic nerve or hypothalamus) that even a very accurate high-dose single fraction of stereotactic radiosurgery could not be tolerated.
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Stereotactic proton beam radiosurgery: please see CPB 0270 - Proton Beam and Neutron Bean Radiotherapy.
Aetna considers stereotactic radiosurgery experimental and investigational for all other indications because its effectiveness for these indications has not been established including (not an all-inclusive list):
- Cluster headaches
- Epilepsy (except when associated with treatment of AV malformations or brain tumors)
- Mammographic microcalcification.
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