Description:
Radiotherapy (RT) is an integral component of treating many brain tumors, both benign and malignant. Intensity-modulated radiotherapy (IMRT) is a method that allows adequate radiation to the tumor while minimizing the dose to surrounding normal tissues and critical structures. Intensity-modulated radiotherapy also allows additional radiation to penetrate specific anatomic areas simultaneously, delivering radiation at a larger target volume.

Additional Information
Clinical input was obtained in 2012 on the use of IMRT, including its use close to critical structures. There was a near-uniform consensus that use of IMRT in the central nervous system is at least as effective as 3-dimensional conformal radiotherapy and that, given the adverse events that could result if nearby critical structures receive toxic radiation doses, IMRT dosimetric improvements should be accepted as meaningful evidence for its benefit. Input, a strong chain of evidence, and the potential to reduce harms supported a decision that IMRT may be considered medically necessary for the treatment of tumors of the central nervous system that are proximate to organs at risk.

Background 
Radiotherapy Techniques
Radiation therapy may be administered externally (i.e., a beam of radiation is directed into the body) or internally (i.e., a radioactive source is placed inside the body, near a tumor). External radiotherapy (RT) techniques include "conventional" or 2-dimensional (2D) RT, 3-dimensional (3D) conformal RT, and intensity-modulated radiation therapy (IMRT).

Conventional External-Beam Radiotherapy
Methods to plan and deliver RT have evolved that permit more precise targeting of tumors with complex geometries. Conventional 2D treatment planning utilizes X-ray films to guide and position radiation beams.¹ Bony landmarks bones visualized on X-ray are used to locate a tumor and direct the radiation beams. The radiation is typically of uniform intensity.

Three-Dimensional Conformal Radiotherapy
Radiation treatment planning has evolved to use 3D images, usually from computed tomography (CT) scans, to more precisely delineate the boundaries of the tumor and to discriminate tumor tissue from adjacent normal tissue and nearby organs at risk for radiation damage. Three-dimensional conformal RT (3D-CRT) involves initially scanning the patient in the position that will be used for the radiation treatment.¹ The tumor target and surrounding normal organs are then outlined in 3D on the scan. Computer software assists in determining the orientation of radiation beams and the amount of radiation the tumor and normal tissues receive to ensure coverage of the entire tumor in order to minimize radiation exposure for at risk normal tissue and nearby organs. Other imaging techniques and devices such as multileaf collimators (MLCs) may be used to "shape" the radiation beams. Methods have also been developed to position the patient and the radiation portal reproducibly for each fraction and to immobilize the patient, thus maintaining consistent beam axes across treatment sessions.

Intensity-Modulated Radiotherapy
IMRT is the more recent development in external radiation. Treatment planning and delivery are more complex, time-consuming, and labor-intensive for IMRT than for 3D-CRT. Similar to 3D-CRT, the tumor and surrounding normal organs are outlined in 3D by a scan and multiple radiation beams are positioned around the patient for radiation delivery.¹ In IMRT, radiation beams are divided into a grid-like pattern, separating a single beam into many smaller "beamlets." Specialized computer software allows for “inverse” treatment planning. The radiation oncologist delineates the target on each slice of a CT scan and specifies the target's prescribed radiation dose, acceptable limits of dose heterogeneity within the target volume, adjacent normal tissue volumes to avoid, and acceptable dose limits within the normal tissues. Based on these parameters and a digitally reconstructed radiographic image of the tumor, surrounding tissues, and organs at risk, computer software optimizes the location, shape, and intensities of the beam ports to achieve the treatment plan's goals.

Increased conformality may permit escalated tumor doses without increasing normal tissue toxicity and is proposed to improve local tumor control, with decreased exposure to surrounding, normal tissues, potentially reducing acute and late radiation toxicities. Better dose homogeneity within the target may also improve local tumor control by avoiding underdosing within the tumor and may decrease toxicity by avoiding overdosing.

Other advanced techniques that may further improve RT treatment by improving dose distribution. These techniques are considered variations of IMRT. Volumetric modulated arc therapy delivers radiation from a continuous rotation of the radiation source. The principal advantage of volumetric modulated arc therapy is greater efficiency in treatment delivery time, reducing radiation exposure and improving target radiation delivery due to less patient motion. Image-guided RT involves the incorporation of imaging before and/or during treatment to more precisely deliver RT to the target volume.

Regulatory Status
In general, IMRT systems include intensity modulators, which control, block, or filter the intensity of radiation; and RT planning systems, which plan the radiation dose to be delivered.

A number of intensity modulators have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. Intensity modulators include the Innocure Intensity Modulating Radiation Therapy Compensators (Innocure) and decimal tissue compensator (Southeastern Radiation Products), cleared in 2006. FDA product code: IXI. Intensity modulators may be added to standard linear accelerators to deliver IMRT when used with proper treatment planning systems.

Radiotherapy treatment planning systems have also been cleared for marketing by the FDA through the 510(k) process. They include the Prowess Panther (Prowess) in 2003, TiGRT (LinaTech) in 2009, and the Ray Dose (RaySearch Laboratories). FDA product code: MUJ.

Fully integrated IMRT systems also are available. These devices are customizable and support all stages of IMRT delivery, including planning, treatment delivery, and health record management. One such device cleared for marketing by the FDA through the 510(k) process is the Varian IMRT system (Varian Medical Systems). FDA product code: IYE.

Policy
Intensity-modulated radiotherapy may be considered MEDICALLY NECESSARY for individuals with malignant or benign brain tumors when the tumor is proximate to organs at risk (brain stem, spinal cord, cochlea and eye structures including optic nerve and chiasm, lens and retina) and 3-dimensional conformal radiotherapy planning is not able to meet dose-volume constraints for normal tissue tolerance (see Policy Guidelines section).

Hippocampal-avoiding intensity-modulated radiotherapy may be considered MEDICALLY NECESSARY for individuals with brain tumor metastases outside a 5-mm margin around either hippocampus and expected survival ≥ 4 months.

Intensity-modulated radiotherapy is investigational/unproven therefore considered NOT MEDICALLY NECESSARY for the treatment of tumors of the central nervous system for all indications not meeting the criteria above.

Policy Guidelines
Organs at risk are defined as normal tissues whose radiation sensitivity may significantly influence treatment planning and/or prescribed radiation dose. Organs at risk may be particularly vulnerable to clinically important complications from radiation toxicity. Table PG1 outlines radiation doses generally considered tolerance thresholds for these normal structures in the central nervous system. Dosimetry plans may be reviewed to demonstrate that radiation by 3-dimensional conformal radiotherapy would exceed tolerance doses to structures at risk.

Table PG1. Radiation Tolerance Doses for Normal Tissues   

Site	TD 5/5 (Gy) a			TD 50/5 (Gy) b			Complication End Point
	Portion of Organ Involved			Portion of Organ Involved
	1/3	2/3	3/3	1/3	2/3	3/3
Brain stem	60	53	50	NP	NP	65	Necrosis, infarct
Spinal cord, cm	50 (5-10)	NP	47 (20)	70 (5-10)	NP	NP	Myelitis, necrosis
Optic nerve and chiasm	50	50	50	65	65	65	Blindness
Retina	45	45	45	65	65	65	Blindness
Eye lens	10	10	10	18	18	18	Cataract requiring intervention

Compiled from: (1) Morgan MA (2011). Radiation Oncology. In DeVita, Lawrence, and Rosenberg, Cancer (p. 308). Philadelphia: Lippincott Williams and Wilkins; and (2) Kehwar TS, Sharma SC. Use of normal tissue tolerance doses into linear quadratic equation to estimate normal tissue complication probability. http://www.rooj.com/Radiation%20Tissue%20Tolerance.htm.
Radiation tolerance doses for the cochlea have been reported to be 50 gray.
NP: not provided; TD: tolerance dose.
^a TD 5/5 is the average dose that results in a 5% complication risk within 5 years.
^b TD 50/5 is the average dose that results in a 50% complication risk within 5 years.

Coding
Please see the Codes table for details.

Benefit Application
BlueCard^®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale  
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net
health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Multiple dose-planning studies generate 3-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) treatment plans from the same scans and then compare predicted dose distributions within the target area and adjacent organs. Results of such planning studies have shown that IMRT is better than 3D-CRT with respect to conformality to, and dose homogeneity within, the target. Results have also demonstrated that IMRT spreads less radiation to nontarget areas. Dosimetry studies using stationary targets generally confirm these predictions. However, because patients move during treatment, dosimetry with stationary targets only approximate actual radiation doses received. Based on these dosimetry studies, radiation oncologists expect IMRT to improve treatment outcomes compared with those of 3D-CRT.

Comparative studies of radiation-induced adverse events from IMRT versus alternative radiation delivery would constitute definitive evidence of establishing the benefit of IMRT. Single-arm series of IMRT can give some insights into the potential for benefit, particularly if an adverse event that is expected to occur at high rates is shown to decrease by a large amount. Studies of treatment benefit are also important to establish that IMRT is at least as good as other types of delivery, but, absent such comparative trials, it is likely that benefit from IMRT is at least as good as with other types of delivery.

In general, when the indication for IMRT is to avoid radiation to sensitive areas, dosimetry studies have been considered sufficient evidence to demonstrate that harm would be avoided by using IMRT. For other IMRT indications, such as using IMRT to provide better tumor control, comparative studies of health outcomes are needed to demonstrate such a benefit.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., people of color [African American, Asian, Black, Latino and Native American]; LGBTQIA [lesbian, gay, bisexual, transgender, queer, intersex, asexual]; women; and people with disabilities [physical and invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study
populations.

Malignant Brain Tumors
Clinical Context and Therapy Purpose
The purpose of IMRT in individuals who have malignant brain tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with malignant brain tumors.

Interventions
The therapy being considered is IMRT.

Radiotherapy (RT) is an integral component of treating many brain tumors, both benign and malignant. Intensity-modulated radiotherapy is a method that allows adequate radiation to the tumor while minimizing the dose to surrounding normal tissues and critical structures. Intensity-modulated radiotherapy also allows additional radiation to penetrate specific anatomic areas simultaneously, delivering radiation at a larger target volume.

Comparators
The following practice is currently being used to treat malignant brain tumors: 3D-CRT.

Outcomes
The general outcomes of interest are overall survival (OS), disease-specific survival (DSS), reductions in symptoms, functional outcomes, and treatment-related adverse events. A proposed benefit of IMRT is to reduce toxicity to adjacent structures, allowing dose escalation to the target area and fewer breaks in treatment courses due to a reduction in side effects. However, this may come with a loss of locoregional control and OS due to the factors discussed above. The time frame for outcome measures varies from short-term management of toxicity and symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Amelio et al. (2010) conducted a systematic review of the clinical and technical issues of using IMRT in newly diagnosed glioblastoma multiforme.² Articles were selected through December 2009 and included 17 studies (9 on dosimetric data and technical considerations, 7 on clinical results, 1 on both dosimetric and clinical results) for a total of 204 treated patients and 148 patient datasets used in planning studies. No RCTs were identified, and a meta-analysis was not performed.

For the 6 articles related to planning studies that compared 3D-CRT with IMRT, the report by Fuller et al. (2007) showed a noticeable difference between 3D-CRT and IMRT for the planning target volume (PTV; 13% benefit in V95 [volume that received 95% of the prescribed dose] from IMRT ; p < .001);³ the remaining studies suggested that IMRT and 3D-CRT provided similar PTV coverage, with differences between 0% and 1%. Target dose conformity was improved with IMRT. The organs at risk in the studies typically were the brainstem, optic chiasm, optic nerves, lens, and retina. In general, IMRT provided better sparing of the organs at risk than 3D-CRT but with considerable variation from study to study.

Of the 8 studies that included clinical results, 3 were retrospective; 1 was a prospective phase 1 study, and 4 were prospective phase 2 single-institution studies. Of these 8 studies, 2 used conventional total dose and dose per fraction, 2 used a hypofractionated regimen, and the others used a hypofractionated scheme with a simultaneous integrated boost. The median follow-up ranged from 8.8 to 24 months. Almost all patients (96%) completed treatment without interruption or discontinuation due to toxicity. Acute toxicity was reported as negligible, with grade 3 adverse events observed in only 2 studies at rates of 7% and 12%. Grade 4 toxicity was recorded in only 1 series, with an absolute rate of 3%. Data for late toxicities were available in 6 of 8 studies, with 1 recording grade 4 adverse events with an incidence of 20%. One- and 2-year OS rates varied between 30% and 81.9% and between 0% and 55.6%, respectively. When OS was reported as a median time, it ranged from 7 to 24 months. Progression-free survival (PFS) rates ranged from 0% to 71.4% at 1 year and from 0% to 53.6% at 2 years. The median PFS ranged from 2.5 to 12 months.

Reviewers also conducted a comprehensive qualitative comparison using data reported in the literature on similar non-IMRT clinical studies. The planning comparisons revealed that 3D-CRT and IMRT provided similar results in terms of target coverage. Intensity-modulated radiotherapy was somewhat better than 3D-CRT in reducing the maximum dose delivered to the organs at risk, although the extent varied by case. Intensity-modulated radiotherapy was also better than 3D-CRT when it came to dose conformity and sparing of the healthy brain tissue at medium to low doses; there were no aspects where IMRT performed worse than 3D-CRT.

The systematic review was limited by a number of factors: there was an absence of comparative studies with clinical outcomes; all studies were small in size, from a single institution; most patients (53%) were retrospectively analyzed; and chemotherapy administration varied across studies.

Dose-Planning Studies
MacDonald et al. (2007) compared the dosimetry of IMRT with 3D-CRT in 20 patients treated for high-grade glioma.⁴ Prescription dose and normal tissue constraints were identical for the 3D-CRT and IMRT treatment plans. The IMRT plan yielded superior target coverage compared with the 3D-CRT plan. The IMRT plan reduced the percent volume of brainstem receiving a dose greater than 45 gray (Gy) by 31% (p = .004) and the percent volume of brain receiving a dose greater than 18 Gy, 24 Gy, and 45 Gy by 10% (p = .059), 14% (p = .015), and 40% (p < .001), respectively. With IMRT, the percent volume of optic chiasm receiving more than 45 Gy was reduced by 30.4% (p = .047). Compared with 3D-CRT, IMRT significantly increased tumor control probability (p<.001) and lowered the normal tissue complication probability for brain and brainstem (p < .033).

Narayana et al. (2006) compared IMRT treatment plans with 3D plans performed in 20 patients of a case series of 58 patients.⁵ Regardless of tumor location, IMRT did not improve PTV compared with 3D planning. However, IMRT decreased the maximum dose to the spinal cord, optic nerves, and eye by 16%, 7%, and 15%, respectively.

Nonrandomized Comparison Studies
Paulsson et al. (2014) compared treatment failure rates in glioblastoma patients with differing target margins (the size of the region between the tumor and edge of the PTV).⁶ In 161 patients, treatment margins were not associated with treatment failure. There was no difference in treatment failure rates between IMRT and 3D-CRT.

A large cohort study conducted by Xiang et al. (2020) that included > 450,000 patients with cancer (of which 12,143 had brain or central nervous system cancer) compared the risk of secondary tumors following treatment with IMRT and 3D-CRT across cancer types. After a mean 5 years follow-up, multivariate, matched analysis showed no difference in risk of secondary cancers between IMRT and 3D-CRT (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.98 to 1.03). These results were consistent when limited to patients who had not received chemotherapy (OR, 1.01; 95% CI, 0.96 to 1.06).⁷

Section Summary: Malignant Brain Tumors
Dosimetry studies have demonstrated lower radiation exposure to organs at risk with IMRT treatment plans than with 3D-CRT treatment plans. The evidence appears to be consistent in supporting lower neurotoxicity associated with IMRT. No conclusions can be made about the efficacy of IMRT compared with conventional RT.

Benign Brain Tumors
Clinical Context and Therapy Purpose
The purpose of IMRT in individuals who have benign brain tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

For benign and low-grade brain tumors, gross total resection remains the primary goal. However, RT may be used in select cases, such as when total resection is not possible, when a more conservative surgical approach may be necessary to achieve long-term treatment goals, and when atypical tumors may need RT even after gross total resection to reduce the risk of local recurrence. Therefore, RT, either definitive or in the postoperative adjuvant setting, remains an integral component in the management of residual, recurrent, and/or progressive benign and low-grade brain tumors for maximizing local control.⁸

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with benign brain tumors.

Interventions
The therapy being considered is IMRT. Radiotherapy is an integral component of treating many brain tumors, both benign and malignant. Intensity-modulated radiotherapy is a method that allows adequate radiation to the tumor while minimizing the dose to surrounding normal tissues and critical structures. Intensity-modulated radiotherapy also allows additional radiation to penetrate specific anatomic areas simultaneously, delivering radiation at a larger target volume.

Comparators
The following practice is currently being used to treat benign brain tumors: 3D-CRT.

Outcomes
The general outcomes of interest are OS, DSS, functional outcomes, and treatment-related adverse events. A proposed benefit of IMRT is to reduce toxicity to adjacent structures, allowing dose escalation to the target area and fewer breaks in treatment courses due to a reduction in side effects. However, this may come with a loss of locoregional control and OS due to the factors discussed above. The time frame for outcome measures varies from short-term management of toxicity and symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Case Series
The evidence for the use of IMRT in patients with benign brain tumors consists mostly of case series. Previously discussed dosimetry studies, which evaluated patients with malignant brain tumors, should be generalizable to patients with benign tumors.

Milker-Zabel et al. (2007) reported on results of treatment of complex-shaped meningiomas at the skull base with IMRT.⁹ Ninety-four patients received RT as primary treatment (n = 26), for residual disease after surgery (n = 14), or after local recurrence (n = 54). Tumor histology, classified using the World Health Organization (WHO), was grade 1 in 54.3%, grade 2 in 9.6%, and grade 3 in 4.2%. Median follow-up was 4.4 years. The overall local tumor control rate was 93.6%. After IMRT, 69 patients had stable disease (by computed tomography [CT] or magnetic resonance imaging [MRI]), and 19 had a tumor volume reduction. Six patients had local tumor progression on MRI at a median of 22.3 months after IMRT. In 39.8% of patients, preexisting neurologic deficits improved. Treatment-induced loss of vision was seen in 1 of 53 re-irradiated patients, with a grade 3 meningioma 9 months after retreatment with IMRT.

Mackley et al. (2007) reported on outcomes of treating pituitary adenomas with IMRT.¹⁰ A retrospective chart review was conducted on 34 patients treated between 1998 and 2003. Median follow-up was 42.5 months. Radiographic local control was 89% and, among patients with secretory tumors, 100% had a biochemical response. One patient required salvage surgery for disease progression, resulting in a clinical PFS of 97%. One patient who received more than 46 Gy experienced optic neuropathy 8 months after radiation.

Sajja et al. (2005) reported on outcomes for 35 patients with 37 meningiomas treated with IMRT.¹¹ Tumor histology was benign in 35 tumors and atypical in 2 tumors. The median CT with MRI follow-up was 19.1 months (range, 6.4 to 62.4 months). Fifty-four percent of the meningiomas had received surgery or radiosurgery before IMRT, and 46% were treated with IMRT, primarily after diagnosis was established by CT or MRI. Three patients had local failure after treatment. No long-term complications from IMRT were documented among the 35 patients.

Rogers et al. (2020) published a more recent case series that included 57 patients with new or recurrent meningioma (WHO Grade 2 or 3) treated with 60 Gy high dose and 54 Gy low dose IMRT following resection. Three-year PFS was 58.8% and OS at a mean follow-up of 4 years was 78.6%. Serious adverse events were rare (1.9%).¹²

Section Summary: Benign Brain Tumors
The evidence on IMRT for treating benign brain tumors includes case series. Case series results have consistently shown low radiation toxicity but have not demonstrated better tumor control or improved survival with IMRT versus other RT techniques. The dose-planning studies evaluating IMRT in patients with malignant tumors should generalize to patients with benign brain tumors because the benefit of minimizing radiation toxicity to sensitive brain areas is identical.

Brain Metastases
Clinical Context and Therapy Purpose
The purpose of IMRT to avoid hippocampal exposure in individuals who have brain metastases is to provide a treatment option that is an alternative to or an improvement on existing therapies. Intensity-modulated radiotherapy can deliver additional radiation boosts to specific metastases concurrent with whole-brain radiotherapy (WBRT). Clinicians have treated patients using this RT technique rather than treating them separately with WBRT and stereotactic radiosurgery (SRS), the latter having been shown to be more effective than WBRT alone in an RCT.

Brain metastases occur in up to 40% of adults with cancer and can shorten survival and detract from the quality of life. Many patients who develop brain metastases will die of progressive intracranial disease. Among patients with good performance status, controlled extracranial disease, favorable prognostic features, and solitary brain metastasis, randomized studies have shown that surgical excision followed by WBRT prolongs survival.⁴ Stereotactic radiosurgery can replace surgery in certain circumstances, delivering high single doses to discrete metastases.⁴ For bulky cerebral metastases, level 1 evidence has also shown that delivering a higher radiation dose with an SRS boost is beneficial in addition to standard WBRT. The use of a concomitant boost with IMRT during WBRT has been attempted to improve overall local tumor control without the use of SRS to avoid additional planned radiation after WBRT ("phase 2" or SRS) and its additional labor and expense.⁴ Another indication for the use of IMRT in WBRT is to avoid radiation exposure to the hippocampus. It is thought that avoiding the hippocampus may minimize cognitive decline associated with WBRT.

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with brain metastases.

Interventions
The therapy being considered is IMRT to avoid hippocampal exposure.

Comparators
The following practice is currently being used to treat benign brain metastases: WBRT.

Outcomes
The general outcomes of interest are OS, DSS, functional outcomes, and treatment-related adverse events. A proposed benefit of IMRT is to reduce toxicity to adjacent structures, allowing dose escalation to the target area and fewer breaks in treatment courses due to a reduction in side effects. However, this may come with a loss of locoregional control and OS due to the factors discussed above. The time frame for outcome measures varies from short-term management of toxicity and symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Studies
Dosimetry studies have previously established techniques that avoided radiation exposure to this region but still provided coverage and conformality to the remaining brain. Dosimetry studies alone have not been sufficient to establish IMRT as a standard treatment because the toxic effects of radiation on the hippocampus are less well established.

Brown et al. (2020) reported results from a phase III trial of 518 patients with brain metastases that assessed the comparative effectiveness of hippocampal-avoiding WBRT (HA-WBRT) using IMRT with conventional WBRT; both groups received memantine.¹³ Study inclusion criteria required that patients have no brain metastases outside a 5-mm margin around either hippocampus (Table 1). The primary outcome was time to loss of cognitive function, though OS and toxicity were also reported. After a mean 8-months follow-up, HA-WBRT was associated with a reduced loss of cognitive function (adjusted hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95) without any difference between groups in OS (HR, 1.13; 95% CI, 0.90 to 1.41) (Table 2). Specifically, at 4-month follow-up, the HA-WBRT showed less loss of executive function (23.3% vs. 40.4%; p = .01), while at 6 months, there was less decline in learning (11.5% vs. 24.7% ; p = .049) and memory (16.4% vs. 33.3% ; p = .02) in the HA-WBRT group. At 6 months, patients in the HA-WBRT plus memantine arm reported less difficulty with remembering things (mean, 0.16 vs. 1.29; p = .01) and less difficulty speaking (mean, 20.20 vs. 0.45; p = .049) compared with the WBRT plus memantine arm. There was no difference between groups in quality of life at any time point, nor was there a difference between groups in grade 3 or higher toxicity. The study authors noted that the treatment was likely to be most effective in patients with > 4 months expected survival, due to cognitive deterioration likely to occur in those with shorter expected survival. This trial indicates evidence of benefit of HA-WBRT versus WBRT on cognitive outcomes (absolute risk difference, 10%) and there were no differences in toxicity, intracranial PFS, or OS.

The study has some limitations. At 4-month follow up, only about half of the enrolled participants in both groups provided data for the individual cognitive assessments, because a large proportion of the participants had died. This was also the time point at which a clear difference emerged between groups showing a lower risk of cognitive failure in the HA-WBRT group. In addition, a significantly higher proportion of those allocated to HA-WBRT did not receive treatment: 10.7% (28/261) compared to 3.1% (8/257) in the WBRT group (p = .0016). Study limitations are further described in Table 3.

Table 1. Summary of Randomized Controlled Trial Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Brown et al. (2020); NRG Oncology CC001 (Phase 3)13	U.S., Canada	220	2015-2018	Adults with brain metastases outside a 5-mm margin around either hippocampus; Karnofsky performance score ≥70; pathologically proven diagnosis of solid tumor malignancy. Prior resection or radiosurgery was allowed.	N = 261 HA-WBRT: Bilateral hippocampal contours were manually generated on a fused thin-slice MRI-CT image set and expanded by 5 mm to generate the HA region + 30 Gy in 10 fractions) + memantine (5 to 7mg/day titrated to 20 to 28 mg/day)	N = 257 WBRT (30 Gy in 10 fractions) + memantine (5 to 7 mg/day titrated to 20 to 28 mg/day)

Gy: gray; HA: hippocampal-avoiding; MRI-CT: magnetic resonance imaging-computed tomography; WBRT: whole-brain radiotherapy. 

Table 2. Summary of Key Randomized Controlled Trial Results

Study; Trial	Cognitive failure, cumulative incidence, 12 months	Overall survival	Quality of Life	Grade ≥3 adverse event
Brown et al. (2020); NRG Oncology CC001 (Phase 3)13	N = 518	N = 518	N = 135	N = 433
HA-WBRT + memantine	117/261 (44.8%)	144/261 (55.2%)	5.34 (SD, 21.80)	124/211 (58.8%)
WBRT + memantine	142/257 (55.2%)	150/257 (58.4%)	3.18 (SD, 24.98)	137/222 (61.7%)
HR/Diff/RR (95% CI)	unadjusted HR, 0.76 (95% CI, 0.60 to 0.98)1 adjusted HR, 0.74 (95% CI, 0.58 to 0.95) ARD, -0.10 (95% CI, -0.19 to -0.02)	HR, 1.13 (95% CI, 0.90 to 1.41)	MD, 2.16 (95% CI, -5.73 to 10.05)1	RR, 0.95 (95% CI, 0.82 to 1.11)1

ARD: absolute risk difference; CI: confidence interval; HA-WBRT: hippocampal-avoiding whole body radiation; HR: hazard ratio; MD: mean difference; RR: relative risk; SD: standard deviation.
¹ Calculated estimate based on available data.

Table 3. Study Design and Conduct Limitations

Study	Allocation	Blinding	Selective Reporting	Data Completeness	Power	Statistical
Brown et al. (2020); NRG Oncology CC001 (Phase 3)13	--	1. Due to the nature of the treatment, blinding was deemed not possible. However, assessors were blinded for the cognitive outcome.	--	1. The proportion of patients withdrawing from the study in the first 6 months ranged from 14% to 27%; the study protocol adjusted for missing data using imputation	--	3. Risk estimates were not reported for individual timepoints for the primary outcome "time to cognitive failure"; Risk estimates not reported for quality of life outcome or harms

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician. 3. Blinding unclear
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Nonrandomized Comparative Studies
Gondi et al. (2014) evaluated IMRT as a method to avoid radiation exposure to the hippocampus and prevent adverse cognitive events in patients receiving WBRT.¹⁴ The Gondi et al. (2014) study was a prospective trial with a prespecified comparison to a historical control group derived from a previously conducted clinical trial. The outcomes were standardized cognitive assessments, and health-related quality of life evaluated at baseline and 2 month intervals (out to 6 months). Of 100 eligible patients, 42 patients were evaluable at 4 months; 17 patients were alive but did not have cognitive testing, and 41 had died. The mean decline in the primary cognitive endpoint was 7.0%, which was significantly less than the 30% decline in the historical control group (p < .001). Median survival in the experimental group was 6.8 months and 4.9 months in the historical control group. Although the trial results suggested that hippocampal-sparing WBRT using IMRT is associated with less cognitive decline, the historical control design adds uncertainty to the conclusion. Because the experimental group had survived longer, even though the radiation dose was intended to be equivalent to the historical control, possible unmeasured patient factors associated with better survival may have also caused less cognitive decline. The trial did not provide conclusive evidence that hippocampal-sparing IMRT causes less cognitive decline.

Case Series
A retrospective study by Zhou et al. (2014) evaluated the feasibility of WBRT plus simultaneous integrated boost with IMRT for inoperable brain metastases of non-small-cell lung cancer.¹⁵ Twenty-nine non-small-cell lung cancer patients with 87 inoperable brain metastases were included. All patients received WBRT at a dose of 40 Gy and simultaneous integrated boost with IMRT at a dose of 20 Gy concurrent with WBRT in week 4. Prior to each fraction of image-guided IMRT boost, online positioning verification and correction were used to ensure that the set-up errors were within 2 mm by cone beam CT in all patients. The 1-year intracranial control rate, local brain failure rate (BFR), and distant BFR were 63%, 14%, and 19%, respectively. The 2-year intracranial control rate, local BFR, and distant BFR were 42%, 31%, and 36%, respectively. Both the median intracranial PFS and the median OS were 10 months; 6-month, 1-year, and 2-year OS rates were 66%, 41%, and 14%, respectively. Patients had better survival rates when their Score Index for Radiosurgery in Brain Metastases was greater than 5, when they had fewer than 3 intracranial lesions, and when they had a history of epidermal growth factor receptor tyrosine kinase inhibitor treatment. Radiation necrosis was observed in 3 (3.5%) lesions after RT. Grades 2 and 3 cognitive impairment with grade 2 radiation leukoencephalopathy were observed in 4 (14%) patients. No dosimetric parameters were found to be associated with these late toxicities. Patients who received epidermal growth factor receptor tyrosine kinase inhibitor treatment had higher incidences of grades 2 and 3 cognitive impairment with grade 2 leukoencephalopathy. This evidence would suggest WBRT plus simultaneous integrated boost with IMRT is a tolerable treatment for non-small-cell lung cancer patients with inoperable brain metastases. However, the evidence does not permit conclusions about efficacy.

Section Summary: Brain Metastases
For the treatment of brain metastases, IMRT has been investigated as a technique to avoid hippocampal radiation exposure when delivering WBRT and to deliver additional radiation to specific areas of the brain as a substitute for SRS. Evidence from randomized and nonrandomized studies found IMRT associated with better cognitive outcomes versus WBRT and historical controls. Evidence regarding improvements in other health outcomes is not definitive.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2012 Input
In response to requests, input was received from 3 specialty medical societies (8 reviewers) and 3 academic medical centers (3 reviewers) while this policy was under review in 2012. There was a near-uniform consensus that intensity-modulated radiotherapy (IMRT) to treat central nervous system tumors should be considered medically necessary, particularly for tumors in close proximity to critical structures. Reviewers considered the evidence sufficient that IMRT is regarded equally effective as 3-dimensional conformal radiotherapy (3D-CRT). Further, given the possible adverse events that could result if nearby critical structures receive toxic radiation doses (e.g., blindness), IMRT dosimetric improvements should be accepted as meaningful evidence for its benefit.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines on Central Nervous System Cancers ( v.1.2024) support the use of highly conformal fractionated radiotherapy (RT) techniques (e.g., IMRT) to "spare critical structures and uninvolved tissue."¹⁶ When RT is given to patients with low-grade gliomas, NCCN states that "every attempt should be made to decrease the RT dose outside the target volume. This can be achieved with 3-dimensional (3D) planning or IMRT, with improved target coverage and normal brain/critical structure sparing often shown with IMRT." The guideline also states that for high-grade gliomas: "conformal RT (CRT) techniques, which include 3D-CRT and IMRT are recommended for performing focal brain irradiation. IMRT often will provide superior dosimetric target coverage and better sparing of critical structures than 3D-CRT."

For patients with brain metastases and a prognosis of 4 months or longer, the guidelines recommend hippocampal-sparing WBRT and memantine during and after WBRT for a total of 6 months.¹⁶ The guidelines did not include recommendations for the use of IMRT to treat high-grade tumors as well as limited or extensive metastases to the central nervous system.

American Society for Radiation Oncology
In 2022, the American Society for Radiation Oncology (ASTRO) authored a white paper on safety considerations for IMRT.¹⁷ Many topics related to IMRT program quality are addressed, but there is no guidance about patient selection for IMRT.

Also in 2022, the ASTRO authored a guideline on managing grade 2 and grade 3 diffuse glioma with isocitrate dehydrogenase mutations.¹⁸ Intensity-modulated radiotherapy/volumetric modulated arc therapy (VMAT) was strongly recommended in this population to reduce toxicity, especially for tumors listed near organs at risk (low quality of evidence). If IMRT/VMAT is not available, 3-D CRT is strongly recommended (moderate quality of evidence).

A 2016 model policy from ASTRO on IMRT states that IMRT is considered reasonable and medically necessary when sparing the surrounding tissue is beneficial.¹⁹ Primary, metastatic, or benign tumors of the central nervous system (including brain, brain stem, and spinal cord) are listed as clinical indications that frequently support the use of IMRT, as well as medically necessary irradiation. The list of clinical scenarios that do not support the use of IMRT includes situations when IMRT does not offer an advantage over conventional or 3-D CRT, or in cases that are too urgent to allow for the planning that is required before administering IMRT.

American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Section on Tumors
In 2020, the American Association of Neurological Surgeons and Congress of Neurological Surgeons Joint Section on Tumors sponsored a systematic review and evidence-based clinical practice guideline update on the role of radiation therapy in the treatment of adults with newly diagnosed glioblastoma multiforme.²⁰ Among the 14 clinical questions that were examined, 1 question was specific for the use of IMRT: "In adult patients with newly diagnosed supratentorial glioblastoma is image-modulated RT or similar techniques as effective as standard regional RT in providing tumor control and improved survival?" The authors reviewing the clinical data concluded that: "There is no evidence that IMRT is a better RT delivering modality when compared to conventional RT in improving survival in adult patients with newly diagnosed glioblastoma. Hence, IMRT should not be preferred over the conventional RT delivery modality."

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished or ongoing trials that might influence this review are listed in Table 4.

Table 4. Summary of Key Trials

NCT No.	Trial Name		Planned Enrollment	Completion Date
Ongoing
NCT04397679	Treatment of Adults With Newly Diagnosed Glioblastoma With Partial Brain Radiation Therapy Plus Temozolomide and Chloroquine Followed by Tumor Treating Fields Plus Temozolomide and Chloroquine -- A Pilot Study		2	Apr 2026
NCT02635009	Randomized Phase II/III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small Cell Lung Cancer		418	Apr 2027
NCT04801342	Neurocognitive Outcome of Conformal Whole Brain Radiotherapy With Bilateral or Unilateral Hippocampal Avoidance Plus Memantine for Brain Metastases: A Phase II Single Blind Randomized Trial		72	Feb 2025
Unpublished
NCT02147028	A Randomized Phase II Trial of Hippocampal Sparing Versus Conventional Whole Brain Radiotherapy After Surgical Resection or Radiosurgery in Favourable Prognosis Patients With 1-10 Brain Metastases		23	Feb 2021

NCT: national clinical trial.

References:  

1. Misher C. Radiation Therapy: Which type is right for me? Updated March 15, 2024. https://www.oncolink.org/cancer-treatment/radiation/introduction-to-radiation-therapy/radiation-therapy-which-type-is-right-for-me. Accessed June 10, 2024.
2. Amelio D, Lorentini S, Schwarz M, et al. Intensity-modulated radiation therapy in newly diagnosed glioblastoma: a systematic review on clinical and technical issues. Radiother Oncol. Dec 2010; 97(3): 361-9. PMID 20926149
3. Fuller CD, Choi M, Forthuber B, et al. Standard fractionation intensity modulated radiation therapy (IMRT) of primary and recurrent glioblastoma multiforme. Radiat Oncol. Jul 14 2007; 2: 26. PMID 17629934
4. MacDonald SM, Ahmad S, Kachris S, et al. Intensity modulated radiation therapy versus three-dimensional conformal radiation therapy for the treatment of high grade glioma: a dosimetric comparison. J Appl Clin Med Phys. Apr 19 2007; 8(2): 47-60. PMID 17592465
5. Narayana A, Yamada J, Berry S, et al. Intensity-modulated radiotherapy in high-grade gliomas: clinical and dosimetric results. Int J Radiat Oncol Biol Phys. Mar 01 2006; 64(3): 892-7. PMID 16458777
6. Paulsson AK, McMullen KP, Peiffer AM, et al. Limited margins using modern radiotherapy techniques does not increase marginal failure rate of glioblastoma. Am J Clin Oncol. Apr 2014; 37(2): 177-81. PMID 23211224
7. Xiang M, Chang DT, Pollom EL. Second cancer risk after primary cancer treatment with three-dimensional conformal, intensity-modulated, or proton beam radiation therapy. Cancer. Aug 01 2020; 126(15): 3560-3568. PMID 32426866
8. Gupta T, Wadasadawala T, Master Z, et al. Encouraging early clinical outcomes with helical tomotherapy-based image-guided intensity-modulated radiation therapy for residual, recurrent, and/or progressive benign/low-grade intracranial tumors: a comprehensive evaluation. Int J Radiat Oncol Biol Phys. Feb 01 2012; 82(2): 756-64. PMID 21345610
9. Milker-Zabel S, Zabel-du Bois A, Huber P, et al. Intensity-modulated radiotherapy for complex-shaped meningioma of the skull base: long-term experience of a single institution. Int J Radiat Oncol Biol Phys. Jul 01 2007; 68(3): 858-63. PMID 17379447
10. Mackley HB, Reddy CA, Lee SY, et al. Intensity-modulated radiotherapy for pituitary adenomas: the preliminary report of the Cleveland Clinic experience. Int J Radiat Oncol Biol Phys. Jan 01 2007; 67(1): 232-9. PMID 17084541
11. Sajja R, Barnett GH, Lee SY, et al. Intensity-modulated radiation therapy (IMRT) for newly diagnosed and recurrent intracranial meningiomas: preliminary results. Technol Cancer Res Treat. Dec 2005; 4(6): 675-82. PMID 16292888
12. Rogers CL, Won M, Vogelbaum MA, et al. High-risk Meningioma: Initial Outcomes From NRG Oncology/RTOG 0539. Int J Radiat Oncol Biol Phys. Mar 15 2020; 106(4): 790-799. PMID 31786276
13. Brown PD, Gondi V, Pugh S, et al. Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001. J Clin Oncol. Apr 01 2020; 38(10): 1019-1029. PMID 32058845
14. Gondi V, Pugh SL, Tome WA, et al. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. Dec 01 2014; 32(34): 3810-6. PMID 25349290
15. Zhou L, Liu J, Xue J, et al. Whole brain radiotherapy plus simultaneous in-field boost with image guided intensity-modulated radiotherapy for brain metastases of non-small cell lung cancer. Radiat Oncol. May 21 2014; 9: 117. PMID 24884773
16. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Central Nervous System Cancers. Version 1.2024. Updated May 31, 2024. https://www.nccn.org/professionals/physician_gls/PDF/cns.pdf. Accessed June 10, 2024.
17. Moran JM, Bazan JG, Dawes SL, et al. Quality and Safety Considerations in Intensity Modulated Radiation Therapy: An ASTRO Safety White Paper Update. Pract Radiat Oncol. 2023; 13(3): 203-216. PMID 36710210
18. Halasz LM, Attia A, Bradfield L, et al. Radiation Therapy for IDH-Mutant Grade 2 and Grade 3 Diffuse Glioma: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol. 2022; 12(5): 370-386. PMID 35902341
19. ASTRO Model Policy - Intensity Modulated Radiation Therapy (IMRT). https://www.astro.org/ASTRO/media/ASTRO/Daily%20Practice/PDFs/IMRTMP.pdf. Accessed June 10, 2024.
20. Ziu M, Kim BYS, Jiang W, et al. The role of radiation therapy in treatment of adults with newly diagnosed glioblastoma multiforme: a systematic review and evidence-based clinical practice guideline update. J Neurooncol. Nov 2020; 150(2): 215-267. PMID 33215344

Coding Section

Codes	Number	Description
CPT	77301	Intensity modulated radiotherapy plan, including dose volume histograms for target and critical structure partial tolerance specification
	77338	Multi-leaf collimator (MLC) device(s) for intensity modulated radiotherapy (IMRT), design and construction per IMRT plan
	77385	Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple
	77386	complex
HCPCS	G6015	Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session
	G6016	Compensator-based beam modulation treatment delivery of inverse planned treatment using 3 or more high resolution (milled or cast) compensator, convergent beam modulated fields, per treatment session
ICD-10-CM	C71.0-C71.9	Malignant neoplasm of brain, code range
	C72.0-C72.9	Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system, code range.
	C79.31-C79.32	Secondary malignant neoplasm of brain and cerebral meninges, code range
	C79.40-C79.49	Secondary malignant neoplasm of other and unspecified parts of nervous system, code range
	D33.0-D33.2	Benign neoplasm of brain series
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services
	D0000ZZ, D0001ZZ, D0002ZZ, D0010ZZ, D0011ZZ, D0012ZZ	Radiation oncology, brain or brain stem, beam radiation, codes by anatomical location and modality (photons < 1 MeV, photons 1-10 MeV and photons > 10 MeV)
Type of service	Radiology
Place of service	Inpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2024 Forward     

09/11/2024	Annual review, no change to policy intent. Updating rationale and references.
01/01/2024	New Policy