**_Overview_**

**_Intensity Modulated Radiation Therapy (IMRT)_**

IMRT is a form of 3D conformal radiation therapy (3D-CRT) that changes the
intensity of radiation within different parts of single radiation beams while
the treatment is delivered. Thus, IMRT can simultaneously treat multiple areas
within the target to different dose levels. It most commonly utilizes 5, 7, or
9 treatment beams from different directions, with each field being from a
stationary direction, but in which the radiation output varies across the
field with time of irradiation. IMRT is especially useful in radiating
treatment targets positioned near other normal tissues that need exposure to
be minimized.

Volumetric modulation arc radiotherapy (VMAT) is a form of IMRT in which the
radiation source moves in an arc around the patient while delivering the
radiation treatment. VMAT delivery is more efficient and can be given in half
the usual time as compared to IMRT.

IMRT utilizes a treatment-planning technique called inverse planning. IMRT
treatment plans are tailored to the target volumes and are more precise than
conventional or CRT plans. Through a computerized optimization process, the
physicist or dosimetrist enters the anatomic information of tumors and organs
at risk (OARs), as detailed by the radiation oncologist, specifies the desired
dosimetric outcome and its constraint for each structure of interest and then
lets the computerized treatment-planning system identify the best beam
orientation and intensity pattern over the treatment fields. After inverse
planning, an optimized treatment plan is developed.

Delivery of IMRT may be done with various combinations of gantry motion, table
motion, slice-by-slice treatment (tomotherapy) and multi-leaf collimator (MLC)
or solid compensators to modulate the beam or arc intensities.

The treatment plan for IMRT must be carefully followed with each session. The
required precision and accuracy exceed that of conventional RT. The radiation
team of oncologists, medical physicists, medical dosimetrists and radiation
therapists must be well-coordinated. Drawbacks to IMRT include the potential
for dose heterogeneity within a specific structure. This heterogeneity is the
trade-off for improved dose conformity. Also, IMRT involves an increased
"integral dose" resulting from unintended radiation outside the intended
treatment volumes due to the use of multiple, fixed fields or rotating arcs.
The long-term risk of second malignancies from this integral dose is still
unclear.1

**_Stereotactic Radiosurgery (SRS)_**

SRS combines anatomic accuracy and reproducibility with very high doses of
highly precise, externally generated ionizing radiation to optimally ablate or
eradicate the target(s) in the head while minimizing collateral damage to
adjacent tissues. "Stereotactic" means a target lesion is localized relative
to a known 3-dimensional (3D) reference system. Markers might be used on or in
the body such as seeds, clips, or surface markers. Devices used in SRS for
stereotactic guidance could include rigid head frames affixed to the patient,
fixed bony landmarks, implanted fiducial markers, or mask-based systems.
Imaging, planning and treatment typically are performed in close temporal
proximity. The delivery of a high dose of ionizing radiation that conforms to
the shape of the lesion mandates an overall accuracy of approximately 1 mm. To
assure quality of patient care, the procedure involves a multidisciplinary
team consisting of a neurosurgeon, radiation oncologist, medical physicist,
and radiation therapist. For some tumors involving the skull base, the
multidisciplinary team may include a head and neck surgeon with training in
SRS.

All SRS procedures include the following: position stabilization with or
without a frame, imaging for localization, computer-assisted tumor
localization (i.e., "image guidance"), treatment planning, isodose
distributions/dose prescription/dose calculation, setup and accuracy
verification testing, simulation of prescribed arcs or fixed portals, and
radiation delivery.

**_Stereotactic Body Radiation Therapy (SBRT)_**

__

SBRT is also known as stereotactic ablative radiotherapy (SABR) or
ultrahypofractionated RT.

SBRT is a treatment that couples a high degree of anatomic targeting accuracy
and reproducibility with very high doses of extremely precise, externally
generated, ionizing radiation. The therapeutic intent of SBRT is to maximize
cell-killing effect on the target(s) while minimizing radiation-related injury
in adjacent normal tissues.

SBRT is used to treat extra-cranial sites as opposed to SRS, which is used to
treat intra-cranial and spinal targets. Treatment of extra-cranial sites,
excluding the spinal cord and related spinal structures, requires accounting
for internal organ motion as well as for patient motion. Thus, reliable
immobilization or repositioning systems must often be combined with devices
capable of decreasing organ motion or accounting for organ motion, e.g.,
respiratory gating. Additionally, all SBRT is performed with at least 1 form
of image guidance to confirm proper patient positioning and tumor localization
prior to delivery of each fraction.

SBRT may be delivered in 1 to 5 sessions (fractions). Each fraction requires
an identical degree of precision, localization and image guidance. Since the
goal of SBRT is to intensify the potency of the radiotherapy by completing an
entire course of treatment within an extremely accelerated time frame, any
course of radiation treatment extending beyond 5 fractions is not considered
SBRT.

Inverse treatment planning is used for IMRT/SRS/SBRT and involves multiple
steps1,2,3:

  1. For SRS procedures, position stabilization would be needed via a patient affixed frame or a stereotactic mask fixation system (frameless). 
  2. Imaging: 3D image acquisition of the target area by simulation using computed tomography (CT), magnetic resonance (MR), positron emission tomography (PET) or similar image fusion technology is done. Usually, CT images will serve as the baseline image set for dose calculations. With IMRT or SBRT, when respiratory or organ motion is expected during radiation delivery, multi-phasic treatment planning imaging sets might also be done. 
  3. Contouring: This is done in multiple steps and defines the target and avoidance. The radiation oncologist reviews the 3D images and outlines the treatment target on each image slice. The sum of these contours equals the gross tumor volume (GTV). If SRS is being planned, the neurosurgeon may also be involved in the contouring process. Next, a margin may also be drawn around the GTV (if no previous surgical treatment has occurred) to also include areas at risk for microscopic disease. This is the clinical target volume (CTV). And then, to account for daily patient set-up variation and motion issues, a final may be added to create a planning target volume (PTV). Any combination of these volumes may be contoured depending on the clinical scenario and treatment intent. Proximate normal structures that could be harmed (OARs) must also be contoured.
  4. Prescription: The radiation oncologist prescribes specific radiation doses. Usually, a prescribed dose must be given to at least 90-95% of the PTV. There is often a dose constraint describing an acceptable range of dose homogeneity. Dose constraints for the OARs should be present as an upper limit of mean dose and/or a maximum allowable point dose and/or a critical volume of the OAR that must not receive a dose above a certain limit. Prescribed doses to targets and OARs should maximize disease control and minimize radiation injury risk to normal tissue.
  5. Dosimetric Planning, Calculations and Verification: The physicist or supervised dosimetrist will calculate a multiple static beam and/or modulated arc treatment plan to deliver the prescribed radiation doses to the PTV and also meet OAR dose constraints. Dose volume histograms must be prepared for the PTV and OARs. Continuously moving MLCs are used to deliver the optimized modulated radiation doses to the tumor and nearby organs within that patient. The distinguishing feature of an IMRT plan is that it demonstrates how treatment with non-uniform beam intensities will be delivered. Basic dose calculations are done on each of the modulated beams or arcs in order to verify the computerized calculations. The calculated beams or arcs are delivered to a phantom or a dosimetry measuring device to confirm the intended dose will be accurate and that delivery will be technically feasible. For SRS, the quality assurance must be quite stringent to ensure dose delivery within 1 mm accuracy.

*** WHEN INVERSE TREATMENT PLANNING IS PERFORMED AND THAT PLAN IS UTILIZED,
THE RADIATION ONCOLOGIST OR PHYSICIST MUST DOCUMENT THAT FACT. [Despite
notations of optimization or use of certain computerized systems or other
data, it is still necessary for the type of treatment planning either
conventional forward planning or inverse planning to be specifically
documented. Collaboration with one's electronic medical record vendor is
strongly recommended to help support meeting this documentation requirement.]

Image-guided radiation therapy (IGRT) uses imaging to maximize accuracy and
precision throughout the process of full treatment delivery, not just during
treatment planning. It is particularly applicable to highly conformal
treatment modalities, such as CRT and IMRT. With SBRT and SRS, IGRT is
considered a necessary and integral component of the entire procedure. IGRT
techniques might use onboard kilovoltage radiation imaging, cone beam CT
scanning, MRI or ultrasound alone or in combination. This allows smaller
margins to account for day-to-day differences in positioning of the patient.
It is often used in conjunction with IMRT and other advanced forms of RT. IGRT
would typically be used with tumors in areas that move such as the lungs,
liver, pancreas, cervix and prostate. Marked obesity in conjunction with deep
tumors in the abdomen, pelvis or mediastinum might require the help of IGRT.
The medical necessity for the imaging modality and frequency must be assessed
and documented for each patient. If applicable, the methods used to minimize
organ motion should be documented.

**COVERAGE GUIDANCE**

This limited LCD pertains to various types of RT treatment approaches.

**_Indications and Limitations of Coverage and/or Medical Necessity_**

**_IMRT_**

IMRT is clinically indicated when highly conformal dose planning is required
to spare normal surrounding tissue as a specific clinical benefit to that
individual beneficiary.

Based on medical necessity, disease sites that may support the use of IMRT
include the following:

  * Primary, metastatic or benign tumors of the central nervous system (CNS) including the brain, the brain stem, and spinal cord
  * Primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated
  * Primary, metastatic, benign or recurrent head and neck malignancies, with treatment directly impacting the orbits, paranasal sinuses, skull base, aero-digestive tract-nasopharynx, oropharynx, hypopharynx, and larynx/glottic areas, salivary glands, oral cavity, nasal cavity
  * Thoracic malignancies
  * Abdominal malignancies when dose constraints to small bowel or other normal abdominal tissue are exceeded
  * Pelvic malignancies including: prostatic, gynecologic and anal carcinomas
  * Other pelvic or retroperitoneal malignancies
  * Reirradiation that meets the requirements for medical necessity and which is duly documented

Documentation of the medical necessity for each unique, individual beneficiary
is crucial for allowing coverage and must include the following (please see
the related billing and coding article for further detail):

  * The specific diagnosis and target volume requiring IMRT; the total dose and dose per fraction
  * The type of treatment planning used must be specified (i.e., forward or inverse)
  * The specific prior history of any RT related to site and total dose
  * A narrative statement documenting the special need for IMRT rather than conventional or 3D RT relating to the individual specific beneficiary

Medical necessity documentation for IMRT should include 1 or more of the
following clinical scenarios:

  *     * An immediately adjacent area has been previously irradiated and highly precise planning is needed for the current therapy with abutting portals
    * Dose escalation is planned to deliver radiation doses exceeding those commonly used for similar tumors with conventional treatment
    * The target volume is concave or convex, and the critical normal tissues are within or around that convexity or concavity
    * The target volume is very close to critical structures that must be protected
    * The volume of interest must be covered with narrow margins to adequately protect immediately adjacent structures

  * With claimed delivery of prescribed IMRT, an easily identified, authenticated dose prescription must be present along with clearly labeled, color comparative treatment plans which include the dose volume histograms. Toward this requirement, collaboration with one's electronic medical record vendor is strongly recommended.

Other malignancies not delineated above as potentially covered could be
considered for coverage with submission of documentation for medical necessity
should a denial occur. The determination of appropriateness and medical
necessity for IMRT for any site shall be found in the documentation from the
radiation oncologist and must be available when requested or submitted in the
appeals process.

**Limitations of Coverage:**

****

IMRT is not considered reasonable and necessary when at least 1 of the above
criteria relating to medical necessity are not documented as present.

Clinical scenarios that would not typically support the use of IMRT include:

  * When conventional or CRT techniques can deliver good clinical outcomes and low toxicity
  * In clinically urgent scenarios such as spinal cord compression, superior vena cava syndrome or airway obstruction
  * For palliative treatment of metastatic disease where the prescribed dose does not approach normal tissue tolerances
  * Inability to allow for organ motion, such as for a mobile lung tumor
  * For a patient who cannot cooperate or who cannot tolerate immobilization to achieve accurate and reproducible delivery of doses

**Non-Coverage**

At this juncture, the following treatment is not considered reasonable and
necessary due to insufficient evidence-based support:

  * IMRT used in conjunction with proton beam RT61

**_SRS_**

__

SRS may be considered medically reasonable and necessary for the following
indications:

  1. Primary CNS malignancies, generally used as a boost or salvage therapy for lesions under 5 cm
  2. As a boost treatment for larger cranial or spinal lesions that have been treated initially with external beam RT or surgery (e.g., sarcomas, chondrosarcomas, chordomas, and nasopharyngeal or paranasal sinus malignancies)
  3. Primary and secondary tumors involving the brain parenchyma, meninges/dura, or immediately adjacent bony structures. For new brain metastases, the patient must have a documented Karnofsky Performance Status (KPS) score _>_ 70% or an Eastern Cooperative Oncology Group (ECOG) status score of 0-2, be absent of leptomeningeal metastases, and not have a primary diagnosis of a lymphoma, germ cell tumor or small cell carcinoma. For repeat brain metastases therapy, the patient must have a KPS score _>_ 70% or ECOG of 0-2, no leptomeningeal metastases, stable extra-cranial disease on restaging studies done within the prior 2 months, and a life expectancy of > 6 months. (In the case of brain metastases, this contractor will not attempt to calculate the performance scale score based on information pieced together from the record; the numeric scale specific score and the life expectancy must be documented in the patient's record. Please see the additional information below under _**Associated Information**_ and **_Sources of Information_** for KPS and ECOG scoring information.)
  4. Benign brain tumors such as meningiomas, acoustic neuromas of Grade 3 or less, other schwannomas, pituitary adenomas, pineocytomas, craniopharyngiomas, glomus tumors, and hemangioblastomas
  5. Cranial arteriovenous malformations (AVMs) and cavernous malformations
  6. __ Trigeminal neuralgia, medically refractory epilepsy, severe Parkinson's disease movement disorder, or severe and quality of life (QOL) impacting essential tremor that has not been responsive to medical management with at least 2 different agents at optimal doses. (The precise therapies, durations offered and responses to each therapy must be documented in the medical record.) __
  7. Uveal or ocular melanoma
  8. Relapse in a previously irradiated cranial field where the additional stereotactic precision is required to avoid unacceptable vital tissue radiation

**Limitations of Coverage:**

SRS is not considered reasonable and necessary under the following clinical
circumstances:

  * When functional improvement is not expected
  * When directed toward anything other than a severe symptom or serious threat to life or critical functions
  * When clinically meaningful stabilization of the disease is not expected
  * When other treatment could result in equally meaningful functional improvement or clinical stabilization
  * Patients with poor performance status (KPS score < 40 or ECOG score > 3)
  * Patients with widespread cerebral or extra-cranial metastases with limited life expectancy

**_SBRT_**

**__**

SBRT may be considered medically reasonable and necessary for the following
indications:

  1. Primary malignant tumors and tumors metastatic to the lung when the following criteria are met: 
    * Early stage primary tumors in medically inoperable patients, OR
    * Recurrent early stage lung cancer in medically inoperable patients, OR
    * Early stage primary tumors in high operative risk patients, OR
    * Limited metastatic disease, good performance status, and the intention is eradicating all known active disease or greatly reducing the total disease burden in a manner that can extend progression-free survival (PFS).
  2. Primary tumors and tumors metastatic to the liver when the following criteria are met: 
    * Primary tumors when the patient is not a surgical candidate, OR
    * Limited metastatic disease, good performance status, and the intention is eradicating all known active disease or greatly reducing the total disease burden in a manner that can extend PFS.
  3. Primary tumors and tumors metastatic to the kidney when the following criteria are met: 
    * Primary tumors when the patient is not a surgical candidate, OR
    * Limited metastatic disease, good performance status, and the intention is eradicating all known active disease or greatly reducing the total disease burden in a manner that can extend PFS.
  4. Primary tumors and tumors metastatic to the adrenal gland when the following criteria are met: 
    * Primary tumors when the patient is not a surgical candidate, OR
    * Limited metastatic disease, good performance status, and the intention is eradicating all known active disease or greatly reducing the total disease burden in a manner that can extend PFS.
  5. Primary tumors and tumors metastatic to the pancreas when the following criteria are met: 
    * Primary tumors when the patient is not a surgical candidate, OR
    * Limited metastatic disease, good performance status, and the intention is eradicating all known active disease or greatly reducing the total disease burden in a manner that can extend PFS.
  6. For treatment of pelvic and head and neck tumors that have recurred after primary irradiation when the following criteria are met: 
    * The patient's general medical condition (namely, the performance status) justifies aggressive, curative treatment to a primary, non-metastatic cancer, OR
    * Metastatic disease requiring palliation cannot be treated by conventional methods due to proximity of adjacent prior irradiated volumes and other measures are not appropriate or safe for the particular patient, OR
    * The patient's general medical condition (namely, the performance status) justifies aggressive local therapy to 1 or more deposits of metastatic cancer in an effort either to achieve total disease clearance in the setting of oligometastatic disease or to reduce the patient's overall burden of systemic disease for a specifically defined clinical benefit, AND
    * The targeted tumor(s) can be completely encompassed with acceptable risk to nearby critical normal structures.
  7. Low- to intermediate-risk prostate cancer without a need for pelvic nodal irradiation (if nodal irradiation is needed, that area should be managed with conventional radiation fractions due to the risk for toxicity)
  8. Bone metastases in the vertebral bodies or the paraspinous region where extra care must be taken to avoid excess irradiation of the spinal cord when tumor-ablative doses are administered and when the following criteria are met: 
    * Limited metastatic disease, good performance status, and the intention is eradicating all known active disease or greatly reducing the total disease burden in a manner that can extend PFS.
  9. Tumors arising in or near previously irradiated regions when a high level of precision and accuracy is required to minimize the risk of injury to surrounding normal tissues. (Medical records must describe the specific circumstances unique to the beneficiary.)
  10. Tumors requiring a high dose per fraction treatment above the level obtainable with other methods of RT. (Medical records must describe the specific circumstances unique to the beneficiary.) __

**Limited coverage:**

****

  * SBRT of clinically localized prostate cancer or a primary spinal tumor may be covered on an individual case by case basis.
  * For all SBRT therapy, the patient's general medical condition (per the documented performance status scale score) must be sufficient to reasonably justify aggressive SBRT therapy to the primary or metastatic tumor. (For this purpose, an ECOG or KPS score must be documented and updated as necessary. These scales are noted under _**Associated Information**_ section of this LCD.)

There is a genuine distinction between patients with primary or secondary
tumors for whom curative intent or at least marked reduction in total disease
burden that will extend PFS is sought vs those patients with metastatic
disease in need of palliation. Palliative RT, when needed, can generally be
accomplished with much less technically complex and more conventional
approaches than SBRT.

**Non-covered:**

****

  * Primary treatment of lesions of bone, breast, uterus, ovary and other internal organs not listed above as covered are not considered medically necessary.
  * Treatment that is unlikely to result in clinical cancer control and/or functional improvement
  * The tumor burden cannot be completely targeted with acceptable risk to nearby critical structures
  * Patients with poor performance status scores (a KPS score < 40 or an ECOG status of 3 or worse)

The evolution of IMRT technology has demonstrated improved clinical outcomes
to the point that many disease sites need to be considered as potentially
appropriate for this therapy. Professional society and national clinical
guidelines create the foundation for this LCD's limited coverage related to
evidence-based RT approaches.

Sources for this coverage LCD, such as American Society for Therapeutic
Radiology and Oncology (ASTRO) and National Comprehensive Cancer Network
(NCCN), have compiled many peer-reviewed publications which report clinical
outcomes for these therapies related to cancer type and disease site. These
publications have thus informed those credible specialty organization model
policies and guidelines. In turn, these model policies and guidelines have all
been reviewed for purposes of creating a foundation for this coverage LCD.

The ASTRO Model Policies for IMRT, SRS, and SBRT1,2,3 address coverage and
limitations based on a review of available literature.

**_IMRT Evidence Review_**

**__**

_Anal Cancer_

__

American College of Radiology (ACR) Appropriateness Criteria states that in
terms of the dosage of ionizing radiation, IMRT can reduce the dose to normal
structures and is associated with decreased acute toxicity when compared to
CRT for anal carcinoma. They recommend IMRT use as "usually appropriate" if
given outside of a protocol setting and note that further evaluations are
underway.4

NCCN guidelines for the treatment of anal carcinoma state that IMRT is
preferred over 3D-CRT, citing benefits of reduced toxicity while maintaining
local control (LC) in multiple studies (2021).5

_Breast Cancer_

__

Jagsi et al6 conducted a randomized controlled trial (RCT) comparing IMRT and
deep inspiration breath hold (DIBH) vs standard, free-breathing, forward-
planned, 3D-CRT in individuals with left-sided, node-positive breast cancer in
whom the internal mammary nodal region was targeted. The purpose of the study
was to determine whether using these technologies reduces cardiac or pulmonary
toxicity during breast RT. Endpoints included dosimetric parameters and
changes in pulmonary and cardiac perfusion and function, measured by single
photon emission computed tomography (SPECT) scans and pulmonary function
testing performed at baseline and 1 year post treatment. Of 62 patients
randomized, 54 who completed all follow-up procedures were analyzed. Mean
doses to the ipsilateral lung, left ventricle, whole heart, and left anterior
descending coronary artery were lower with IMRT-DIBH; the percent of left
ventricle receiving 5 Gy averaged 15.8% with standard RT and 5.6% with IMRT-
DIBH. SPECT revealed no differences in perfusion defects in the left anterior
descending coronary artery territory, the study's primary endpoint, but did
reveal statistically significant differences (P=0.02) in left ventricular
ejection fraction (LVEF), a secondary endpoint. No differences were found for
lung perfusion or function. The authors concluded that this study suggests a
potential benefit in terms of preservation of cardiac ejection fraction among
patients with left-sided disease in whom the internal mammary region was
targeted. Future studies are essential, including comparative evaluation of
outcomes and the impact of advances in radiation treatment planning and
delivery, in order to inform and shape clinical practice and policy.

NCCN guidelines for breast cancer state that greater target dose homogeneity
and sparing of normal tissues can be accomplished using compensators such as
wedges, forward planning using segments and IMRT. Respiratory control
techniques and prone positioning may be used to try to further reduce dose to
adjacent normal tissues, particularly the heart and lungs (2021).7

_Central Nervous System (CNS) Tumors_

__

In its CNS Cancers guideline, NCCN states that lower doses of targeted
conformal RT (including 3D-CRT and IMRT) are recommended for treatment of low-
grade anaplastic gliomas, infiltrative astrocytomas, oligodendrogliomas,
glioblastomas and meningiomas. Higher doses of RT are found to be no more
effective than lower doses. For medulloblastomas, the guidelines state that
for patients at average risk, a regimen of IMRT or proton craniospinal
irradiation (CSI) alone or with chemotherapy are both viable treatment options
(2021).8

_Cervical Cancer_

__

Tsuchida et al9 conducted a retrospective cohort analysis to compare clinical
outcomes and toxicity incidence among patients diagnosed with cervical cancer
that underwent radical hysterectomy and were treated with either 3D-CRT or
IMRT. Concurrent chemotherapy was not given during the study. Outcomes of
interest included gastrointestinal (GI), genitourinary (GU) and hematologic
(HT) toxicities, and overall survival (OS), disease-free survival (DFS) and
loco-regional control (LRC). A total of 73 patients (33 received 3D-CRT and 40
received IMRT) were included in the final analysis. The median follow-up
period differed between the group with 82 months in the 3D-CRT group and 50
months in the IMRT group (P<0.001). After 4 years, there was no difference OS
or DFS between the groups. Loco-regional recurrence was more frequent in
patients with vaginal invasion reported in the post-operative pathological
report (17% vs 2.3%; P=0.033). GI obstruction was more frequent in the group
that received 3D-CRT vs IMRT (27% vs 7.5%; P=0.026) and surgical intervention
for the obstruction was higher in the 3D-CRT group as well (18% vs 0%;
P=0.005). There was no significant difference in acute GI, GU or HT
toxicities; however, in the IMRT group, there were fewer late toxicities, GI
2 (P=0.026) and GU G2 (P=0.038). The authors concluded that their results
show that IMRT could reduce the incidence of late severe GI obstruction and
that additional studies are warranted.

Lin et al10 conducted a meta-analysis to compare the efficacies and toxicities
of IMRT with 3D-CRT or 2D-RT for definitive treatment of cervical cancer. A
search for relevant studies was conducted using PubMed, the Cochrane Library,
Web of ScienceTM, and Elsevier. Outcomes of interest included OS, DFS, and
acute and chronic toxicities. The literature review yielded 2,808 publications
and after screening and review, a total of 6 articles, with 1,008 participants
(350 IMRT and 658 CRT) were included in the final analysis. Three-year OS and
3-year DFS revealed no significant differences between IMRT and 3D-CRT or
2D-RT (3-year OS: OR, 2.41, CI, 0.62 to 9.39, p=0.21; 3-year DFS: OR, 1.44,
95% CI, 0.69 to 3.01, p=0.33). The incidence of acute GI toxicity and GU
toxicity in patients who received IMRT was significantly lower than that in
the control group (GI: Grade 2: OR, 0.5, 95% CI, 0.28 to 0.89, p=0.02; Grade 3
or higher: OR, 0.55, 95% CI, 0.32 to 0.95, p=0.03; GU: Grade 2: OR, 0.41, 95%
CI, 0.2 to 0.84, p=0.01; Grade 3 or higher: OR, 0.31, 95% CI, 0.14 to 0.67,
p=0.003). Furthermore, patients who received IMRT experienced fewer incidences
of chronic GU toxicity than patients in the control group (Grade 3: OR, 0.09,
95% CI, 0.01 to 0.67, p=0.02). The authors concluded that IMRT and CRT
demonstrated equivalent efficacy in terms of 3-year OS and DFS, and that IMRT
significantly reduced acute GI and GU toxicities as well as chronic GU
toxicity in patients with cervical cancer.

Mell et al11 conducted an international, multicenter, single-arm phase II
clinical trial (NCT01554397, still ongoing) to evaluate the incidence of HT
and GI toxicities in patients with stage IB-IVA, biopsy-proven invasive
carcinoma of the cervix among patients who were treated with IMRT. All 83
patients received daily IMRT concurrently with weekly cisplatin for 6 weeks,
with an intracavitary brachytherapy boost given at completion of the
chemoradiation regimen. Additionally, the researchers conducted a subgroup
analysis on whether the use of PET-based image-guided IMRT (IG-IMRT) had an
influence on the development of neutropenia compared to standard IMRT. Post-
simple hysterectomy patients were included, initiating the regimen within 8
weeks of surgery. Individuals who underwent radical hysterectomy with
extensive nodal involvement were excluded. Primary outcome measures were
either acute grade 3 neutropenia or clinically significant GI toxicity
occurring within 30 days of regimen completion. The median follow-up was 26
months. The incidence of any primary event was 26.5%, significantly less than
the 40% hypothesized in historical data. The incidence of grade 3 neutropenia
and clinically significant GI toxicity was 19.3% and 12.0%, respectively. In
the analysis on neutropenia, those treated with IG-IMRT (n=35) had a
significantly lower incidence (8.6%) compared with the 48 patients who
received standard IMRT (27.1%). The differences in the incidence of grade 3
leukopenia and any grade 3 HT toxicity were considered insignificant between
the 2 types of IMRT delivery. The authors concluded that IMRT, compared with
standard therapy, reduces both acute HT events and GI toxicity and that PET-
based IG-IMRT reduces the incidence of acute neutropenia compared with
historical data.

In a 2020 ASTRO Cervical Cancer Guideline, Chino et al recommended IMRT for
women with cervical cancer treated with postoperative RT with or without
chemotherapy to decrease acute and chronic toxicity (strength of
recommendation: strong). For women with cervical cancer treated with
definitive RT with or without chemotherapy, IMRT is conditionally recommended
to decrease acute and chronic toxicity.12

NCCN guidelines for cervical cancer13 state that IMRT and similar highly
conformal methods of dose delivery may be helpful in minimizing the dose to
the bowel and other critical structures in the post-hysterectomy setting, in
treating the para-aortic nodes when necessary, and when high doses are
required to treat gross regional lymph nodes disease. IMRT should not be used
as a routine alternative to brachytherapy for treatment of central disease in
patients with an intact cervix. Very careful attention to detail and
reproducibility is required for proper delivery (2021).

_Endometrial Cancer_

__

Klopp et al14 conducted a multicenter, phase III RCT (NCT01672892, still
ongoing) to evaluate patient reported acute toxicity and QOL in patients with
invasive cervical or endometrial cancer and treated with standard 4 field
pelvic RT or pelvic IMRT. The primary end point, change in acute GI toxicity,
was measured at baseline and end of RT (5 weeks) using the bowel domain of the
Expanded Prostate Cancer Index Composite (EPIC). The secondary endpoints,
measured at the same points in time, were change in GU toxicity and the extent
to which it interfered with daily activities. To measure GU toxicity, the
urinary domain of the EPIC was used and to determine the extent to which GU
toxicity impacted daily activities, the Patient Reported Outcomes-Common
Terminology Criteria for Adverse Events (PRO-CTCAE), Functional Assessment of
Cancer Therapy-General (FACT-Cx), Functional Assessment of Cancer Therapy -
General (FACT-G) and Trial Outcome Index were used. A total of 278 patients
were included in the final analysis, 149 received standard RT and 129 received
IMRT. Compared to baseline, the standard RT arm had larger mean EPIC bowel and
urinary score declines compared with the IMRT arm (-26.3 vs -18.6; P=0.05 and
-10.4 vs -5.3, P=0.03, respectively). The FACT-Cx mean scores showed a decline
of 4.9 points in the standard RT group vs 2.7 points in the IMRT group
(P=0.015). There was no difference between the arms in the FACT-G subscale or
Trial Outcome Index scores. In addition, the PRO-CTCAE results showed that at
the end of therapy, more patients in the standard RT arm experienced diarrhea
frequently or almost constantly compared with the IMRT arm (51.9% vs 33.7%,
respectively; P=0.01) and were taking antidiarrheal medications 4 or more
times daily (20.4% vs 7.8%, respectively; P=0.04). The authors concluded based
on the patient's perspective, pelvic IMRT was associated with significantly
less acute GI and urinary toxicity.

Wahl et al15 developed consensus guidelines on adjuvant radiotherapy for
early-stage endometrial cancer from a multidisciplinary expert panel convened
by the ACR. Per the ACR appropriateness criteria, IMRT has been shown to
reduce dose to critical structures in dosimetric studies, and retrospective
reviews of IMRT for early-stage endometrial cancer have shown excellent LC
rates, with low GI toxicity rates. The ACR appropriateness criteria for
advanced stage endometrial cancer states IMRT may further improve treatment of
areas at risk for tumor recurrence while sparing adjacent normal tissues. The
authors note that several studies of IMRT for gynecologic malignancies showed
that, compared with external beam pelvic RT, IMRT improved target coverage,
reduced the volume of normal tissues receiving the prescription dose, and that
the reduction in dose resulted in a decrease in both acute and chronic GI side
effects compared with historic controls.

_Esophageal Cancer_

__

Xu et al16 performed a systematic review and meta-analysis to compare IMRT and
3D-CRT in the treatment of esophageal cancer (EC) via analysis of dose-volume
histograms and survival/toxicity outcomes. Overall, 7 studies were included.
Of them, 5 studies (80 patients) were included in the dosimetric comparison, 3
studies (871 patients) were included in the OS analysis, and 2 studies (205
patients) were included in the irradiation toxicity analysis. For lungs and
hearts, the average irradiated volumes of IMRT were less than those from
3D-CRT. IMRT resulted in a higher OS than 3D-CRT. However, no significant
difference was observed in the incidence of radiation pneumonitis and
radiation esophagitis between the 2 radiotherapy techniques.

NCCN guidelines for esophageal and esophagogastric junction cancers17 state
that IMRT is appropriate in clinical settings where reduction in dose to OAR
(e.g., heart and lungs) is required that cannot be achieved by 3D techniques
(2021).

_Head and Neck Cancer_

Gupta et al18 compared long-term disease-related outcomes and late radiation
morbidity between IMRT and 3D-CRT in head and neck squamous cell carcinoma
(HNSCC) in a prospective RCT. The primary endpoint was the incidence of
physician rated acute salivary gland toxicity (grade 2). Secondary endpoints
included other acute toxicity (mucositis, dermatitis, dysphagia), late
radiation morbidity, patterns of failure, loco-regional disease status, and
OS. Patients (n=60) who were previously untreated and had early to moderately
advanced non-metastatic squamous carcinoma of the oropharynx, larynx, or
hypopharynx planned for comprehensive irradiation of primary site and
bilateral neck nodes were randomly assigned to either IMRT or 3D-CRT.
Treatment consisted of 6MV photons to a total dose of 70 Gy/35 fractions over
7 weeks (3D-CRT) or 66 Gy/30 fractions over 6 weeks (IMRT). At a median
follow-up of 140 months for surviving patients, 10-year Kaplan-Meier estimates
of locoregional control (LRC), PFS, and OS with 95% confidence interval were
73.6%, 45.2%, and 50.3% respectively. There were no significant differences in
10-year disease-related outcomes between 3D-CRT and IMRT for LRC 79.2% vs
68.7%; PFS 41.3% vs 48.6%; or OS 44.9% vs 55.0%. Significantly lesser
proportion of patients in the IMRT arm experienced  grade 2 late xerostomia
and subcutaneous fibrosis at all time-points. At longer follow-up, fewer
patients remained evaluable for late radiation toxicity reducing statistical
power and precision. The authors concluded IMRT provides sustained clinically
meaningful benefit compared to 3D-CRT in reducing the late morbidity of
radiation without compromising disease-related outcomes in long-term survivors
of non-nasopharyngeal HNSCC. Limitations include lack of blinding to treatment
arm and small study size with even much lesser numbers on long-term follow-up
(between 5 and 10 years).

In 2018, the International Lymphoma Radiation Oncology Group conducted a
literature review and developed guidelines covering staging, work-up, and RT
management of patients with plasma cell neoplasms. With a localized
plasmacytoma in the bone or in extramedullary (extraosseous) soft tissues,
definitive RT is the standard treatment. It provides long-term LC in solitary
bone plasmacytomas and is potentially curative in the extramedullary cases. On
the basis of comparative treatment planning (comparison dose-volume histogram)
and determination of the priority of the OARs to protect, the radiation
oncology team should make a clinical judgment as to which treatment technique
to use. In some situations, more conformal techniques such as IMRT, helical-
IMRT, or VMAT approaches may offer significantly better sparing of critical
normal structures, usually at the cost of a larger total volume of normal
tissue irradiated, but with a lower dose.19

Nutting et al20 assessed whether parotid-sparing IMRT reduced the incidence of
severe xerostomia, a common late side effect of RT to the head and neck.
Ninety-four patients with pharyngeal squamous cell carcinoma were randomly
assigned to receive IMRT (n=47) or CRT (n=47). The primary endpoint was the
proportion of patients with grade 2 or worse xerostomia at 12 months. Median
follow-up was 44 months. Six patients from each group died before 12 months; 7
patients from the CRT and 2 from the IMRT group were not assessed at 12
months. At 12 months, xerostomia side effects were reported in 73 of 82
patients. Grade 2 or worse xerostomia at 12 months was significantly lower in
the IMRT group (38%) than in the CRT group (74%). The only recorded acute AE
of grade 2 or worse that differed significantly between the treatment groups
was fatigue, which was more prevalent in the IMRT group. At 24 months, grade 2
or worse xerostomia was significantly less common with IMRT than with CRT. At
12 and 24 months, significant benefits were seen in recovery of saliva
secretion with IMRT compared with CRT, as were clinically significant
improvements in dry-mouth-specific and global QOL scores. At 24 months, no
significant differences were seen between randomized groups in non-xerostomia
late toxicities, LRC or OS. The authors concluded that sparing the parotid
glands with IMRT significantly reduces the incidence of xerostomia and leads
to recovery of saliva secretion and improvements in associated QOL.

NCCN guidelines for head and neck cancers state that IMRT is appropriate and
may offer clinically relevant advantages to spare important OARs, such as
brain, brain stem, cochlea, semicircular canals, optic chiasm, cranial nerves,
retina, lacrimal glands, cornea, spinal cord, brachial plexus, mucosa,
salivary glands, bone, pharyngeal constrictors, larynx, esophagus, and
decrease the risk for late, normal tissue damage and toxicity while still
achieving the primary goal of local tumor control (2022).21

_Hippocampal-Avoidance Whole Brain Radiation Therapy (HA-WBRT)_

__

Brown et al22 conducted a phase III trial to determine if hippocampal
avoidance using IMRT during whole-brain radiotherapy (WBRT) preserves
cognition. Between July 2015 and March 2018, 518 patients were randomly
assigned to 2 groups, 1 group with brain metastases to HA-WBRT plus memantine,
and 1 group with WBRT plus memantine. Time to cognitive function failure,
defined as decline using the reliable change index on at least 1 of the
cognitive tests was the primary endpoint. OS, intracranial PFS, toxicity, and
patient-reported symptom burden, were secondary endpoints. Median follow-up
for alive patients was 7.9 months. Risk of cognitive failure was significantly
lower after HA-WBRT plus memantine vs WBRT plus memantine (adjusted hazard
ratio, 0.74; 95% CI, 0.58 to 0.95; P=0.02). This difference was attributable
to less deterioration in executive function at 4 months, and learning and
memory at 6 months. Treatment arms did not differ significantly in OS,
intracranial PFS, or toxicity. At 6 months, using all data, patients who
received HA-WBRT plus memantine reported less fatigue (P=0.04), less
difficulty with remembering things (P=0.01), and less difficulty with speaking
(P=0.049) and using imputed data, less interference of neurologic symptoms in
daily activities (P=0.008) and fewer cognitive symptoms (P=0.01). The authors
concluded HA-WBRT plus memantine effectively spares the hippocampal
neuroregenerative niche to better preserve cognitive function and patient-
reported symptoms and should be considered a standard of care for patients
with good performance status who plan to receive WBRT for brain metastases
with no metastases in the HA region. Additionally, no differences were
observed in intracranial PFS, toxicity, or OS. Limitations include lack of
blinding.

The American Society of Clinical Oncology (ASCO)/Society for NeuroOncology
(SNO)/ASTRO guidelines for patients with brain metastases from solid tumors
recommends memantine and hippocampal avoidance should be offered to patients
who receive WBRT, and have no hippocampal lesions, and 4 months or more
expected survival. Patients with asymptomatic brain metastases with either KPS
 50 or KPS < 70 with systemic therapy options do not derive benefit from
RT.23

NCCN guidelines for CNS cancers state that HA-WBRT (plus memantine) 30 Gy in
10 fractions is preferred for patients with a better prognosis (4) and no
metastases within 5 mm of the hippocampi (2021).8

_Mediastinal Tumors_

__

Besson et al24 evaluated toxicities secondary to different RT modalities and
the evolution of those modalities in the treatment of mediastinal tumors
associated with Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL). Between 2003
and 2015, 173 individuals with Stage I-III nodal lymphoma were treated at a
single institution with either 3D-CRT or IMRT as part of a chemoradiotherapy
protocol (HL=64, NHL=5). Of interest, between 2003 and 2006, 16 patients were
treated by 3D-CRT vs zero patients treated by IMRT. Between 2007-2009, 16
patients were treated by 3D-CRT vs 1 patient receiving IMRT. Between 2010-
2015, 19 patients were treated by IMRT, and zero received 3D-CRT. All patients
were followed for 5 years alternately by a radiation oncologist or a
hematologist. Results demonstrated LC at 100% in both groups and acute (grade
1 or 2) toxicities of 55% and 71.4% with IMRT vs 3D-CRT, respectively. Authors
concluded that the use of IMRT as an improved RT technique over 3D-CRT has
promoted the evolution of improved acute and late outcomes for HL and NHL
patients. Longer follow-up is necessary to evaluate very late toxicities, as
this study only evaluated acute (grade 1 and 2) toxicities.

NCCN guidelines for lymphomas state that advanced RT technologies, such as
IMRT, breath hold or respiratory gating, and/or IGRT or Proton Beam Therapy
(PBT), may offer significant and clinically relevant advantages in specific
instances to spare OAR and decrease the risk for late, normal tissue damage
while still achieving the primary goal of local tumor control. Randomized
studies to test these concepts are unlikely to be done since these techniques
are designed to decrease late effects which take 10+ years to evolve.
Therefore, the guidelines recommend that RT delivery techniques that are found
to best reduce the doses to the OAR in a clinically meaningful way without
compromising target coverage should be considered in these patients, who are
likely to enjoy long life expectancies following treatment (2022).25

NCCN guidelines for thymomas and thymic carcinomas state that RT should be
given by 3D conformal technique to reduce surrounding normal tissue damage
(e.g., heart, lungs, esophagus, spinal cord). The guideline states that since
these patients are younger and mostly long-term survivors, the mean total dose
to the heart should be as low as reasonably achievable to potentially maximize
survival. IMRT is preferred over 3D-CRT and may further improve the dose
distribution and decrease the dose to the normal tissue as indicated (2022).26

_Non-Small Cell Lung Cancers (NSCLC), Stage III_

NCCN guidelines for NSCLC state that in a prospective trial of
definitive/consolidative chemo/RT for patients with stage III NSCLC (RTOG
0617), IMRT was associated with a nearly 60% decrease in high-grade radiation
pneumonitis as well as similar survival and tumor control outcomes despite a
higher proportion of stage IIIB and larger treatment volumes compared to
3D-CRT; as such, IMRT is preferred over 3D-CRT in this setting (2022).27

_Pancreatic Cancer_

__

Bittner et al28 conducted a systematic review to determine whether toxicities
can be reduced by using IMRT rather than 3D-CRT in patients with pancreatic
cancer, and to compare OS and PFS between the 2 techniques. A search for
relevant studies was conducted using PubMed/Medline. Outcomes of interest
included details regarding the therapy given, acute and late toxicities, and
patient survival (OS and PFS). A total of 13 IMRT and 7 3D-CRT studies were
included in the final analysis. For acute toxicities, nausea and vomiting 
grade 3 were 13.4% (109/747 patients) vs 7.8% (35/446 patients) for 3D-CRT and
IMRT, respectively (p<0.001). Late toxicities were predominantly GI:
toxicities  grade 3 were 10.6% (22/207) and 5.0% (19/381), for 3D-CRT and
IMRT, respectively (p=0.017). However, those were mainly attributed to the
group of patients with GI bleeding/duodenal ulcer. There were no differences
in HT, OS and PFS between the 2 techniques. The authors concluded that when
comparing 3D-CRT and IMRT in the treatment of pancreatic cancer, there is no
significant differences in OS and PFS, however; treatment-related toxicities
(i.e., nausea, vomiting, diarrhea and late GI toxicity) are significantly
reduced with IMRT.

ASTRO's 2019 clinical practice guideline states that modulated treatment
techniques such as IMRT and VMAT for planning and delivery of both
conventionally fractionated and hypofractionated RT are recommended for
treatment of localized pancreatic cancer (Strength of recommendation:
Strong).29

NCCN guidelines for pancreatic adenocarcinoma state that IMRT with breath
hold/gating techniques can result in improved PTV coverage with decreased dose
to OAR. IMRT is increasingly being applied in treatment of locally advanced
pancreatic adenocarcinoma and in the adjuvant setting with the aim of
increasing radiation dose to the gross tumor while minimizing toxicity to
surrounding tissues. There is no clear consensus on appropriate maximum dose
of radiation when IMRT is used (2021).30

_Prostate Cancer_

__

Viani et al31 compared IMRT with 3D-CRT for the treatment of prostate cancer
through a randomized, phase III clinical trial (NCT02257827). In total, 215
patients were enrolled in the study, randomly selected into the IMRT group
(n=109) or the 3D-CRT group (n=106). Primary outcome measures included early
and late GU and GI toxicities as well as freedom from biochemical failure,
determined through use of Phoenix criteria (PSA + 2 ng/mLnadir). The median
follow-up period was 3 years. The 3D-CRT arm reported incidences of grade  2
acute GU and GI toxicities at 27% and 24%, respectively, compared with 9% and
7%, respectively, in the IMRT group. In assessing the rate of grade 2 late GU
and GI toxicities spanning the entire follow-up period, the 3D-CRT group
reported 12.3% and 21%, respectively, compared to the IMRT arm which reported
3.7% and 6.4%, respectively. The 5-year rate of freedom from biochemical
failure was 95.4% in the IMRT arm and 94.3% in the 3D-CRT arm (P=0.678). The
authors concluded that the use of IMRT resulted in significantly less acute
and late toxicities than 3D-CRT when used in the treatment of prostate cancer.

NCCN guidelines state that highly CRT, such as IMRT, should be used to treat
prostate cancer. IMRT significantly reduces the risk of GI toxicities and
rates of salvage therapy compared to 3D-CRT in some but not all older studies.
Moderately hypofractionated image guided IMRT regimens have been tested in
randomized trials with similar efficacy and toxicity to conventionally
fractionated IMRT in some studies, and they can be considered as an
alternative to conventionally fractionated regimens when clinically indicated
(2022).32

At the time of this evidence review, no evidence was identified in the
clinical literature supporting the combined use of IMRT and proton beam RT in
a single treatment plan.

**_SRS Evidence Review_**

**__**

SRS is limited to 1 to 5 fractions delivered to intracranial targets and
selected tumors around the base of the skull. According to the Skeie33
article, nearly all glioblastoma multiforme (GBM) patients suffer a relapse
after the initial treatment. In this study, 77 consecutive patients with
recurrent GBM treated with Gamma Knife surgery (GKS), reoperation, or both
were reviewed. Thirty-two patients were treated with GKS, 26 patients
underwent reoperation, and 19 patients were treated with both. Patients
treated with GKS at the time of tumor progression had significantly better
local tumor control and significantly longer survival than patients not
treated with GKS.

Three articles evaluated SRS for brain metastases. Yomo et al34 noted that
patients treated with SRS for limited brain metastases from small cell lung
cancer survived slightly more than 8 months following SRS. Although SRS
provided durable local tumor control, repeat treatment was required in nearly
half of the patients to control distant brain metastases. Soike et al35
conducted a review of nonrandomized prospective and retrospective data
supporting the use of SRS in patients with 4 or more brain metastases. The
absolute number of brain metastases was not as prognostic as other factors
such as the KPS, age, histology of the tumors, and presence of mutations that
could be targeted. WBRT has been the standard treatment for brain metastases.
However, new technology has allowed use of SRS to treat 4 or more brain
metastases, but there has been a lack of randomized evidence supporting its
use. The authors concluded the role of SRS in brain metastases should be
carefully considered on an individual basis. More multi-institutional trials
were recommended to determine whether SRS is the most appropriate treatment in
such patients. Badiyan et al36 noted that brain metastases are the most common
intracranial malignancy. Surgery and SRS are both commonly used to treat
patients with brain metastases. Surgery is preferred for patients with a
single brain metastasis. Surgery also has the advantage of treating metastases
greater than 4 cm and those that abut critical structures. SRS has the
advantage of being noninvasive, with the ability to treat multiple tumors
simultaneously. Some patients receive both treatments. SRS is also sometimes
used post operatively to treat the residual tumor cavity to decrease the risk
of local recurrence. Although the 2 treatments have never been compared in a
randomized trial, data point to potentially poorer LC with surgery alone. The
ASTRO SRS Model Policy does recommend coverage for metastatic brain lesions,
independent of the number of such lesions assuming other positive clinical
factors exist such as decent performance status and stable systemic disease.2

A systematic review and meta-analysis was performed to evaluate the safety and
efficacy of fractionated stereotactic radiotherapy (FSRT) and SRS for
pituitary adenomas.37 The authors concluded SRS and FSRT have comparable
clinical outcomes and are in agreement with current reviews in the literature.
FSRT and SRS have similar efficacy and safety profiles. In the Przybylowski38
study, a retrospective review was performed regarding SRS for acoustic
neuromas. It was concluded that SRS affords effective tumor control for
acoustic neuromas with an acceptable rate of hearing preservation. Koos grade
IV tumors were significantly less likely to respond to SRS than grades I to
III tumors and should be strongly considered for surgical resection when
possible. Two studies evaluated SRS for intracranial AVMs. Gupta et al39
conducted a retrospective review of 114 patients with intracranial AVMs
treated with the CyberKnife device. Interdisciplinary treatment regimens that
may involve endovascular embolization, surgical resection and SRS are
increasingly being used. The multimodal treatment approach is believed to
ensure obliteration of the AVM while minimizing AVM rupture. This article
presented single institution data on a series of patients whose AVMs proved
resistant to radiosurgery with the CyberKnife device over a 10-year period.
The average follow-up was over 7 years. The incidence of delayed hemorrhage
after CyberKnife treatment was 11 percent. Functional and clinical outcomes
after radiosurgery remained the same in most cases. Two thirds of these AVMs
were eventually completely obliterated at last imaging follow-up. Even AVMs
persisting for over 4 years following CyberKnife radiosurgery might
eventually obliterate, with or without adjunctive endovascular and/or
radiosurgical treatment. In the Ding40 article, 11 patients' diagnoses with
large localized cerebral AVMs were selected for multi-stage robotic SRS. The
CyberKnife and MultiPlan radiation delivery and treatment planning systems
were concluded to be practical for multi-stage SRS of large cerebral AVMs. The
ASTRO SRS Model Policy does recommend coverage for AVMs and cavernous
malformations; the evidence for SRS, particularly as part of a
multidisciplinary approach to assure success appears to be reasonable and
necessary.2

**_SBRT Evidence Review_**

**__**

The ASTRO Model Policy for SBRT3 addresses coverage and limitations based on a
review of available literature. SBRT is used to treat extracranial sites.
ASTRO also has an evidence-based guideline for SBRT for early stage NSCLC.63
It notes indications for SBRT in early stage lung cancer for medically
inoperable or high surgical risk patients and for patients with limited
metastatic disease, good performance status with the intention of eradicating
all known active disease or greatly reducing the total disease burden in a
manner that can extend PFS. Cao et al41 performed a systematic review and
meta-analysis of SBRT vs surgery for patients with NSCLC. The authors found
that current evidence suggests surgery is superior to SBRT in terms of mid-
and long-term clinical outcomes, but SBRT is associated with lower
perioperative mortality. It was also noted that the data on improved outcomes
after surgery might be skewed due to an imbalance of baseline characteristics.
Future studies were recommended that would confirm malignancy histopathology
and then compare SBRT with minimally invasive anatomical resections. Rosen et
al42 found that among healthy patients with clinical stage I NSCLC in the
National Cancer Database, lobectomy was associated with a significantly better
outcome than SBRT. This was also found in the Li43 article which noted a
superior OS and long-term distant control for early stage NSCLC after surgery
compared with SBRT after propensity score matching. Lischalk et al44 noted
SBRT in 5 fractions to a total dose of 35 or 40 Gy was a safe and effective
management strategy for high-risk central pulmonary metastatic lesions, though
care had to be taken to limit the maximum point dose to the mainstem bronchus.
In the Lodeweges45 article, pulmonary metastasectomy (PME) with clear margins
was compared to SABR. The authors found despite higher age and shorter
metastasis-free interval suggesting higher baseline risk for death after SABR,
unadjusted reanalysis at almost 6 years of follow-up actually did not support
that surgery for pulmonary oligometastases would result in better survival or
LC compared with SABR. Nikitas et al46 noted that patients who received either
synchronous or metachronous SBRT had no significant reduction in OS or
toxicity when compared to single-course patients.

Yeung et al47 looked at the use of SBRT in hepatocellular carcinoma (HCC).
They reported that SBRT provided good LC to small inoperable HCC. Also, SBRT
could be delivered safely even after previous liver-directed therapies. It
also did not preclude later additional alternative liver therapies. Although
overall 32 percent of patients experienced greater than or equal to 3 plus
toxicities, and 19 percent had a deterioration in Child-Pugh score of 2 or
more points, these changes were mainly transient. The authors noted that
excellent LC existed while disease progression outside of the irradiated site
was prominent. Further studies were urged to examine combined therapy
approaches to maximize disease control. The Onal48 study was designed to
evaluate the feasibility of SBRT to breast cancer metastasized to the liver.
They concluded SBRT was a conservative approach with excellent LC and limited
toxicities. The Brunner49 study is the largest reported series on SBRT in
cholangiocarcinoma. OS and LC were significantly improved after higher doses
and tolerance was excellent.

Francolini et al50 noted that surgical resection was the treatment of choice
for localized renal cell carcinoma (RCC) as nephron-sparing is so important.
But it was also noted that RCC patients are often unfit for surgery due to
multiple comorbidities. Therefore, active surveillance or ablative techniques
are often suggested. This author notes that SBRT might be considered as an
alternative treatment in these inoperable patients with primary RCC. Dose
escalation to 48 Gy in 3 to 4 fractions was effective and well tolerated.
Further studies to explore interactions between SBRT and immune therapy in the
approach to RCC.

Draulans et al51 finds that SBRT is a valid treatment option for patients with
low- and intermediate-risk prostate cancer. A study by King et al52 notes that
prostate specific antigen (PSA) relapse-free survival rates after SBRT
compared favorably with other definitive treatments for low- and intermediate-
risk patients. The authors concluded that current evidence supports
consideration of SBRT among the therapeutic options for low- and intermediate-
risk patients. Freeman et al53 reported 5-year results for SBRT in localized
prostate cancer demonstrating efficacy and safety for shorter course high
fraction dose SBRT. ASTRO/ASCO/AUA have published an evidence-based guideline
concerning hypofractionated RT for localized prostate cancer. Based on high-
quality evidence, strong consensus was reached for offering moderate
hypofractionation across risk groups to patients who opted to have external
beam RT. The task force only conditionally recommended ultrahypofractionated
radiation for low- and intermediate-risk prostate cancer. The task force
strongly encouraged treatment of intermediate-risk patients to occur within
the construct of a clinical trial or multi-institutional registry. And for
high-risk patients, the task force conditionally recommended against routine
use of ultrahypofractionated external beam RT.61

Zhan et al54 conducted a systematic review of the literature related to
treatment for spinal AVMs. The authors identified 11 studies associated with
radiosurgery or fractionated radiotherapy treatments for spinal vascular
malformations. Four were done at the same institution and included overlapping
patients. So there were truly 8 total articles that qualified. In this review,
microsurgery and transarterial embolization were the mainstays of treatment
for spinal AVMs. The use of SRS and fractionated radiotherapy for spinal AVM
management has very limited associated literature.

Yazici et al65 recently reported (2022) on long term results of retrospective
analysis regarding both stereotactic surgery and FSRT in 443 patients with 445
uveal melanomas who underwent CyberKnife treatment between 2007 and 2019. 70%
of the tumors were small/medium and 30% were large. The primary endpoints were
LC, local recurrence-free survival (LRFS), enucleation-free survival (EFS) and
treatment toxicity. After a median 74 month follow-up, SRS/FSRT demonstrated
an 83% overall LC rate. The 5- and 10-year LRFS rate was 74% and 56%
respectively. An increased dose was associated with higher LRFS and higher EFS
rates. Related toxicity was noted in 49% of the eyes. Overall eye preservation
rate was 62% and the 5- and 10-year EFS rate was 64% and 36% respectively. The
authors also noted that the delivery of FSRT every other day resulted in a
significantly lower rate of toxicity and enucleation compared to FSRT on
consecutive days. Akbaba et al64 retrospectively analyzed the clinical
outcomes, visual acuity and enucleation rates for 24 patients with primary
uveal melanoma who were treated with linear accelerator-based SFRT during a
period between 1991 and 2015. This therapy offered good LC rates with a local
PFS of 82% after 5 years. Of all local progressions, 80% happened within the
first 5 years post radiotherapy. In 1 case, enucleation was eventually needed.
EFS was related to the radiotherapy dose (p<0.0001). A 2-year sight
preservation rate of 75% was achieved which was comparable to brachytherapy or
PBT and which was available in small center. Six late toxicities were
observed. The ASTRO Model Policy for SRS2 does recommend coverage for uveal or
ocular melanoma. That policy lists numerous evidence-based resources
underlying that recommendation. While toxicity of RT to the eye is a concern,
the risk of enucleation is not remarkably higher with other therapy
approaches. Overall, the evidentiary support indicates that SRS is likely
reasonable and necessary.

Regarding PBT, ASTRO reviewed this treatment via its emerging technology
committee in 2012. Data was reviewed for PBT in CNS tumors, GI malignancies,
lung, head and neck, prostate and pediatric tumors. There was not sufficient
evidence to recommend it in lung cancer, head and neck cancer, and GI
malignancies. There did appear to be some efficacy for PBT in HCC and prostate
cancer, but there was no suggestion that it was superior to photon based
approaches. Investigation is ongoing for use of PBT in large ocular melanomas
and chordomas. More robust prospective clinical trials are needed to determine
the appropriate clinical setting for PBT.60

The literature supports the use of SRS for intracranial targets and lesions at
the base of the skull. The articles included primary brain tumors and
metastatic brain tumors. The studies also included pituitary adenomas,
acoustic neuromas and intracranial AVMs. Both NCCN and ASTRO model policies
were given weight regarding recommendations for potential coverage, if
reasonable and necessary, for a wide expanse of IMRT indications and for non-
cancer related diagnoses such as some refractory epilepsy, movement disorders
and essential tremor. Likewise, the ASTRO Model Policy recommended
consideration for potential coverage related to uveal melanoma indications was
accepted. The entirety of the ASTRO Model Policy was not incorporated into
this coverage LCD based on overall evidence review. For SBRT, the literature
supports its use for patients who are not surgical candidates and have early-
stage NSCLC, HCC, and RCC. The studies also supported low- and intermediate-
risk prostate cancer treatment. The studies were not felt to support SBRT for
spinal AVMs.

Particular attention was given to the use of SRS and SBRT in spinal cord tumor
treatment. While preliminary evidence suggests that SBRT and SRS may be
effective and safe for treating intradural and intramedullary spinal cord
disease, it is clear that surgical resection remains the best approach for
both primary and metastatic spinal cord lesions. Limited coverage, via this
LCD, is available regarding the common occurrence of vertebral metastases and
for spinal cord tumors that remain after resection or reside in or near
previously irradiated tissue. For primary spinal lesions, which certainly
encompass a large proportion of benign slow-growing tumors, the long-term
consequences of spinal injury secondary to RT impact might have much greater
impact in a setting with prolonged life expectancies. Again, it is quite
likely that primary surgical resection would be the better approach. Though
some guidelines and other literature have been published regarding spine
tumors and stereotactic RT, the accepted tolerance for radiation to the spinal
cord remains debated. Furthermore, all incidences of radiation-injury do not
necessarily correlate with the degree of stereotactic radiation intensity. The
risk of injury from RT is likely multifactorial. It is possible that
radiation-related injury is oversimplified when only the maximum tumor dose is
considered. A much greater understanding of the implications of radiation-
induced injury in the spine after SRS or SBRT is necessary and strong evidence
supporting these therapies in primary spinal nerve sheath tumors or
meningiomas or hemangioblastomas is judged insufficient.62