Description:
Radiotherapy may be an integral component of the treatment of cancers of the abdomen and pelvis. Intensity-modulated radiotherapy (IMRT) has been proposed as a method that allows adequate radiation to the tumor while minimizing the radiation dose to surrounding normal tissues and critical structures.

Background
Radiation Techniques
Over the past several decades, methods to plan and deliver radiotherapy (RT) have evolved in ways that permit more precise targeting of tumors with complex geometries. Most early trials used 2-dimensional treatment planning, based on flat images and radiation beams with cross-sections of uniform intensity that were sequentially aimed at the tumor along 2 or 3 intersecting axes. Collectively, these methods are termed conventional external-beam radiotherapy.

Three-Dimensional Conformal Radiotherapy
Treatment planning evolved by using 3-dimensional images, usually from computed tomography (CT) scans, to delineate the boundaries of the tumor and discriminate tumor tissue from adjacent normal tissue and nearby organs at risk for radiation damage. Computer algorithms were developed to estimate cumulative radiation dose delivered to each volume of interest by summing the contribution from each shaped beam. Methods also were developed to position the patient and the radiation portal reproducibly for each fraction and immobilize the patient, thus maintaining consistent beam axes across treatment sessions. Collectively, these methods are termed 3-dimensional conformal radiotherapy (3D-CRT).

Intensity-Modulated Radiotherapy
Intensity-modulated radiotherapy (IMRT), which uses computer software and CT and magnetic resonance imaging (MRI) images, offers better conformality than 3D-CRT, because it is able to modulate the intensity of the overlapping radiation beams projected on the target and to use multiple shaped treatment fields. Treatment planning and delivery are more complex, time consuming, and labor intensive for IMRT than for 3D-CRT. The technique uses a multileaf collimator [MLC]), which, when coupled with a computer algorithm, 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 thus may 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.

Technologic development has produced advanced techniques that may further improve RT treatment by improving dose distribution. These techniques are considered variations of IMRT. Volumetric modulated arc therapy (VMAT) delivers radiation from a continuous rotation of the radiation source. The principal advantage of VMAT 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.

IMRT methods to plan and deliver RT are not uniform. IMRT may use beams that remain on as MLCs move around the patient (dynamic MLC) or that are off during movement and turn on once the MLC reaches prespecified positions ("step and shoot" technique). A third alternative uses a very narrow single beam that moves spirally around the patient (tomotherapy). Each method uses different computer algorithms to plan treatment and yields somewhat different dose distributions in and outside the target. Patient position can alter target shape and thus affect treatment plans. Treatment plans are usually based on 1 imaging scan, a static 3D-CT image. Current methods seek to reduce positional uncertainty for tumors and adjacent normal tissues by various techniques. Patient immobilization cradles and skin or bony markers are used to minimize day-to-day variability in patient positioning. In addition, many tumors have irregular edges that preclude drawing tight margins on CT scan slices when radiation oncologists contour the tumor volume. It is unknown whether omitting some tumor cells or including some normal cells in the resulting target affects outcomes of IMRT.

Note the evidence for the following abdominal and pelvic cancers has not yet been reviewed and is beyond the scope of this document: bladder, kidney, ureter, and esophageal cancer and sarcoma.

Regulatory Status 
In general, intensity-modulated radiotherapy (IMRT) systems include intensity modulators, which control, block, or filter the intensity of radiation; and radiotherapy (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 Inc., Tempe, AZ) and decimal tissue compensator (Southeastern Radiation Products, Sanford, FL), 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.

RT treatment planning systems have also been cleared for marketing by FDA through the 510(k) process. These include the Prowess Panther (Prowess, Concord, CA) in 2003, TiGRT (LinaTech, Sunnyvale, CA) in 2009, and the Ray Dose (RaySearch Laboratories, Stockholm, Sweden). 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 FDA through the 510(k) process is the Varian IMRT system (Varian Medical Systems, Palo Alto, CA). FDA product code: IYE.

Related Policies
80147 Intensity-Modulated Radiation Therapy (IMRT) of the Prostate
80148 Intensity-Modulated Radiation Therapy (IMRT): Cancer of the Head and Neck or Thyroid
80159 Intensity-Modulated Radiotherapy: Central Nervous System Tumors

Policy:
Intensity-modulated radiation therapy may be considered MEDICALLY NECESSARY as an approach to delivering radiation therapy for patients with cancer of the anus/anal canal.

When dosimetric planning with standard 3-D conformal radiation predicts that the radiation dose to an adjacent organ would result in unacceptable normal tissue toxicity (see Policy Guidelines), intensity-modulated radiation therapy (IMRT) may be considered MEDICALLY NECESSARY for the treatment of cancer of the abdomen and pelvis, including but not limited to:

• stomach (gastric);
• hepatobiliary tract;
• pancreas;
• esophageal cancer,
• rectal locations; or
• gynecologic tumors (to include cervical, endometrial, and vulvar cancers).

Intensity-modulated radiotherapy would be is investigational/unproven is considered NOT MEDICALLY NECESSARY for all other uses in the abdomen and pelvis.

Policy Guidelines
Table PG1 outlines radiation doses that are generally considered tolerance thresholds for these normal structures in the abdomen and pelvis.

Table PG1. Radiation Tolerance Doses for Normal Tissues of the Abdomen And Pelvis

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
Heart	60	45	40	70	55	50	Pericarditis
Lung	45	30	17.5	65	40	24.5	Pneumonitis
Spinal cord	50	50	47	70	70	NP	Myelitis/necrosis
Kidney	50	30	23	NP	40	28	Clinical nephritis
Liver	50	35	30	55	45	40	Liver failure
Stomach	60	55	50	70	67	65	Ulceration/perforation
Small intestine	50	NP	40	60	NP	55	Obstruction/perforation
Femoral head	NP	NP	52	NP	NP	65	Necrosis

The tolerance doses in the table are a compilation from the following 2 sources:
  Morgan MA (2011). Radiation oncology. In DeVita, Lawrence, and Rosenberg, Cancer (p.308). Philadelphia: Lippincott
  Williams and Wilkins. 
  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 
NP: not provided. 
^a TD 5/5, the average dose that results in a 5% complication risk within 5 y. 
^b TD 50/5, the average dose that results in a 50% complication risk within 5 y. 

For intensity-modulated radiotherapy (IMRT) to provide outcomes that are superior to 3-dimensional conformal radiation (3D-CRT), there must be a clinically meaningful decrease in the radiation exposure to normal structures with IMRT compared with 3D-CRT. There is no standardized definition for a clinically meaningful decrease in radiation dose. In principle, a clinically meaningful decrease would signify a significant reduction in anticipated complications of radiation exposure. To document a clinically meaningful reduction in dose, dosimetry planning studies should demonstrate a significant decrease in the maximum dose of radiation delivered per unit of tissue, and/or a significant decrease in the volume of normal tissue exposed to potentially toxic radiation doses. While radiation tolerance dose levels for normal tissues are well-established, the decrease in the volume of tissue exposed that is needed to provide a clinically meaningful benefit has not been standardized. Therefore, precise parameters for a clinically meaningful decrease cannot be provided. 

Coding
The following CPT codes are used for simple and complex IMRT delivery:

77385: Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple

77386: complex.

The Centers for Medicare and Medicaid Services decided not to implement these CPT codes and instead created HCPCS G codes with the language of the previous CPT codes. So the following codes may be used for IMRT:

G6015: Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC [multileaf collimator], 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.

Code 77301 remains valid:

77301: Intensity-modulated radiotherapy plan, including dose-volume histograms for target and critical structure partial tolerance specifications.

The following CPT code may also be used:

77338: Multi-leaf collimator (MLC) device(s) for intensity-modulated radiation therapy (IMRT), design and construction per IMRT plan.

Code 77338 is to be reported only once per IMRT plan.

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 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 the 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.

Note that the evidence for the following abdominal and pelvic cancers has not yet been reviewed and is beyond the scope of this review: bladder, kidney, and ureter cancer and sarcoma.

Intensity-Modulated Radiotherapy for Cancers of the Abdomen and Pelvis
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 the target and dose homogeneity within the target. Results have also demonstrated that IMRT delivers 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 insights into the potential for benefit, particularly if an adverse event expected to occur at high rates is shown to decrease significantly. 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 using IMRT. For other indications, such as using IMRT to provide better tumor control, comparative studies of health outcomes are needed to demonstrate such a benefit.

Gastrointestinal Tract Cancers
Clinical Context and Therapy Purpose
The purpose of IMRT in patients who have gastrointestinal tract cancers is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of IMRT for the treatment of patients with gastrointestinal tract cancers improve net health outcomes?

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

Populations
The relevant population of interest is patients with gastrointestinal (GI) cancers (eg, stomach, hepatobiliary, and pancreatic cancers) who are recommended for radiotherapy (RT).

Interventions
The therapy being considered is IMRT. Intensity-modulated radiotherapy uses computer software and magnetic resonance imaging for increased conformality, permitting the delivery of higher doses of radiation to the tumor while limiting the exposure of surrounding normal tissues.

Comparators
The following therapy is currently being used: 3D-CRT. This therapy uses 3-dimensional images typically from computed tomography to discriminate tumor tissue from adjacent normal tissue and nearby organs. Computer algorithms are used to estimate radiation doses being delivered to each treatment segment.

Outcomes
The general outcomes of interest are overall survival (OS), recurrence (locoregional control), quality of life, and treatment-related adverse events (e.g., toxicity). Toxicity can be assessed using the U.S. Department of Health and Human Services grading criteria for adverse events (1 = mild, 2 = moderate, 3 = severe or medically significant, 4 = life-threatening, and 5 = death).

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
Stomach
Systematic Review
Ren et al. (2019) completed a systematic review and meta-analysis evaluating the efficacy and safety of IMRT versus 3D-CRT that included 9 controlled clinical trials enrolling 516 patients with gastric cancer.² Results revealed a slightly improved 3-year OS rate (risk ratio [RR], 1.16; 95% CI, 0.98 to 1.36) and a significantly better 2-year OS rate with IMRT (RR, 2.49; 95% CI, 1.18 to 5.25; p = .02) as compared to 3D-CRT. Additionally, the 3-year rate of locoregional recurrence was improved with IMRT versus 3D-CRT (RR, 0.62; 95% CI, 0.39 to 0.98; p < .05). Similar 3-year disease-free survival rates were noted between the techniques (RR, 1.16; 95% CI, 0.95 to 1.43; p > .05). No significant differences in liver, GI, and kidney toxicity were observed among patients receiving IMRT compared with 3D-CRT. Limitations of this analysis included the small number of enrolled subjects (i.e., the majority of studies had < 100 subjects), retrospective nature of included studies, which increased the risk of selective reporting bias, and the heterogeneity of IMRT or 3D-CRT techniques in studies. Additionally, the detail and radiation fields of RT varied considerably among the studies, impacting the efficacy and toxicity seen by investigators.

Nonrandomized Comparative Studies
Boda-Heggemann et al. (2009) evaluated the efficacy and safety of 2 different adjuvant chemoradiotherapy regimens using 3D-CRT or IMRT in 2 consecutive cohorts who underwent primarily D2 resection for gastric cancer.³ A subsequent report (2013) from this group included 27 3D-CRT patients and 38 IMRT patients.⁴ The cohorts were generally well-matched, with American Joint Committee on Cancer advanced stage (II – IV) disease. Most (96%) who received 3D-CRT were treated with 5-fluorouracil plus folinic acid. Patients in the IMRT cohort received capecitabine plus oxaliplatin (70%) or 5-fluorouracil plus folinic acid (30%). Radiation was delivered to a total prescribed dose of 45 gray (Gy) at 1.8 Gy per fraction. In the 3D-CRT cohort, 5 patients received less than 45 Gy because of treatment intolerance. Two patients in the IMRT cohort did not tolerate the full course, and 1 patient received 47 Gy. Overall, the IMRT plus chemotherapy regimen decreased renal toxicity with a trend toward improved survival (Table 1). However, interpretation of the safety and efficacy of IMRT in this study is limited by differences in the chemotherapy regimens.

Table 1. Outcomes for IMRT With Capecitabine Plus Oxaliplatin versus 3D-CRT With 5-FU Plus FA for Stomach Cancer

Outcomes	3-Dimensional Conformal Radiotherapy	Intensity-Modulated Radiotherapy	p
Sample	27	38
Renal toxicity, n (%)	2 (8)	0	.021
Median disease-free survival, mo	14	35	.069
Median overall survival, mo	18	43	.060
Actutimes 2-y overall survival, %	37	67
Actutimes 5-y overall survival, %	22	44

Adapted from Boda-Heggemann et al. (2009, 2013).^3,4
3D-CRT: 3-dimensional conformal radiotherapy; 5-FU: 5-fluorouracil; FA: folinic acid; IMRT: intensity-modulated radiotherapy.

Hepatobiliary
Fuller et al. (2009) compared a retrospective series with a historical control cohort. Clinical results using image-guided IMRT (n = 24) were compared with results using 3D-CRT (n = 24) in patients with primary adenocarcinoma of the biliary tract.⁵ Most patients underwent postsurgical chemoradiotherapy with concurrent fluoropyrimidine-based regimens. Treatment plans prescribed 46 to 56 Gy to the planning target volume that included the tumor and involved lymph nodes, in daily fractions of 1.8 to 2 Gy. Both groups received boost doses of 4 to 18 Gy as needed. The IMRT cohort had a median OS of 17.6 months (range, 10.3 to 32.3 months), while the 3D-CRT cohort had a median OS of 9.0 months (range, 6.6 to 17.3 months). There was no significant differences between patient cohorts in acute GI toxicity. Generalization of results is limited by the small numbers of patients, use of retrospective chart review data, nonrepresentative case spectrum (mostly advanced/metastatic disease), and comparison to a nonconcurrent control RT cohort.

Pancreatic
Literature searches have identified a few comparative studies and case series on IMRT for pancreatic cancer. For example, Lee et al. (2016) reported on a prospective comparative study of GI toxicity in patients treated with concurrent chemoradiotherapy plus IMRT or 3D-CRT for treatment of borderline resectable pancreatic cancer.⁶ Treatment selection was by patient choice after consultation with a radiation oncologist. Symptoms of dyspepsia, nausea or vomiting, and diarrhea did not differ between groups. Upper endoscopy revealed more patients with gastroduodenal ulcers in the 3D-CRT group than in the IMRT group (Table 2). Overall survival was longer in the IMRT group than in the 3D-CRT group but the interpretation of survival results was limited by the risk of bias in this nonrandomized study.

Prasad et al. (2016) retrospectively reviewed charts of patients with locally advanced pancreatic cancer who were treated with IMRT (n = 134) or 3D-CRT (n = 71).⁷ Propensity score analysis was performed to account for potential confounding variables, including age, sex, radiation dose, RT field size, and concurrent RT. Grade 2 GI toxicity occurred in significantly more patients treated with 3D-CRT than with IMRT (propensity score odds ratio [OR], 1.26; 95% CI, 1.08 to 1.45; p = .001; Table 2). Hematologic toxicity and median survival were similar in the 2 groups.

Table 2. Outcomes for IMRT versus 3D-CRT for Pancreatic Cancer

Comparison	3D-CRT	IMRT	p
Lee et al. (2016)6	n = 40	n = 44
Grade 1-2 gastroduodenal ulcers, n (%)	11 (42.3)	3 (9.1)	.003
Overall survival, mo	15.8	22.6	.006
Prasad et al. (2016)7	n = 71	n = 134
Grade 2+ gastrointestinal toxicity, n (%)	24 (33.8)	21 (15.7)	.001
Overall survival whole population, mo	NR	NR	NS

3D-CRT: 3-dimensional conformal radiotherapy; IMRT: intensity-modulated radiotherapy; NR: not reported; NS: not significant.

Section Summary: Gastrointestinal Tract Cancers
The evidence on IMRT for GI tract cancers includes nonrandomized comparative studies, retrospective series, and a systematic review. Intensity-modulated radiotherapy has been compared with 3D-CRT for the treatment of stomach, hepatobiliary, and pancreatic cancers, with some data reporting longer OS and decreased toxicity with IMRT. For the treatment of stomach cancer, IMRT improved survival compared with 3D-CRT, with a comparable or improved safety profile. The evidence on hepatobiliary cancer includes a series of historical controls that found an increase in median survival with no difference in toxicity. Two comparative studies (1 prospective, 1 retrospective) were identified on IMRT for pancreatic cancer. The prospective comparative study found an increase in survival with a reduction in GI toxicity, while the retrospective study found a decrease in GI toxicity. Although most studies were limited by their retrospective designs and changes in practice patterns over time, the available evidence would suggest that IMRT improves survival and decreases toxicity better than 3D-CRT in patients with GI cancers.

Gynecologic Cancers
Clinical Context and Therapy Purpose
The purpose of IMRT in patients who have gynecologic cancers is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of IMRT for the treatment of patients with gynecologic cancers improve net health outcomes?

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

Populations
The relevant population of interest is patients with gynecologic cancers (i.e., cervical and endometrial cancers) who are recommended for radiotherapy (RT).

Interventions
The therapy being considered is IMRT. Intensity-modulated radiotherapy uses computer software and magnetic resonance imaging for increased conformality, permitting the delivery of higher doses of radiation to the tumor while limiting the exposure of surrounding normal tissues.

Comparators
The following therapy is currently being used: 3D-CRT. This therapy uses 3-dimensional images typically from computed tomography to discriminate tumor tissue from adjacent normal tissue and nearby organs. Computer algorithms are used to estimate radiation doses being delivered to each treatment segment.

Outcomes
The general outcomes of interest are OS, recurrence (locoregional control), quality of life, and treatment-related adverse events (e.g., toxicity). Toxicity can be assessed using the U.S. Department of Health and Human Services grading criteria for adverse events (1 = mild, 2 = moderate, 3 = severe or medically significant, 4 = life-threatening, and 5 = death).

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 Review
Lin et al. (2018) completed a meta-analysis of 6 studies enrolling 1008 subjects in order to compare the efficacy and safety of IMRT with 3D-CRT or 2D (2-dimensional)-RT for definitive treatment of cervical cancer.⁸ Results revealed a nonsignificant difference in 3-year OS (OR, 2.41; 95% CI, 0.62 to 9.39; p = .21) and disease-free survival rates (OR, 1.44; 95% CI, 0.69 to 3.01; p = .33) between IMRT and 3D-CRT or 2D-RT. However, IMRT was associated with a significantly reduced rate of acute GI and genitourinary (GU) toxicity: Grade 2 GI: OR, 0.5; 95% CI, 0.28 to 0.89; p = .02; Grade 3 or higher GI: OR, 0.55; 95% CI, 0.32 to 0.95; p = .03; Grade 2 GU: OR, 0.41; 95% CI, 0.2 to 0.84; p = .01; Grade 3 or higher GU: OR, 0.31; 95% CI, 0.14 to 0.67; p = .003. Some chronic GU toxicity also occurred less frequently with IMRT (Grade 3: OR, 0.09; 95% CI, 0.01 to 0.67; p = .02). This analysis had several limitations including the fact that most included studies had relatively small sample sizes and were retrospective and nonrandomized in nature. Additionally, some of the included studies did not compare clinical outcomes between the RT techniques.

Randomized Controlled Trials
Klopp et al. (2018) designed a randomized trial that measured the impact of pelvic IMRT versus standard 4-field RT on patient-reported toxicity and quality of life in 278 women with cervical and endometrial cancer.⁹ Results revealed that the mean Expanded Prostate Cancer Index Composite (EPIC) bowel score decreased significantly less in the IMRT as compared to the standard RT group from baseline to end of RT (18.6 vs. 23.6 points; p = .048). Additionally, both the mean EPIC urinary score (5.6 vs.10.4 points; p = .03) and Trial Outcome Index score (8.8 vs. 12.8 points; p = .06) declined significantly less with IMRT as compared to standard RT. Frequent or almost constant diarrhea was also reported more frequently among women receiving standard RT versus IMRT at the end of RT (51.9% vs. 33.7%; p = .01) and significantly more women administered standard RT were taking antidiarrheal medications 4 or more times daily (20.4% vs. 7.8%; p = .04).

A trial by Naik et al. (2016) randomized 40 patients with cervical cancer to IMRT or 3D-CRT.^10, Both arms received concurrent chemotherapy (cisplatin) plus RT at 50 Gy in 25 fractions. Dosimetric planning showed higher conformality and lower doses to organs at risk with IMRT. With follow-up through 90 days posttreatment, vomiting and acute GI and GU toxicity were significantly higher in the 3D-CRT group (Table 3).

Gandhi et al. (2013) reported on a prospective randomized study that compared whole-pelvis IMRT with whole-pelvis 2D-RT in 44 patients with locally advanced cervical cancer.¹¹ Each treatment arm had 22 patients. The OS rate at 27 months was 88% with IMRT and 76% with 2D-RT (p = .645). However, fewer grade 2, 3, or 4 GI toxicities were experienced in the IMRT group than in the conventional RT group (Table 3).

Table 3. Acute Toxicity of Grade 2, 3 or 4 With 3D-CRT versus IMRT for Cervical Cancer

Toxicity	3D-CRT, n (%)	IMRT, n (%)	95% CI for the Difference	p
Naik et al. (2016)10
Hematologic	8 (40)	7 (35)	-0.219 to 0.119	.644
Leukopenia	3 (15)	2 (10)	-0.1479 to 0.479	.424
Vomiting	7 (35)	3 (15)	0.338 to 0.061	.007
Acute gastrointestinal toxicity	9 (45)	4 (20)	-0.408 to -0.091	.003
Acute genitourinary toxicity	7 (35)	4 (20)	-0.295 to -0.004	.058
Gandhi et al. (2013)11
Gastrointestinal, grade ≥ 2	14 (64)	7 (32)	0.002 to 0.604	.034
Gastrointestinal, grade ≥ 3	6 (27)	1 (5)	0.003 to 0.447	.047
Genitourinary, grade ≥ 2	7 (32)	5 (24)	-0.202 to 0.361	.404
Genitourinary, grade ≥ 3	3 (14)	0 (0)	-0.019 to 0.291	.125

3D-CRT: 3-dimensional conformal radiotherapy; CI: confidence interval; IMRT: intensity-modulated radiotherapy.

Nonrandomized Comparative Studies
Shih et al. (2016) conducted a retrospective comparison of bowel obstruction following IMRT (n = 120) or 3D-CRT (n = 104) after hysterectomy for endometrial or cervical cancer.¹² Groups were generally comparable, except more patients in the 3D-CRT group had open hysterectomy (81% vs. 47%, p < .001). Patients received regular examinations throughout a median follow-up of 67 months, and the 5-year rate of bowel obstruction was 0.9% in the IMRT group compared with 9.3% in the 3D-CRT group (p = .006). A body mass index of 30 kg/m² or more was also associated with less bowel obstruction. However, on multivariate analysis, the only significant predictor of less bowel obstruction was IMRT (p = .022).

Chen et al. (2014) reported on 101 patients with endometrial cancer treated with hysterectomy and adjuvant RT.¹³ No significant differences between IMRT patients (n = 65) and CRT patients (n = 36) were found in 5-year OS (82.9% vs. 93.5%; p = .26), local failure-free survival (93.7% vs. 89.3%; p = .68), or disease-free survival (88.0% vs. 82.8%; p = .83). However, IMRT patients experienced fewer acute and late toxicities.

Section Summary: Gynecologic Cancers
The evidence on IMRT for gynecologic cancers includes a systematic review, 3 RCTs, and nonrandomized comparative studies. There is limited comparative evidence on survival outcomes following IMRT or 3D-CRT. However, available results have generally been consistent that IMRT reduces GI and GU toxicity. Based on evidence with other cancers of the pelvis and abdomen in close proximity to organs at risk, it is expected that OS with IMRT would be at least as good as 3D-CRT, with a decrease in toxicity.

Anorectal Cancer
Clinical Context and Therapy Purpose
The purpose of IMRT in patients who have anorectal cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of IMRT for the treatment of patients with anorectal cancer improve net health outcomes?

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

Populations
The relevant population of interest is patients with anorectal cancer who are recommended for radiotherapy (RT).

Interventions
The therapy being considered is IMRT. Intensity-modulated radiotherapy uses computer software and magnetic resonance imaging for increased conformality, permitting the delivery of higher doses of radiation to the tumor while limiting the exposure of surrounding normal tissues.

Comparators
The following therapy is currently being used: 3D-CRT. This therapy uses 3-dimensional images typically from computed tomography to discriminate tumor tissue from adjacent normal tissue and nearby organs. Computer algorithms are used to estimate radiation doses being delivered to each treatment segment.

Outcomes
The general outcomes of interest are OS, recurrence (locoregional control), quality of life, and treatment-related adverse events (eg, toxicity). Toxicity can be assessed using the U.S. Department of Health and Human Services grading criteria for adverse events (1 = mild, 2 = moderate, 3 = severe or medically significant, 4 = life-threatening, and 5 = death).

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 Trials
Rattan et al. (2016) conducted a small (n = 20) RCT assessing IMRT for the treatment of anal canal cancer.¹⁴ Grade 3 GI toxicity during treatment was not observed in any patients in the IMRT group but was seen in 60% of patients treated with 3D-CRT (p = .010). Hematologic grade 3 toxicity was not seen in any patients treated with IMRT but was noted in 20% of patients treated with 3D-CRT (p = .228). Other parameters indicating better tolerance to treatment with IMRT were reduced need for parenteral fluid (10% vs. 60%, p = .019) and blood transfusion (0% vs. 20%, p = .060).

Nonrandomized Comparative Studies
Sun et al. (2017) reported on a comparative analysis of the National Cancer Database of IMRT with 3D-CRT for the treatment of rectal adenocarcinoma.¹⁵ A total of 7386 patients with locally advanced rectal carcinoma were treated with neoadjuvant chemoradiotherapy (45 to 54 Gy) from 2006 to 2013; 3330 (45%) received IMRT and 4065 (55%) received 3D-CRT. Use of IMRT increased from 24% in 2006 to 50% in 2013. Patient age, race, insurance status, Charlson-Deyo comorbidity score, hospital type, income and educations status, and clinical disease stage were not predictive of which RT was used. The mean radiation dose was higher with IMRT (4735 centigray vs. 4608 centigray, p < .001) and the occurrence of sphincter loss surgery was higher in the IMRT group (Table 4). However, patients treated with IMRT had a higher risk of positive margins. Multivariate analysis found no significant differences between the treatments for pathologic downstaging, unplanned readmission, 30-day mortality, or long-term survival. This study used unplanned readmission as a surrogate measure of adverse events but could not assess acute or late toxicity.

Table 4. Outcomes Following Radiochemotherapy With 3D-CRT or IMRT for Rectal Cancer

Outcome	3D-CRT, %	IMRT, %	Adjusted Odds Ratio	95% CI	p
Pathologic downstaging	57.0	55.0	0.89	0.79 to 1.01	.051
Sphincter loss surgery	28.3	34.7	1.32	1.14 to 1.52	< .001
Positive resection margin	5.6	8.0	1.57	1.21 to 2.03	< .001
Unplanned readmission	7.9	6.4	0.79	0.61 to 1.02	.07
30-d mortality	0.8	0.6	0.61	0.24 to 1.57	.31
Survival at 5 y	64	64	1.06	0.89 to 1.28	.47

Adapted from Sun et al. (2017).¹⁵
3D-CRT: 3-dimensional conformal radiotherapy; CI: confidence interval; IMRT: intensity-modulated radiotherapy.

Huang et al. (2017) reported on a retrospective comparison of outcomes and toxicity for preoperative image-guided IMRT and 3D-CRT in locally advanced rectal cancer.¹⁶ A total of 144 consecutive patients treated between 2006 and 2015 were analyzed. The 3D-CRT group was treated with 45 Gy in 25 fractions while the IMRT group was treated with 45 Gy in 25 fractions with a simultaneous integrated boost of 0.2 Gy per day for the primary tumor up to a total dose of 50 Gy. Statistical analysis was performed for grade 0, 1, 2, 3, or 4 toxicity and was significant only for acute GI toxicity (p = .039; Table 5). Four-year OS and disease-free survival did not differ between the 2 groups. Multivariate analysis found IMRT to be an independent predictor of local failure-free survival (hazard ratio, 0.35; 95% CI, 0.11 to 0.95; p = .042).

Table 5. Grade 3 or Greater Toxicity Following Chemoradiotherapy for Rectal Cancer

Comparison	3D-CRT (n = 99), n (%)	IMRT (n = 45), n (%)
Skin	3 (3)	1 (2.2)
Acute gastrointestinal	14 (14.1)	3 (6.7)
Acute genitourinary	3 (3)	0 (0)
Hematologic	2 (2.0)	0 (0)
Late gastrointestinal	10 (10.1)	2 (4.4)
Late genitourinary	3 (3.1)	0 (0)

Adapted from Huang et al. (2017).¹⁶
3D-CRT: 3-dimensional conformal radiotherapy; IMRT: intensity-modulated radiotherapy.

In a retrospective review of 89 consecutive patients (52 IMRT, 37 3D-CRT), Chuong et al. (2013) found that 3-year OS, progression-free survival, locoregional control, and colostomy-free survival did not differ significantly between patients treated with IMRT or with 3D-CRT (p > .1).¹⁷ Adverse events with 3D-CRT were more frequent and severe and required more treatment breaks than IMRT (11 days vs. 4 days; p = .006) even though the median duration of treatment breaks did not differ significantly (12.2 days vs. 8.0 days; p = .35). Intensity-modulated radiotherapy patients had fewer acute grade 3 or 4 nonhematologic toxicity (p < .001), improved late grade 3 or 4 GI toxicity (p = .012), and fewer acute grade 3 or 4 skin toxicity (p < .001) than 3D-CRT patients.

Dasgupta et al. (2013) retrospectively reviewed 223 patients (45 IMRT, 178 CRT) to compare outcomes for anal cancer.¹⁸ They reported that 2-year OS, distant metastases-free survival, and locoregional recurrence-free survival did not differ significantly between patients in the IMRT and CRT groups.

Dewas et al. (2012) retrospectively reviewed 51 patients with anal cancer treated with IMRT (n = 24) or 3D-CRT (n = 27).¹⁹ Outcomes also did not differ significantly between patients in the IMRT and 3D-CRT groups in 2-year OS, locoregional relapse-free survival, and colostomy-free survival. Grade 3 acute toxicity occurred in 11 IMRT patients and in 10 3D-CRT patients.

Case Series
A GI toxicity study by Devisetty et al. (2009) reported on 45 patients who received concurrent chemotherapy plus IMRT for anal cancer.²⁰ Intensity-modulated radiotherapy was administered to a dose of 45 Gy in 1.8-Gy fractions, with areas of gross disease subsequently boosted with 9 to 14.4 Gy. Acute GU toxicity was grade 0 in 25 (56%) cases, grade 1 in 10 (22%) patients, grade 2 in 5 (11%) patients, with no grade 3 or 4 toxicities reported; 5 (11%) patients reported no GU tract toxicities. Grades 3 and 4 leukopenia were reported in 26 (56%) cases, neutropenia in 14 (31%), and anemia in 4 (9%). Acute GI toxicity included grade 0 in 2 (4%) patients, grade 1 in 11 (24%), grade 2A in 25 (56%), grade 2B in 4 (9%), grade 3 in 3 (7%), and no grade 4 toxicities. Univariate analysis of data from these patients suggested a statistical correlation between the volume of bowel that received 30 Gy or more of radiation and the risk for clinically significant (grade ≥ 2) GI toxicities.

Pepek et al. (2010) retrospectively analyzed toxicity and disease outcomes associated with IMRT in 47 patients with anal cancer.²¹ Thirty-one patients had squamous cell carcinoma. Intensity-modulated radiotherapy was prescribed to a dose of at least 54 Gy to areas of gross disease at 1.8 Gy per fraction. Forty (89%) patients received concurrent chemotherapy with various agents and combinations. The 2-year OS for all patients was 85%. Eight (18%) patients required treatment breaks. Toxicities included grade 4 leukopenia (7%) and thrombocytopenia (2%); grade 3 leukopenia (18%) and anemia (4%); and grade 2 skin toxicity (93%). These rates were lower than those reported in previous trials of chemoradiation, where grade 3 or 4 skin toxicity was noted in about 50% of patients and grade 3 or 4 GI toxicity noted in about 35%. In addition, the rate of treatment breaks was lower than in many studies; and some studies of chemoradiation included a break from RT.

Section Summary: Anorectal Cancer
The evidence on IMRT for anorectal cancer includes a small RCT with 20 patients, nonrandomized comparative studies, and case series. Survival outcomes have not differed significantly between IMRT and 3D-CRT. Studies have found that patients receiving IMRT plus chemotherapy for the treatment of anal cancer experience fewer acute and late adverse events than patients receiving 3D-CRT plus chemotherapy, primarily in GI toxicity.

Esophageal Cancer
Clinical Context and Therapy Purpose
The purpose of IMRT in patients who have esophageal cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of IMRT for the treatment of patients with esophageal cancer improve net health outcomes?

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

Populations
The relevant population of interest is patients with esophageal cancer who are recommended for radiotherapy (RT).

Interventions
The therapy being considered is IMRT. Intensity-modulated radiotherapy uses computer software and magnetic resonance imaging for increased conformality, permitting the delivery of higher doses of radiation to the tumor while limiting the exposure of surrounding normal tissues.

Comparators
The following therapy is currently being used: 3D-CRT. This therapy uses 3-dimensional images typically from computed tomography to discriminate tumor tissue from adjacent normal tissue and nearby organs. Computer algorithms are used to estimate radiation doses being delivered to each treatment segment.

Outcomes
The general outcomes of interest are OS, recurrence (locoregional control), quality of life, and treatment-related adverse events (e.g., toxicity). Toxicity can be assessed using the U.S. Department of Health and Human Services grading criteria for adverse events (1 = mild, 2 = moderate, 3 = severe or medically significant, 4 = life-threatening, and 5 = death).

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
Xu et al. (2017) performed a systematic review and meta-analysis to compare IMRT and 3D-CRT in the treatment of esophageal cancer with regard to dosimetry and clinical outcomes (n = 7 studies).²² For the dosimetric comparison of organs at risk, 5 studies were included. Results revealed that the mean dose of 3D-CRT was significantly higher as compared to IMRT for the lung (mean difference dose: 2.18; 95% CI, 0.83 to 3.53; p = .002), with patients treated with ≥ 20 Gy having significantly higher irradiated volumes for 3D-CRT than for IMRT. For the heart, the mean dose was not significantly different between 3D-CRT and IMRT (mean difference dose: 0.17; 95% CI, -3.73 to 4.07; p = .93); however, the heart in patients treated with 50 Gy had significantly higher irradiated volumes for 3D-CRT. The maximum dose in the spinal cord revealed no difference between the 2 RT techniques (p = .33). Evaluated clinical outcomes included OS (n = 3 studies; 871 patients) and toxicity (n = 2 studies; 205 patients). The 3-year OS was significantly improved with IMRT as compared to 3D-CRT (OR, 0.68; 95% CI, 0.52 to 0.90; p = .007). No difference between the 2 RT techniques was seen with regard to the incidence of radiation pneumonitis or radiation esophagitis, regardless of grade. Limitations of the review were the small number of studies available for OS and toxicity outcome analyses and the retrospective nature of clinical outcomes studies.

Nonrandomized Comparative Studies
Lan et al. (2020) retrospectively compared survival outcomes and symptomatic radiation pneumonitis in patients with esophageal cancer who received either IMRT (n = 297) or 3D-CRT (n = 91) from 2010 through 2017.²³ The median age of patients was 60 years and the median radiation dose for the entire cohort was 60 Gy. Results revealed significantly improved OS (p = .001), progression-free survival (PFS) (p = .008), and distant-metastases free survival (p = .011) with IMRT versus 3D-CRT; locoregional failure-free survival was not significantly different between the groups (p = .721). Intensity-modulated radiotherapy was also associated with significantly less grade ≥ 2 radiation pneumonitis as compared to 3D-CRT (5.4% vs. 23.1%; p < .001).

Ito et al. (2017) retrospectively compared failure patterns and toxicities between IMRT (n = 32) and 3D-CRT (n = 48) in patients with cervical esophageal cancer.²⁴ All patients were administered systemic chemotherapy consisting of either induction chemotherapy or concurrent chemoradiotherapy, with or without adjuvant chemotherapy. The median follow-up of the entire cohort was 24.6 months and the median follow-up time for survivors was 35.9 months. Results revealed a 3 year OS of 81.6%, 57.2% (p = .037 vs. IMRT), and 66.6% for the IMRT, 3D-CRT, and total groups, respectively. However, there was no significant difference between IMRT and 3D-CRT with regard to complete response rate (75% vs. 68.9%; p = .62). Rates of locoregional control or PFS were not different between the groups as well. Overall, 47 patients developed recurrence of any type; there was no apparent difference in the failure pattern between the 2 RT techniques. The incidence of late toxicities was also not significantly different between IMRT and 3D-CRT. Ten patients in the IMRT groups were salvaged, and 60% survived without recurrence compared to 20% of the 3D-CRT group.

Haefner et al. (2017) reported a retrospective analysis of 93 patients with esophageal cancer and compared outcomes and acute toxicity among patients receiving definitive CRT with either 3D-CRT (n = 49) or IMRT (n = 44).²⁵ The median follow-up for all patients was 20.1 months. The 1- and 3-year local relapse rates were 20.4% and 28.6% in the 3D-CRT group and 15.9% and 22.7% in the IMRT group, respectively (p = .62 for the 3-year rate). Median PFS and OS were not significantly different between the groups; 13.8 months 3D-CRT versus 16.6 months IMRT (p = .448) and 18.4 months 3D-CRT versus 42 months IMRT (p = .198), respectively. The incidence of acute toxicities (dysphasia, radio dermatitis, nausea/vomiting, mucositis, bleeding, pneumonitis) were also not significantly different between the 2 RT techniques.

Section Summary: Esophageal Cancer
The evidence on IMRT for esophageal cancer includes a systematic review and nonrandomized comparative studies. Survival outcomes from studies have been mixed with some concluding improved survival with IMRT and others demonstrating no difference from 3D-CRT. Similarly, some studies have concluded that IMRT is associated with a reduced dose for organs at risk and potentially less radiation-related toxicity as compared to 3D-CRT.

Summary of Evidence
For individuals who have GI tract cancers who receive IMRT, the evidence includes nonrandomized comparative studies, retrospective series, and a systematic review. Relevant outcomes are OS, disease-specific survival, recurrence, quality of life, and treatment-related morbidity. IMRT has been compared with 3D-CRT for the treatment of stomach, hepatobiliary, and pancreatic cancers. Evidence has been inconsistent with the outcome of survival, with some studies reporting increased survival among patients receiving IMRT compared with patients receiving 3D-CRT, and other studies reporting no difference between groups. However, most studies found that patients receiving IMRT experienced significantly less GI toxicity compared with patients receiving 3D-CRT. The available comparative evidence, together with dosimetry studies of organs at risk, would suggest that IMRT decreases toxicity compared with 3D-CRT in patients who had GI cancers. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have gynecologic cancers who receive IMRT, the evidence includes a systematic review, 3 RCTs, and nonrandomized comparative studies. Relevant outcomes are OS, disease-specific survival, recurrence, quality of life, and treatment-related morbidity. There is limited comparative evidence on survival outcomes following IMRT or 3D-CRT. However, results are generally consistent that IMRT reduces GI and genitourinary toxicity. Based on evidence with other cancers of the pelvis and abdomen that are proximate to organs at risk, it is expected that OS with IMRT would be at least as good as 3D-CRT, with a decrease in toxicity. A reduction in GI toxicity is likely to improve the quality of life in patients with gynecologic cancer. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have anorectal cancer who receive IMRT, the evidence includes a small RCT (n = 20), nonrandomized comparative studies, and case series. Relevant outcomes are OS, disease-specific survival, recurrence, quality of life, and treatment-related morbidity. Survival outcomes have not differed significantly between patients receiving IMRT and 3D-CRT. However, studies have found that patients receiving IMRT plus chemotherapy for the treatment of anal cancer experience fewer acute and late adverse events than patients receiving 3D-CRT plus chemotherapy, primarily in GI toxicity. A reduction in GI toxicity is likely to improve the quality of life in patients with anorectal cancer. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have esophageal cancer who receive IMRT, the evidence includes a systematic review and nonrandomized comparative studies. Relevant outcomes are OS, disease-specific survival, recurrence, quality of life, and treatment-related morbidity. Survival outcomes have been mixed with some studies concluding that IMRT is associated with a significant improvement in OS, PFS, or distant-metastases free survival versus 3D-CRT and others reporting no difference between the RT techniques. Intensity-modulated radiotherapy appears to be associated with a reduced dose for organs at risk and may result in less radiation-induced toxicity. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

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 1 physician specialty society (4 reviewers) and 3 academic medical centers while this policy was under review in 2012. Input was mixed but there was support for use of intensity-modulated radiotherapy (IMRT) in a number of cancers discussed herein. In general, this support was based on normal tissue constraints for radiation doses and whether these dose constraints could not be met without IMRT.

2010 Input
In response to requests, input was received from 1 physician specialty society (2 reviewers) and 3 academic medical centers while this policy was under review in 2010. There was support for use of IMRT in a number of cancers discussed herein. In general, this support was based on normal tissue constraints for radiation doses and whether these dose constraints could not be met without IMRT.

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 US professional society, an international society with US 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 Guidelines
Gastrointestinal Tract Cancers
The NCCN guideline (v.2.2021) for gastric cancer indicates that IMRT "may be used in clinical settings where dose reduction to organs at risk is required, and cannot be achieved by 3D techniques."²⁶ In addition, target volumes need to be carefully defined and encompassed while taking into account variations in stomach filling and respiratory motion.

The NCCN guideline (v.2.2021) for hepatobiliary cancers states that "All tumors irrespective of the location may be amenable to external beam radiation therapy (3D conformal radiation therapy, intensity-modulated radiation therapy [IMRT], or stereotactic body radiation therapy [SBRT])."²⁷

Intensity-modulated radiotherapy is mentioned as an option in the NCCN guideline (v.2.2021) for pancreatic adenocarcinoma, stating that IMRT "is increasingly being applied for the therapy 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."²⁸ In addition, the guideline states that "there is no clear consensus on the appropriate maximum dose of radiation when IMRT technique is used."

Gynecologic Cancers
For cervical cancer, the NCCN guideline (v.1.2021) indicates IMRT "is helpful in minimizing the dose to the bowel and other critical structures in the post-hysterectomy setting and in treating the para-aortic nodes when necessary." This technique can also be useful "when high doses are required to treat gross disease in regional lymph nodes."^29, Intensity-modulated radiotherapy "should not be used as a routine alternative to brachytherapy for treatment of central disease in patients with an intact cervix." The guideline also mentions that "very careful attention to detail and reproducibility (including consideration of target and normal tissue definitions, patient and internal organ motion, soft tissue deformation, and rigorous dosimetric and physics quality assurance) is required for proper delivery of IMRT and related highly conformal technologies."

The NCCN guideline (v.2.2021) on uterine neoplasms states that radiotherapy for uterine neoplasms includes external-beam radiotherapy and/or brachytherapy but that IMRT may be considered "for normal tissue sparing."³⁰

The NCCN guideline (v.1.2021) on ovarian cancer does not mention IMRT.³¹

Anorectal Cancers
The NCCN guideline (v.1.2021) for anal carcinoma states that IMRT "is preferred over 3D conformal RT [radiotherapy] in the treatment of anal carcinoma"; and that its use "requires expertise and careful target design to avoid reduction in local control by so-called ‘marginal-miss'."³²

The NCCN guideline (v.1.2021) on rectal cancer indicates that "IMRT ... should only be used in the setting of a clinical trial, in unique clinical situations such as reirradiation of previously treated patients with recurrent disease, or unique anatomical situations."³³

Esophageal Cancer
The NCCN guideline (v.2.2021) for esophageal and esophagogastric junction cancers states that IMRT"is appropriate in clinical settings where reduction in dose to organs at risk (e.g., heart, lungs) is required that cannot be achieved by 3-D techniques."³⁴

American Society for Radiation Oncology
In 2020, the American Society for Radiation Oncology published a clinical practice guideline on RT for cervical cancer.³⁵ One key question within the guideline asked when it was appropriate to deliver IMRT for women administered definitive or postoperative RT for cervical cancer? Recommendations regarding this clinical scenario included:

• "In women with cervical cancer treated with postoperative RT with or without chemotherapy, IMRT is recommended to decrease acute and chronic toxicity." This was a strong recommendation based on moderate quality evidence for acute toxicity and low quality evidence for chronic toxicity.

• "In women with cervical cancer treated with definitive RT with or without chemotherapy, IMRT is conditionally recommended to decrease acute and chronic toxicity." This was a conditional recommendation based on moderate quality evidence for acute and chronic toxicity.

The guideline also notes that there are "no data that IMRT improves disease-specific survival or OS over 2D/3D techniques."

In 2021, the American Society for Radiation Oncology published a clinical practice guideline on RT for rectal cancer.³⁶ Within this guideline, IMRT-specific recommendations include:

• "For patients with rectal cancer treated with RT, an IMRT/volumetric modulated arc therapy (VMAT) technique is conditionally recommended (low quality of evidence). IMRT/VMAT may be beneficial when the external iliac nodes and/or the inguinal nodes require treatment or when 3-D conformal techniques may confer a higher risk for toxicity.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 6.

Table 6. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03239626	Postoperative Hypofractionated Intensity-Modulated Radiation Therapy in Cervical Cancer: A Prospective Exploratory Trial (POHIM_RT Trial)	120	Apr 2025
NCT03239613	Postoperative Hypofractionated Intensity-Modulated Radiation Therapy with Concurrent Chemotherapy in Cervical Cancer: A Prospective Exploratory Trial (POHIM_CCRT Trial)	84	Apr 2024
Unpublished
NCT02964468	Multicenter Dose-escalation Trial of Radiotherapy in Patients with Locally Advanced Rectal Cancer	525	May 2020

NCT: national clinical trial.

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35. Chino J, Annunziata CM, Beriwal S, et al. Radiation Therapy for Cervical Cancer: Executive Summary of an ASTRO Clinical Practice Guideline. Pract Radiat Oncol. Jul 2020; 10(4): 220-234. PMID 32473857
36. Wo JY, Anker CJ, Ashman JB, et al. Radiation Therapy for Rectal Cancer: Executive Summary of an ASTRO Clinical Practice Guideline. Pract Radiat Oncol. Jan-Feb 2021; 11(1): 13-25. PMID 33097436

Coding Section 

Codes	Number	Description
CPT	77301	Intensity modulated radiotherapy plan, including dose volume histograms for target and critical structure partial tolerance specification
	77338	Multileaf collimator device(s) for intensity-modulated radiation therapy (IMRT), design and construction per IMRT plan
	77385	Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple (new code 01/01/15)
	77386	complex (new code 01/01/15)
	77418	Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary dynamic multileaf collimator, per treatment session (code deleted 12/31/14)
	0073T	Compensator-based beam modulation treatment delivery of inverse planned treatment using three or more high resolution compensator convergent beam modulated fields, per treatment session (code deleted 12/31/14)
HCPCS	G6015	Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session (new code 01/01/15)
	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 (new code 01/01/15)
ICD-9-CM Diagnosis	151.0-151.9	Malignant neoplasm of stomach, code range
	152.0-152.9	Malignant neoplasm of small intestine code range
	153.0-153.9	Malignant neoplasm of colon code range
	154.0-154.8	Malignant neoplasm of rectum, rectosigmoid junction and anus code range (154.2 and 154.3 are specific to the anal canal and anus, unspecified)
	155.0-155.2	Malignant neoplasm of liver and intrahepatic bile ducts code range
	156.0-156.9	Malignant neoplasm of gallbladder and extrahepatic bile ducts code range
	157.0-157.9	Malignant neoplasm of pancreas code range
	158.0-158.9	Malignant neoplasm of retroperitoneum and peritoneum code range
	159.0-159.9	Malignant neoplasm of other and ill-defined sites within the digestive organs and peritoneum code range
	179	Malignant neoplasm of uterus, part unspecified
	180.0-180.9	Malignant neoplasm of cervix uteri code range
	182.0-182.8	Malignant neoplasm of body of uterus code range
	183.0-183.9	Malignant neoplasm of ovary and other uterine adnexa code range
	184.0-184.9	Malignant neoplasm of other and unspecified female genital organs code range
ICD-10-CM (effective 10/01/15)	C16.0-C16.9	Malignant neoplasm of stomach, code range
	C17.0-C17.9	Malignant neoplasm of small intestine code range
	C18.0-C18.9	Malignant neoplasm of colon code range
	C19	Malignant neoplasm of rectosigmoid junction
	C20	Malignant neoplasm of rectum
	C21.0-C21.8	Malignant neoplasm of anus, code range
	C22.0-C22.9	Malignant neoplasm of liver and intrahepatic bile ducts code range
	C23	Malignant neoplasm of gallbladder
	C24.0-C24.9	Malignant neoplasm of other and unspecified parts of biliary tract code range
	C25.0-C25.9	Malignant neoplasm of pancreas code range
	C26.0-C26.9	Malignant neoplasm of other and ill-defined sites within the digestive organs and peritoneum code range
	C51.0-C51.9	Malignant neoplasm of vulva code range
	C52	Malignant neoplasm of vagina
	C53.0-C53.9	Malignant neoplasm of cervix uteri code range
	C54.0-C54.9	Malignant neoplasm of corpus uteri code range
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this imaging.
Type of Service
Place of Service

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 2014 Forward     

05/09/2022	Annual review, adding esophageal cancer as a medically necessary use of this technology. Also updating rationale and references.
05/06/2021	Annual review, no change to policy intent. Updating rationale and references.
05/11/2020	Annual review, no change to policy intent. Updating rationale and references.
05/02/2019	Annual review, no change to policy intent. Updating rationale and description.
05/15/2018	Annual review, no change to policy intent. Updating description, rationale and references.
05/22/2017	Annual review, no change to policy intent. Updating background, description, rationale, references and guidelines.
05/03/2016	Annual review, no change to policy intent.
05/12/2015	Annual review, no change to policy intent. Updated background, description, rationale, references and guidelines. Added coding.
05/05/2014	Annual review. Added related policies. Updatedg guidelines, rationale and references. No change to policy intent.