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
Radiation therapy may be administered externally (i.e., a beam of radiation is directed into the body) or internally (i.e., a radioactive source is placed inside the body, near a tumor).¹ External radiotherapy (RT) techniques include "conventional" or 2-dimensional (2D) RT, 3-dimensional (3D) conformal RT, and intensity-modulated radiation therapy (IMRT).

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

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

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

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

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

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

A number of intensity modulators have been cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. Intensity modulators include the Innocure Intensity Modulating Radiation Therapy Compensators (Innocure), cleared in 2006, and the decimal tissue compensator (Southeastern Radiation Products), cleared in 2004. FDA product code: IXI. Intensity modulators may be added to standard linear accelerators to deliver IMRT when used with proper treatment planning systems.

RT planning systems have also been cleared for marketing by the FDA through the 510(k) process. They include the FOCUS Radiation Treatment Planning System (Computerized Medical Systems) in 2002, Prowess Panther™ (Prowess) in 2003, TiGRT (LinaTech) in 2009, the RayDose (RaySearch Laboratories) in 2008, and the Eclipse Treatment Planning System (Varian Medical Systems) in 2017. 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. Varian Medical Systems has several 510(k) marketing clearances for high-energy linear accelerator systems that can be used to deliver precision RT such as IMRT. 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.
• 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 generally considered tolerance thresholds for normal structures in the abdomen, pelvis, and chest. Dosimetry plans may be reviewed to demonstrate that radiation by 3-dimensional conformal radiotherapy (3D-CRT) would exceed tolerance doses to structures at risk.

Table PG1. Radiation Tolerance Doses for Normal Tissues of the Abdomen, Pelvis, and Chest

Site	TD 5/5 (Gray)a			TD 50/5 (Gray)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 (5 cm)	50 (10 cm)	47 (20 cm)	70 (5 cm)	70 (10 cm)	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

Compiled from 2 sources: (1) Morgan MA, Ten Taken RK, Lawrence TS. Essentials of radiation therapy. In DeVita, Hellman, and Rosenberg, Cancer: Principles & Practice of Oncology. Philadelphia: Lippincott Williams and Wilkins; 2019; and (2) Kehwar TS, Sharma SC. Use of normal tissue tolerance doses into linear quadratic equation to estimate normal tissue complication probability. http://www.rooj.com/Radiation%20Tissue%20Tolerance.htm. Accessed June 1, 2022.
NP: not provided; TD: tolerance dose.
^a TD 5/5, the average dose that results in a 5% complication risk within 5 years.
^b TD 50/5, the average dose that results in a 50% complication risk within 5 years.

For intensity-modulated radiotherapy (IMRT) to provide outcomes superior to 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
See the Codes table for details.

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

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of 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, two 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 assessed and is beyond the scope of this review: bladder, kidney, and ureter cancer and sarcoma.

Intensity-Modulated Radiotherapy for Cancers of the Abdomen, Pelvis, and Chest
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 (GI) 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 GI 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 GI cancers (e.g., stomach, hepatobiliary, and pancreatic cancers) who are recommended for radiotherapy (RT).

Interventions
The therapy being considered is IMRT. This therapy 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% confidence interval [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 Intensity-Modulated Radiotherapy With Capecitabine Plus Oxaliplatin versus 3-Dimensioinal Conformal Radiotherapy With 5-Fluorouracil Plus Folinic Acid 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

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 Intensity-Modulated Radiotherapy versus 3-Dimensioinal Conformal Radiotherapy 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. IMRT has been compared to 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 RT.

Interventions
The therapy being considered is IMRT. This therapy 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
Chopra et al. (2021) conducted the open-label, parallel-group, randomized, phase 3, Postoperative Adjuvant Radiation in Cervical Cancer (PARCER) trial in order to evaluate whether postoperative image-guided IMRT was associated with an improvement in late GI toxicity compared to 3D-CRT.⁹ In PARCER, 300 patients with cervical cancer and an indication for adjuvant postoperative RT were randomly assigned to image-guided IMRT (n = 151) or 3D-CRT (n = 149), with a median follow-up of 46 months (interquartile range, 20 to 72 months). Results revealed significantly fewer primary endpoint events (i.e., grade ≥ 2 late GI toxicity) in the image-guided IMRT arm versus the 3D-CRT arm (29 vs. 54). The 3-year cumulative incidence of grade ≥ 2 late GI toxicity was significantly reduced in the IMRT arm (21.1% vs. 42.4%; hazard ratio [HR], 0.46; 95% CI, 0.29 to 0.73; p < .001) as was the cumulative incidence of 3-year grade ≥ 3 late GI toxicity (2.9% vs. 15.5%; HR, 0.22; 95% CI, 0.08 to 0.59; p < .003). The cumulative incidence of grade ≥ 2 any late toxicity was also significantly reduced with IMRT (28.1% vs. 48.9%; HR, 0.50; 95% CI, 0.33 to 0.76; p < .001). Patients administered IMRT reported less diarrhea (p = .04), improvement in appetite (p = .008), and fewer bowel symptoms (p = .002) compared to those administered 3D-CRT. No differences in disease outcomes were noted between the RT techniques including 3-year pelvic relapse-free survival (p = .55) and disease-free survival (p = .89).

In the international, randomized, PORTEC-3 trial, Wortman et al. (2021) evaluated whether IMRT compared to 3D-CRT resulted in fewer adverse events and patient-reported symptoms among 658 patients with high-risk endometrial cancer.¹⁰ Of these patients, 559 received 3D-CRT and 99 received IMRT; median follow-up at the time of analysis was 74.6 months. Results revealed no significant differences in frequency and grades of adverse events between the RT techniques. There was an increase in grade ≥ 3 adverse events (mainly GI and hematologic) with 3D-CRT (37.7% vs. 26.3%; p = .03). During follow-up, significantly more grade ≥ 2 diarrhea (15.4% vs. 4%; p < .01) and grade ≥ 2 hematologic adverse events (26.1% vs. 13.1%; p < .01) were observed in patients administered 3D-CRT as compared to IMRT. More patients reported diarrhea (37.5% vs. 28.6%; p = 0.125), bowel urgency (22.1% vs. 10%; p = .0039), and abdominal cramps (18.2% vs. 8.6%; p = .058) following 3D-CRT as compared to IMRT.

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.¹¹ 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 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.¹² 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.¹³ 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 3-Dimensioinal Conformal Radiotherapy versus Intensity-Modulated Radiotherapy for Cervical Cancer

Toxicity	3D-CRT, n (%)	IMRT, n (%)	95% CI for the Difference	p
Naik et al. (2016)12
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)13
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.¹⁴ 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.¹⁵ No significant differences between IMRT (n = 65) and CRT (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, 5 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 RT.

Interventions
The therapy being considered is IMRT. This therapy 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
Randomized Controlled Trials
Rattan et al. (2016) conducted a small (n = 20) RCT assessing IMRT for the treatment of anal canal cancer.¹⁶ 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.¹⁷ 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 education 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 3-Dimensioinal Conformal Radiotherapy or Intensity-Modulated Radiotherapy 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).¹⁷
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.¹⁸ 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 (HR, 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).¹⁸
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 (PFS), locoregional control, and colostomy-free survival did not differ significantly between patients treated with IMRT or with 3D-CRT (p > .1).¹⁹ 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.²⁰ 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).²¹ 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.²² IMRT 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.²³ Thirty-one patients had squamous cell carcinoma. IMRT 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 RT.

Interventions
The therapy being considered is IMRT. This therapy 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).²⁴ 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 2017.²⁵ 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), 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 esophageal cancer.²⁶ 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 in 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).²⁷ 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, radiodermatitis, nausea/vomiting, mucositis, bleeding, pneumonitis) was 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, 5 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. IMRT 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 U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network Guidelines
Gastrointestinal Tract Cancers
The National Comprehensive Cancer Network (NCCN) guideline (v.2.2022 ) for gastric cancer indicates that "CT simulation and conformity treatment planning should be used with either 3D-CRT or IMRT."²⁸ 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.1.2022 ) 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])."²⁹

IMRT is mentioned as an option in the NCCN guideline (v.1.2022 ) 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."³⁰ In addition, the guideline states that "there is no clear consensus on the appropriate maximum dose of radiation when IMRT is used."

Gynecologic Cancers
For cervical cancer, the NCCN guideline (v.1.2022 ) 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."³¹ IMRT "should not be used as routine alternatives 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.1.2022 ) 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."³²

The NCCN guideline (v.2.2022 ) on ovarian cancer does not mention IMRT.³³

Anorectal Cancers
The NCCN guideline (v.1.2022 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'."³⁴

The NCCN guideline (v.1.2022 ) on rectal cancer indicates that "IMRT is preferred for reirradiation of previously treated patients with recurrent disease, patients treated postoperatively due to increased acute or later toxicity, or unique anatomical situations."³⁵

Esophageal Cancer
The NCCN guideline (v.2.2022 ) for esophageal and esophagogastric junction cancers states that "CT stimulation and conformal treatment planning should be used with either 3D conformal radiation or IMRT."³⁶

American Society for Radiation Oncology
In 2020, the American Society for Radiation Oncology published a clinical practice guideline on RT for cervical cancer.³⁷ 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.³⁸ 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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28. National Comprehensive Cancer Network. Gastric Cancer. Version. 2.2022. Updated January 11, 2022. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed June 1, 2022.
29. National Comprehensive Cancer Network. Hepatobiliary Cancers. Version. 1.2022. Updated March 29, 2022 https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf. Accessed June 1, 2022.
30. National Comprehensive Cancer Network. Pancreatic Adenocarcinoma. Version 1.2022. Updated February 24, 2022. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed June 1, 2022.
31. National Comprehensive Cancer Network. Cervical Cancer. Version. 1.2022. Updated October 26, 2021. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed June 2, 2022.
32. National Comprehensive Cancer Network. Uterine Neoplasms. Version 1.2022. Updated November 4, 2021. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf. Accessed June 4, 2022.
33. National Comprehensive Cancer Network. Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer. Version.2.2022. Updated January 18, 2022. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed June 5, 2022.
34. National Comprehensive Cancer Network. Anal Carcinoma. Version. 1.2022. Updated March 2, 2022. https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf. Accessed June 6, 2022.
35. National Comprehensive Cancer Network. Rectal Cancer. Version.1.2022. Updated February 25, 2022. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed June 7, 2022.
36. National Comprehensive Cancer Network. Esophageal and esophagogastric junction cancers. Version 2.2022. Updated February 11, 2022. https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. Accessed June 3, 2022.
37. 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
38. 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
	77386	complex
HCPCS	G6015	Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session
	G6016	Compensator-based beam modulation treatment delivery of inverse planned treatment using 3 or more high resolution (milled or cast) compensator, convergent beam modulated fields, per treatment session
ICD-10-CM	C15.3-C15.9	Malignant neoplasm of esophagus, code range
	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		ICD-10-PCS codes are only used for inpatient services
	DD010ZZ, DD011ZZ, DD012ZZ, DD070ZZ, DD071ZZ, DD072ZZ	Radiation oncology, stomach or rectum, beam radiation, codes by anatomical location and modality (photons < 1 MeV, photons 1 – 10 MeV and photons > 10 MeV)
	DF000ZZ, DF001ZZ, DF002ZZ, DF010ZZ, DF011ZZ, DF012ZZ, DF020ZZ, DF021ZZ, DF022ZZ, DF030ZZ, DF031ZZ, DF032ZZ	Radiation oncology, liver, gall bladder, bile ducts, or pancreas, beam radiation, codes by anatomical location and modality (photons < 1 MeV, photons 1 – 10 MeV and photons > 10 MeV)
	DU000ZZ, DU001ZZ, DU002ZZ. DU010ZZ, DU011ZZ, DU012ZZ, DU020ZZ, DU021ZZ, DU022ZZ	Radiation oncology, ovary, cervix or uterus, beam radiation, codes by anatomical location and modality (photons < 1 MeV, photons 1 – 10 MeV and photons > 10 MeV)
Type of service	Radiology
Place of service	Inpatient

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

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

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

History From 2014 Forward     

05/09/2023	Annual review, no change to policy intent. Updating title, background, guidelines, rationale, references and coding.
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.