Description:
Radiotherapy is an integral component in the treatment of head and neck cancers. Intensity-modulated radiotherapy (IMRT) has been proposed as a method to allow adequate radiation to the tumor, minimizing the radiation dose to surrounding normal tissues and critical structures.

For individuals who have head and neck cancer who receive IMRT, the evidence includes comparative studies, systematic reviews, randomized controlled trials, and nonrandomized studies. The relevant outcomes are overall survival, functional outcomes, quality of life, and treatment-related morbidity. The single randomized controlled trial that compared IMRT with 3-dimensional conformal radiotherapy found a significant benefit of IMRT on xerostomia that persisted through five years. Oncologic outcomes did not differ significantly between treatments. Nonrandomized cohort studies have supported the findings that both short- and long-term xerostomia are reduced with IMRT. Overall, the evidence has shown that IMRT significantly and consistently reduces both early and late xerostomia and improves quality of life domains related to xerostomia compared with 3-dimensional conformal radiotherapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have thyroid cancer in close proximity to organs at risk who receive IMRT, the evidence includes nonrandomized, retrospective studies. The relevant outcomes include overall survival, functional outcomes, quality of life, and treatment-related morbidity. High-quality studies that differentiate the superiority of any type of external-beam radiotherapy to treat thyroid cancer are not available. However, the published evidence plus additional dosimetry considerations together suggest IMRT may be appropriate for thyroid tumors in some circumstances, such as for anaplastic thyroid carcinoma or thyroid tumors located near critical structures (e.g., salivary glands, spinal cord), similar to the situation for head and neck cancers. Thus, when adverse events could result if nearby critical structures receive toxic radiation doses, the ability to improve dosimetry with IMRT might be accepted as meaningful evidence for its benefit. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Clinical input obtained in 2012 provided a uniform consensus that IMRT is appropriate for the treatment of head and neck cancers. There was a near-uniform consensus that IMRT is appropriate in select patients with thyroid cancer. Respondents noted that IMRT for the head, neck, and thyroid tumors may reduce the risk of exposure to radiation in critical nearby structures (e.g., spinal cord, salivary glands), thus decreasing the risks of adverse events (e.g., xerostomia, esophageal stricture).    

Background 
HEAD AND NECK CANCERS
This evidence review focuses on cancers affecting the oral cavity and lip, larynx, hypopharynx, oropharynx, nasopharynx, paranasal sinuses and nasal cavity, salivary glands, and occult primaries in the head and neck region.

RADIOTHERAPY TECHNIQUES
Conventional External-Beam Radiotherapy
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 images, offers better conformality than 3D-CRT because it modulates the intensity of the overlapping radiation beams projected on the target and uses 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 developments have produced advanced techniques that may further improve RT treatment by improving dose distribution. These techniques are considered variations of IMRT. Volumetric modulated arc therapy delivers radiation from a continuously rotating 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 deliver RT to the target volume more precisely.

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 a single 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.

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 received marketing clearance through the FDA 510(k) process. Intensity modulators include the Innocure Intensity Modulating Radiation Therapy Compensators (Innocure) decimal tissue compensator (Southeastern Radiation Products) 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 received FDA 510(k) marketing clearance. These include the Prowess Panther (Prowess), TiGRT (LinaTech), and the Ray Dose (Ray Search Laboratories).FDA product code: MUJ.

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

Related Policies
80146 Intensity-Modulated Radiotherapy of the Breast and Lung
80147 Intensity-Modulated Radiotherapy of the Prostate
80149 Intensity-Modulated Radiation Therapy (IMRT): Abdomen and Pelvis
80159 Intensity-Modulated Radiotherapy: Central Nervous System Tumors

Policy:

• Intensity-modulated radiation therapy may be considered MEDICALLY NECESSARY for the treatment of head and neck cancers.
• Intensity-modulated radiation therapy may be considered MEDICALLY NECESSARY for the treatment of thyroid cancers in close proximity to organ at risk (esophagus, salivary glands, and spinal cord) and 3-D CRT planning is not able to meet dose volume constraints for normal tissue tolerance.  

• Intensity-modulated radiation therapy is NOT MEDICALLY NECESSARY for the treatment of thyroid cancers for all indications not meeting the criteria above.

Policy
For this policy, head and neck cancers are cancers arising from the oral cavity and lip, larynx, hypopharynx, oropharynx, nasopharynx, paranasal sinuses and nasal cavity, salivary glands, and occult primaries in the head and neck region.

Organs at risk are defined as normal tissues whose radiation sensitivity may significantly influence treatment planning and/or prescribed radiation dose. These organs at risk may be particularly vulnerable to clinically important complications from radiation toxicity. Table 1 outlines radiation doses that are generally considered tolerance thresholds for these normal structures in the area of the thyroid.

Table 1. Radiation Tolerance Doses for Normal Tissues    

	TD 5/5 Gya			TD 50/5 Gyb
	Portion of Organ Involved			Portion of Organ Involved
Site	1/3	2/3	3/3	1/3	2/3	3/3	Complication End Point
Esophagus	60	58	55	72	70	68	Stricture, perforation
Salivary glands	32	32	32	46	46	46	Xerostomia
Spinal cord	50 (5 – 10 cm)	NP	47 (20 cm)	70 (5 – 10 cm)	NP	NP	Myelitis, 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. Available online at: 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 years. 
^b TD 50/5, the average dose that results in a 50% complication risk within 5 year

Effective in 2015, code 77418 was deleted and new codes for simple and complex IMRT delivery were created:

77385: Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple
77386: complex.

The Centers for Medicare and Medicaid Services (CMS) decided not to implement this change for 2015 and instead created HCPCS G codes for the radiotherapy codes being deleted Dec. 31, 2014. 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, 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.

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.

For contracts that do not use this definition of medical necessity, other contract provisions including contract language concerning use of out-of-network providers and services may be applied. That is, if the alternative therapies (e.g., 3D-conformal treatments) are available in-network, but IMRT therapy is not, IMRT would not be considered an in-network benefit. In addition, benefit or contract language describing the "least costly alternative" may also be applicable for this choice of treatment.

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 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 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.

Head and Neck Cancers
Clinical Context and Therapy Purpose
The purpose of intensity-modulated radiotherapy (IMRT) in patients who have head and neck 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 improve the net health outcome in patients with head and neck cancers?

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

Populations 
The relevant population of interest is individuals with head and neck cancers. Head and neck cancers account for about 4% of all cancer cases in the U.S.^2, The generally accepted definition of head and neck cancers includes those arising from the oral cavity and lip, larynx, hypopharynx, oropharynx, nasopharynx, paranasal sinuses and nasal cavity, salivary glands, and occult primaries in the head and neck region. Cancers generally not considered as head and neck cancers include uveal and choroidal melanoma, cutaneous tumors of the head and neck, esophageal cancer, and tracheal cancer.

Interventions
The test being considered is IMRT. A proposed benefit of IMRT is to reduce toxicity to adjacent structures, allowing dose escalation to the target area and fewer breaks during treatment to reduce side effects.

Comparators 
The following practices are currently being used to treat cancer of the head and neck: 3-dimensional conformal radiotherapy (3D-CRT) and 2-dimensional radiotherapy (2D-RT).

Outcomes  The general outcomes of interest are overall survival (OS), functional outcomes, and treatment-related morbidity (e.g., xerostomia). Evaluation of patient-reported outcomes and quality of life measures are also of interest.

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 
Systematic reviews have evaluated IMRT compared to 2D-RT or 3D-CRT in patients with head and neck cancers. A comparison of the trials in more recent systematic reviews that included outcomes of interest is shown in Table 1. These systematic reviews included a total of 22 articles published between 2006 and 2018. Characteristics and results of these reviews are summarized in Tables 2 and 3. Overall, Du et al. (2019)³ and Luo et al. (2019)⁴ reported significantly improved OS, locoregional free survival/control, and progression- or disease-free survival (PFS or DFS) with IMRT versus 2D-RT or 3D-CRT among patients with nasopharyngeal carcinoma (NPC). Marta et al. (2014)⁵ concluded that IMRT, when compared with 2D-RT or 3D-CRT, had no significant impact on OS or loco-regional control in previously untreated patients with non-metastatic head and neck cancers. The incidence of xerostomia was significantly reduced with IMRT as compared to patients undergoing 2D-RT or 3D-CRT.^5,3 

There are inherent limitations to the data within some of these systematic reviews, including the prevalence of retrospective and nonrandomized study designs. Some studies had small sample sizes of 20 to 50 subjects. Studies also varied considerably with regard to tumor stage, length of follow-up, and radiological dose. All of these variations contributed to heterogeneity of the data. Additionally, 1 of the reviews specifically noted the existence of publication bias for the OS outcome.³

Table 1. Trials Included in Systematic Reviews of IMRT Versus 2D-RT or 3D-CRT

Trials	Systematic Reviews
	Marta et al. (2014)5,	Luo et al. (2019)4,	Du et al. (2019)3,
Kam et al. (2007)6	⚫		⚫
Lai et al. (2011)7		⚫	⚫
Peng et al. (2012) 8	⚫	⚫	⚫
Zhou et al. (2013)9			⚫
Moon et al. (2016)10		⚫	⚫
Zhang et al. (2015)11		⚫	⚫
Qiu et al. (2017)12		⚫	⚫
Tang et al. (2015)13			⚫
Lee et al. (2014)14			⚫
Zhong et al. (2013)15			⚫
OuYang et al. (2016)16		⚫
Jiang et al. (2015)17		⚫
Fang et al. (2008)18		⚫
Kuang et al. (2012)19		⚫
Huang et al. (2013)20,		⚫
Chen et al. (2014)21		⚫
Zou et al. (2015)22		⚫
Bisof et al. (2018)23		⚫
Pow et al. (2006)24	⚫
Nutting et al. (2011)25	⚫
Gupta et al. (2011)26	⚫
Gupta et al. (2012)27	⚫

2D-RT: 2-dimensional radiotherapy; 3D-CRT: 3-dimensional conformal radiotherapy; IMRT: intensity-modulated radiotherapy.

Table 2. Summary of Systematic Reviews of IMRT versus 2D-RT or 3D-CRT

Study	Dates	Trials	Participants	N (Range)	Design	Duration
Du et al. 20193	To December 1, 2018	10	Patients with nasopharyngeal carcinoma who underwent IMRT or 2D-RT	13,304 (56 to 7,081)	2 RCTs; 8 nonrandomized trials	Follow-up data evaluated up to 5 years for certain outcomes
Luo et al. 20194	To November 20, 2018	13	Patients with nasopharyngeal carcinoma who underwent IMRT or CRT	14,745 (24 to 7,081)	1 RCT; 1 prospective study; 11 retrospective studies	Mean follow-up: 42 to ≥ 60 months
Marta et al. 20145	To December 20, 2012	5 (6 publications corresponding to 5 trials)	Previously untreated patients with non-metastatic head and neck cancers treated with RT either primarily or combined with surgery or chemotherapy with or without brachytherapy boost	871 (45 to 616)	Prospective RCTs; 4 studies compared 2D-RT with IMRT	Follow-up data evaluated up to 5 years for certain outcomes

2D-RT: two-dimensional radiotherapy; 3D-CRT: three-dimensional conformal radiotherapy; CRT: conformal radiotherapy; IMRT: intensity-modulated radiotherapy; RCT: randomized controlled trial; RT: radiotherapy.

Table 3. Results of Systematic Reviews of IMRT versus 2D-RT or 3D-CRT 

Study	Overall survival	Locoregional free survival/ control rate	Progression- or disease-free survival	Metastasis-free survival	Xerostomia
Du et al. (2019)3		Local-regional free survival
Total N	10,851	13,003	9380	10,432	1764
Pooled effect OR (95% CI)	1.70 (1.36 to 2.21) at 5 years	2.08 (1.82 to 2.37) at 5 years	1.40 (1.26 to 1.56) at 5 years	1.11 (0.99 to 1.24)	0.21 (0.09 to 0.51)
I2; p value	68.7%;.007	20.7%;.272	0%;.446	17.9%;.301	87.3%;.00
Luo et al. (2019)4		Locoregional control
Total N	13,018	13,899	2464	4171
Pooled effect OR (95% CI); p value	0.51 (0.41 to 0.65); < .00001	0.59 (0.52 to 0.67); < .00001	0.77 (0.65 to 0.91);.002	0.71 (0.54 to 0.94);.01
I2; p value	63%;.002	44%;.06	38%;.15	54%;.03
Marta et al. (2014)5		Locoregional control
Total N	770	770			826
Pooled effect HR (95% CI); p value	1.12 (0.97 to 1.29);.11	1.07 (0.93 to 1.23);.35			0.76 (0.66 to 0.87); < .0001
I2; p value		0%; NR			0%; NR

2D-RT: two-dimensional radiotherapy; 3D-CRT: three-dimensional conformal radiotherapy; CI: confidence interval; HR: hazard ratio; NR: not reported; OR: odds ratio. 

In addition, to the systematic reviews summarized in Tables 1 to 3, Ursino et al. (2017) published a systematic review of 22 studies (N = 1,311 patients) that focused specifically on swallowing outcomes in patients treated with 3D-CRT or IMRT for head and neck cancer.²⁸ The heterogeneity of the population limited analysis, but reviewers concluded that IMRT produced markedly better results than 3D-CRT in terms of swallowing impairments, aspiration, pharyngeal residue, and functional parameters, especially when swallowing-related organs at risk were specifically taken into account during IMRT treatment planning. The analysis was limited by a lack of standardized evaluation questionnaires, objective instrumental parameter scores, amount and consistency of bolus administration, and timing of evaluations. 

Ge. et al (2020) recently evaluated the effects of IMRT as compared to conventional RT with regard to quality of life and xerostomia severity in 761 patients with head and neck cancer.²⁹ This meta-analysis included data from 7 studies: 3 RCTs, 2 prospective studies, 1 prospective case control study, and 1 retrospective study. Overall, patients who underwent IMRT had a better global health status (pooled standardized mean difference (SMD), 0.80; 95% CI: 0.26 to 1.35; p = .004) and improved cognitive function (pooled SMD, 0.30; 95% CI: 0.06 to 0.54; p = .013) as compared to patients who underwent conventional RT. Intensity-modulated radiotherapy was also associated with significantly lower scores for xerostomia than conventional RT (pooled SMD, -0.60; 95% CI; -0.97 to -0.24; p = .001). There were no differences between the groups with regard to emotional function (p = .531) and social function (p = .348). The analysis was limited by a small number of included studies, heterogeneity of data, and relatively small sample sizes. 

Randomized Controlled Trials 
Beyond the trials included in the systematic reviews, Tandon et al. (2018) published a non-blinded RCT, which compared 2 fractionation schedules of IMRT for locally advanced head and neck cancer — simultaneous integrated boost (SIB-IMRT) and simultaneous modulated accelerated radiotherapy (SMART) — with the endpoint measures of toxicity, PFS, and OS.³⁰ Characteristics and results of this RCT are summarized in Tables 4 and 5. The SIB-IMRT group received 70, 63, and 56 gray (Gy) in 35 fractions to clinical target volumes 1, 2, and 3, respectively. The SMART group received 60 and 50 Gy to clinical target volumes 1 and clinical target volumes 3, respectively. No statistically significant differences in acute or late toxicities were found between the groups except in fatigue, which was experienced by 66.7% of the control group and 40.0% of the study group (p = .038). At 2 years post-treatment, PFS and OS were improved for the SMART versus SIB-IMRT group (Table 5). The small sample sizes within subgroups, which result in greater standard errors and less power, may have prevented any meaningful interpretation of subgroup analysis. Also, due to cost, human papillomavirus (HPV) status was not part of the pre-treatment workup; the treatment response and prognosis for HPV-positive tumors are considerably different compared to HPV-negative tumors, but this factor could not be included in the analysis. Relevance, study design, and conduct limitations of the RCT are detailed in Tables 6 and 7.

Table 4. Characteristics of a RCT Comparing SIB-IMRT versus SMART

Study	Countries	Sites	Dates	Participants	Interventions
Tandon et al. (2018)30	India	1	June 2014 to March 2016	Adults (18 to 65 years) with Stage III or non-metastatic Stage IV locally advanced head and neck cancer	RT using standard SIB-IMRT fractionation RT using SMART boost technique

RCT: randomized controlled trial; RT: radiotherapy; SIB-IMRT: simultaneous integrated boost-intensity-modulated radiotherapy; SMART: simultaneous modulated accelerated radiotherapy.

Table 5. Results of the SIB-IMRT versus SMART RCT 

Study	Overall survival (2 years)	Progression-free survival (2 years)
Tandon et al. (2018)30
N	NR	NR
SIB-IMRT	60%	53.3%
SMART	86.7%	80%
p	.02	.28

NR: not reported; SIB-IMRT: simultaneous integrated boost-intensity-modulated radiotherapy; SMART: simultaneous modulated accelerated radiotherapy.

Table 6. Study Relevance Limitations of the SIB-IMRT versus SMART RCT

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Duration of follow-upe
Tandon et al. (2018)30	4. Small sample sizes within each subgroup			1. Locoregional control not addressed

SIB-IMRT: simultaneous integrated boost-intensity-modulated radiotherapy; SMART: simultaneous modulated accelerated radiotherapy. 
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
^a  Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b  Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c  Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d  Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e  Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms. 

Table 7. Study Design and Conduct Limitations of the SIB-IMRT versus SMART RCT. 

Study	Allocationa	Blindingb	Selective reportingc	Data Completenessd	Powere	Statisticalf
Tandon et al. (2018)30	3. Allocation using "chit method"	1, 2		1. During follow-up, there were 11 disease-related deaths (7 SIB-IMRT; 4 SMART) and 4 non-disease-related deaths each in both arms	3. Sample size calculated based on historical trials; power analysis done to detect a difference in incidence of toxicity not survival	1. Survival statistics required still median follow-up for deriving clinically meaningful results

SIB-IMRT: simultaneous integrated boost-intensity-modulated radiotherapy; SMART: simultaneous modulated accelerated radiotherapy.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

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

Nonrandomized Comparative Studies
Nonrandomized comparative studies have evaluated late toxicities and quality-of-life after treatment with IMRT, 2D-RT, and 3D-CRT.

Qiu et al. (2017) published a retrospective, single-center study comparing 2D-CRT and IMRT as treatments for NPC in children and adolescents.¹² All 176 patients (74 treated with 2D-CRT, 102 with IMRT) identified for the study were between 7 and 20 years old and treated at a single institution. The OS rate at 5 years was significantly higher for IMRT than 2D-CRT (90.4% vs. 76.1%, respectively; hazard ratio (HR), 0.30; 95% CI, 0.12 to 0.78; p = .007), as well as the 5-year DFS rate (85.7% vs. 71.2%, respectively; HR, 0.47; 95% CI, 0.23 to 0.94; p = .029). Grade 2, 3, and 4 xerostomia (52.7% vs. 34%, respectively; p = .015) and hearing loss (40.5% vs. 22.5%, respectively; p = .01) were also significantly lower with IMRT than with 2D-CRT. The duration of follow-up for late-onset radiation-induced toxicity and small sample size are limitations of the report.

A cross-sectional study by Huang et al. (2016) assessed patients who had survived more than 5 years after treatment for NPC.³¹ Of 585 NPC survivors, data were collected on 242 patients who met study selection criteria (no history of tumor relapse or second primary cancers, cancer-free survival > 5 years, completion of the self-reported questionnaire). Treatments were given from 1997 to 2007, with the transition to the IMRT system in 2002. One hundred patients were treated with IMRT. Prior to use of IMRT, treatments included 2D-RT (n = 39), 3D-CRT (n = 24), and 2D-RT plus 3D-CRT boost (n = 79). Patients had scheduled follow-ups at 3- to 4-month intervals until 5 years posttreatment; then, at 6-month intervals thereafter. Late toxicities (e.g., neuropathy, hearing loss, dysphagia, xerostomia, neck fibrosis) were routinely assessed at clinical visits. At the time of the study, the mean follow-up was 8.5 years after 2D-RT or 3D-CRT, and 6.4 years after IMRT. The IMRT group had statistically and clinically superior results for both clinician-assessed and patient-assessed (global quality-of-life, cognitive functioning, social functioning, fatigue, and 11 scales of a head and neck module) outcomes with moderate effect sizes after adjusting for covariates (Cohen d range, 0.47 to 0.53). Late toxicities were less severe in the IMRT group, with adjusted odd ratios (ORs) of 3.2, 4.8, 3.8, 4.1, and 5.3 for neuropathy, hearing loss, dysphagia, xerostomia, and neck fibrosis, respectively. No significant differences in late toxicities were observed between the 2D-RT and the 3D-CRT groups.

Section Summary: Head and Neck Cancer
The literature on IMRT for head and neck cancer includes systematic reviews as well as RCTs and nonrandomized comparative studies. Some of the most recently published systematic reviews compared IMRT to 2D-RT and 3D-CRT in patients with NPC. Results revealed a significant improvement in clinical oncologic outcomes (e.g., OS, PFS, locoregional control/survival) and toxicities such as xerostomia with IMRT in this patient population. A 2014 systematic review concluded that IMRT, when compared with 2D-RT or 3D-CRT, had no significant impact on OS or locoregional control in previously untreated patients with non-metastatic head and neck cancers; however, a significant improvement in xerostomia was observed with IMRT. Nonrandomized comparative studies have compared IMRT with 3D-CRT or with 2D-RT plus 3D-CRT boost. These studies support the findings that both short- and long-term xerostomia is reduced with IMRT. Health-related quality of life was also improved with IMRT compared with 3D-CRT or with 2D-RT plus 3D-CRT boost. Comparators in these nonrandomized studies were generally older technologies (e.g., 2D-RT) with older treatment protocols, both of which limit interpretation of the results. For the outcomes of PFS and OS, another RCT compared 2 fractionation schedules of IMRT and found SMART superior to SIB-IMRT in the areas of 2-year PFS and OS.

Thyroid Cancer
Clinical Context and Therapy Purpose
The purpose of IMRT in patients who have thyroid 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 improve the net health outcome in patients with thyroid cancer?

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

Populations
The relevant population of interest is patients with thyroid cancer in close proximity to organs at risk. Anaplastic thyroid cancer occurs in less than 2% of patients with thyroid cancer.^32,

Interventions
The test being considered is IMRT. A proposed benefit of IMRT is to reduce toxicity to adjacent structures, allowing dose escalation to the target area and fewer breaks during treatment to reduce side effects.

Comparators
The following practices are currently being used to treat cancer of the thyroid: 3D-CRT and 2D-RT. Conventional external-beam radiotherapy is uncommonly used in the treatment of thyroid cancers, but may be considered in patients with anaplastic thyroid cancer and for locoregional control in patients with incompletely resected high-risk or recurrent differentiated (papillary, follicular, or mixed papillary-follicular) thyroid cancer. In particular, for patients with anaplastic thyroid cancer variants, which are uncommon but have often demonstrated local invasion at the time of diagnosis, RT is a critical part of locoregional therapy.

Outcomes
The general outcomes of interest are OS, functional outcomes, and treatment-related morbidity. Evaluation of patient-reported outcomes and quality of life measures are also of interest. Locoregional control and OS should be assessed at 1 and 5 years.

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

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

Review of Evidence
Case Series
The best available evidence for this indication consists of case series. For example, Bhatia et al. (2010) published a series that reviewed institutional outcomes for anaplastic thyroid cancer treated with 3D-CRT or IMRT in 53 consecutive patients.³³ Thirty-one (58%) patients were irradiated with curative intent. Median radiation dose was 55 Gy (range, 4 to 70 Gy). Thirteen (25%) patients received IMRT to a median of 60 Gy (range, 39.9 to 69.0 Gy). The Kaplan-Meier estimate of OS at 1 year for definitively irradiated patients was 29%. Patients without distant metastases receiving 50 Gy or more had superior survival outcomes; in this series, use of IMRT or 3D-CRT did not influence toxicity.

Schwartz et al. (2009) retrospectively reviewed single-institution outcomes for patients treated for differentiated thyroid cancer with postoperative conformal external-beam RT.³⁴ One hundred thirty-one consecutive patients with differentiated thyroid cancer who underwent RT between 1996 and 2005 were included. Histologic diagnoses included 104 papillary, 21 follicular, and 6 mixed papillary-follicular types. Thirty-four (26%) patients had high-risk histologic types, and 76 (58%) had recurrent disease. Extraglandular disease progression was seen in 126 (96%) patients, microscopically positive surgical margins were seen in 62 (47%) patients, and gross residual disease was seen in 15 (11%) patients. Median RT dose was 60 Gy (range, 38 to 72 Gy). Fifty-seven (44%) patients were treated with IMRT to a median dose of 60 Gy (range, 56 to 66 Gy). Median follow-up was 38 months (range, 0 to 134 months). Kaplan-Meier estimates of locoregional relapse-free survival, disease-specific survival, and OS at 4 years were 79%, 76%, and 73%, respectively. On multivariate analysis, high-risk histologic features, M1 (metastatic) disease, and gross residual disease were predictors for inferior disease-specific survival and OS. Intensity-modulated radiotherapy did not impact survival outcomes, but was associated with less frequent severe late morbidity (12% vs. 2%, respectively), primarily esophageal stricture.

Section Summary: Thyroid Cancer
The evidence on IMRT in individuals who have thyroid cancer includes case series data. High-quality studies that differentiate the superiority of any type of external-beam RT technique to treat thyroid cancer are not available. Limitations of published evidence include patient heterogeneity, variability in treatment protocols, short follow-up periods, inconsistency in reporting important health outcomes (e.g., OS vs PFS or tumor control rates), and inconsistency in reporting or collecting outcomes. However, the published evidence plus additional dosimetry considerations together suggest IMRT for thyroid tumors may be appropriate in some circumstances (e.g., anaplastic thyroid carcinoma) or for thyroid tumors located near critical structures (e.g., salivary glands, spinal cord), similar to the situation for head and neck cancers. Given the rarity of both anaplastic thyroid cancer and papillary thyroid cancers that are not treatable by other methods, high-quality trials are unlikely. Thus, when adverse events could result if nearby critical structures receive toxic radiation doses, the ability to improve dosimetry with IMRT may be accepted as meaningful evidence for its benefit.

Summary of Evidence
For individuals who have head and neck cancer who receive IMRT, the evidence includes systematic reviews, RCTs, and nonrandomized comparative studies. Relevant outcomes are OS, functional outcomes, quality of life, and treatment-related morbidity. Recently published systematic reviews compared IMRT to 2D-RT and CRT in patients with NPC. Results revealed a significant improvement in clinical oncologic outcomes (e.g., OS, PFS, locoregional control/survival) and toxicities such as xerostomia with IMRT in this patient population. A 2014 systematic review concluded that IMRT, when compared with 2D-RT or 3D-CRT, had no significant impact on OS or locoregional control in previously untreated patients with non-metastatic head and neck cancers; however, IMRT was associated with a significant improvement in xerostomia. One RCT compared 2 fractionation schedules of IMRT for locally advanced head and neck cancer and found a survival benefit in using SMART boost over SIB-IMRT. Nonrandomized cohort studies have supported the findings that both short- and long-term xerostomia are reduced with IMRT. Overall, evidence has shown that IMRT significantly and consistently reduces both early and late xerostomia and improves quality of life domains related to xerostomia compared with 2D-RT or 3D-CRT. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have thyroid cancer in close proximity to organs at risk who receive IMRT, the evidence includes case series data. Relevant outcomes include OS, functional outcomes, quality of life, and treatment-related morbidity. High-quality studies that differentiate the superiority of any type of external beam RT to treat thyroid cancer are not available. However, the published evidence plus additional dosimetry considerations together suggest IMRT may be appropriate for thyroid tumors in some circumstances, such as for anaplastic thyroid carcinoma or thyroid tumors located near critical structures (e.g., salivary glands, spinal cord), similar to the situation for head and neck cancers. Thus, when adverse events could result if nearby critical structures receive toxic radiation doses, the ability to improve dosimetry with IMRT might be accepted as meaningful evidence for its benefit. 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.

In response to requests, input was received from 2 physician specialty societies (3 reviewers) and 4 academic medical centers while this policy was under review in 2012. There was a uniform consensus that intensity-modulated radiotherapy (IMRT) is appropriate for the treatment of head and neck cancers. There was a near uniform consensus that IMRT is appropriate in select patients with thyroid cancer. Respondents noted IMRT for head, neck, and thyroid tumors may reduce the risk of exposure to radiation in critical nearby structures (e.g., spinal cord, salivary glands), thus decreasing risks of adverse effects (e.g., xerostomia, esophageal stricture).

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

National Comprehensive Cancer Network
The NCCN (v.3.2021) guideline on head and neck cancer notes that: "Advanced radiation therapy technologies such as IMRT, tomotherapy, volumetric modulated arc therapy (VMAT), image-guided radiation therapy (IGRT), and proton beam therapy (PBT) may offer clinically relevant advantages in specific circumstances to spare important organs at risk (OARs) ... and decrease the risk for late, normal tissue damage while still achieving the primary goal of local tumor control.³⁵ The demonstration of clinically significant dose-sparing of these OARS reflects best clinical practice." The NCCN guideline also notes that "randomized studies to test (advanced radiation therapy technologies) are unlikely to be done since specific clinical scenarios represent complex combinations of multiple variables. In light of that, the modalities and techniques that are found best to reduce the doses to the clinically relevant OARs without compromising target coverage should be considered."

The NCCN (v.1.2021) guideline for thyroid cancer states, "External-beam radiotherapy (EBRT) or IMRT can increase short-term survival in some patients with anaplastic thyroid carcinoma; EBRT or IMRT can also improve local control and can be used for palliation (e.g., to prevent asphyxiation)." Additionally, the guideline notes, "IMRT may be useful to reduce toxicity" in these patients.³⁶ The NCCN also states that the use of IMRT can be considered if an unresectable, gross residual disease or locoregional recurrence threatens vital structures in the neck.

American Thyroid Association
The American Thyroid Association published guidelines for the management of patients with anaplastic thyroid cancer in 2021.³⁷ These guidelines contained the following recommendations regarding use of IMRT:

• Following R0 or R1 resection, we recommend that good performance status patients with no evidence of metastatic disease who wish an aggressive approach should be offered standard fractionation IMRT with concurrent systemic therapy. 
  Strength of recommendation: strong; Quality of evidence: low.
• We recommend that patients who have undergone R2 resection or have unresectable but nonmetastatic disease with good performance status and who wish an aggressive approach be offered standard fractionation IMRT with systemic therapy. 
  Strength of recommendation: strong; Quality of evidence: low.
• Among patients who are to receive radiotherapy for unresectable thyroid cancer or in the postoperative setting, IMRT is recommended. 
  Strength of recommendation: strong; Quality of evidence: low.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 8.

Table 8. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01220583	A Randomized Phase II/Phase III Study of Adjuvant Concurrent Radiation and Chemotherapy Versus Radiation Alone in Resected High-Risk Malignant Salivary Gland Tumors	252	Oct 2028

NCT: national clinical trial.

References 

1. Shinohara E, Whaley JT. Radiation therapy: which type is right for me? University of Pennsylvania. OncoLink site. Reviewed March 3, 2020. https://www.oncolink.org/print/pdf/5965?print_5965.pdf. Accessed May 20, 2020
2. American Society of Clinical Oncology. Cancer.Net site. Head and neck cancer: statistics. January 2020. https://www.cancer.net/cancer-types/head-and-neck-cancer/statistics. Accessed May 20, 2020
3. Du T, Xiao J, Qiu Z, et al. The effectiveness of intensity-modulated radiation therapy versus 2D-RT for the treatment of nasopharyngeal carcinoma: A systematic review and meta-analysis. PLoS One. 2019; 14(7): e0219611. PMID 31291379
4. Luo MS, Huang GJ, Liu HB. Oncologic outcomes of IMRT versus CRT for nasopharyngeal carcinoma: A meta-analysis. Medicine (Baltimore). Jun 2019; 98(24): e15951. PMID 31192932
5. Marta GN, Silva V, de Andrade Carvalho H, et al. Intensity-modulated radiation therapy for head and neck cancer: systematic review and meta-analysis. Radiother Oncol. Jan 2014; 110(1): 9-15. PMID 24332675
6. Kam MK, Leung SF, Zee B, et al. Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol. Nov 01 2007; 25(31): 4873-9. PMID 17971582
7. Lai SZ, Li WF, Chen L, et al. How does intensity-modulated radiotherapy versus conventional two-dimensional radiotherapy influence the treatment results in nasopharyngeal carcinoma patients?. Int J Radiat Oncol Biol Phys. Jul 01 2011; 80(3): 661-8. PMID 20643517
8. Peng G, Wang T, Yang KY, et al. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother Oncol. Sep 2012; 104(3): 286-93. PMID 22995588
9. Zhou GQ, Yu XL, Chen M, et al. Radiation-induced temporal lobe injury for nasopharyngeal carcinoma: a comparison of intensity-modulated radiotherapy and conventional two-dimensional radiotherapy. PLoS One. 2013; 8(7): e67488. PMID 23874422
10. Moon SH, Cho KH, Lee CG, et al. IMRT vs. 2D-radiotherapy or 3D-conformal radiotherapy of nasopharyngeal carcinoma : Survival outcome in a Korean multi-institutional retrospective study (KROG 11-06). Strahlenther Onkol. Jun 2016; 192(6): 377-85. PMID 26972085
11. Zhang MX, Li J, Shen GP, et al. Intensity-modulated radiotherapy prolongs the survival of patients with nasopharyngeal carcinoma compared with conventional two-dimensional radiotherapy: A 10-year experience with a large cohort and long follow-up. Eur J Cancer. Nov 2015; 51(17): 2587-95. PMID 26318726
12. Qiu WZ, Peng XS, Xia HQ, et al. A retrospective study comparing the outcomes and toxicities of intensity-modulated radiotherapy versus two-dimensional conventional radiotherapy for the treatment of children and adolescent nasopharyngeal carcinoma. J Cancer Res Clin Oncol. Aug 2017; 143(8): 1563-1572. PMID 28342002
13. Tang LL, Chen L, Mao YP, et al. Comparison of the treatment outcomes of intensity-modulated radiotherapy and two-dimensional conventional radiotherapy in nasopharyngeal carcinoma patients with parapharyngeal space extension. Radiother Oncol. Aug 2015; 116(2): 167-73. PMID 26316395
14. Lee AW, Ng WT, Chan LL, et al. Evolution of treatment for nasopharyngeal cancer--success and setback in the intensity-modulated radiotherapy era. Radiother Oncol. Mar 2014; 110(3): 377-84. PMID 24630534
15. Zhong H, Chen G, Lin D, et al. [Comparison of side effects of intensity modulated radiotherapy and conventional radiotherapy in 69 cases with nasopharyngeal carcinoma]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. May 2013; 27(9): 462-4. PMID 23898610
16. OuYang PY, Shi D, Sun R, et al. Effect of intensity-modulated radiotherapy versus two-dimensional conventional radiotherapy alone in nasopharyngeal carcinoma. Oncotarget. May 31 2016; 7(22): 33408-17. PMID 27058901
17. Jiang H, Wang G, Song H, et al. Analysis of the efficacy of intensity-modulated radiotherapy and two-dimensional conventional radiotherapy in nasopharyngeal carcinoma with involvement of the cervical spine. Oncol Lett. Nov 2015; 10(5): 2731-2738. PMID 26722233
18. Fang FM, Chien CY, Tsai WL, et al. Quality of life and survival outcome for patients with nasopharyngeal carcinoma receiving three-dimensional conformal radiotherapy vs. intensity-modulated radiotherapy-a longitudinal study. Int J Radiat Oncol Biol Phys. Oct 01 2008; 72(2): 356-64. PMID 18355980
19. Kuang WL, Zhou Q, Shen LF. Outcomes and prognostic factors of conformal radiotherapy versus intensity-modulated radiotherapy for nasopharyngeal carcinoma. Clin Transl Oncol. Oct 2012; 14(10): 783-90. PMID 22855156
20. Huang HI, Chan KT, Shu CH, et al. T4-locally advanced nasopharyngeal carcinoma: prognostic influence of cranial nerve involvement in different radiotherapy techniques. ScientificWorldJournal. 2013; 2013: 439073. PMID 24385882
21. Chen C, Yi W, Gao J, et al. Alternative endpoints to the 5-year overall survival and locoregional control for nasopharyngeal carcinoma: A retrospective analysis of 2,450 patients. Mol Clin Oncol. May 2014; 2(3): 385-392. PMID 24772305
22. Zou X, Han F, Ma WJ, et al. Salvage endoscopic nasopharyngectomy and intensity-modulated radiotherapy versus conventional radiotherapy in treating locally recurrent nasopharyngeal carcinoma. Head Neck. Aug 2015; 37(8): 1108-15. PMID 24764204
23. Bisof V, Rakusic Z, Bibic J, et al. Comparison of intensity modulated radiotherapy with simultaneous integrated boost (IMRT-SIB) and a 3-dimensional conformal parotid gland-sparing radiotherapy (ConPas 3D-CRT) in treatment of nasopharyngeal carcinoma: a mono-institutional experience. Radiol Med. Mar 2018; 123(3): 217-226. PMID 29094268
24. Pow EH, Kwong DL, McMillan AS, et al. Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial. Int J Radiat Oncol Biol Phys. Nov 15 2006; 66(4): 981-91. PMID 17145528
25. Nutting CM, Morden JP, Harrington KJ, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol. Feb 2011; 12(2): 127-36. PMID 21236730
26. Gupta T, Jain S, Agarwal JP, et al. Prospective assessment of patterns of failure after high-precision definitive (chemo)radiation in head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. Jun 01 2011; 80(2): 522-31. PMID 20646862
27. Gupta T, Agarwal J, Jain S, et al. Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: a randomized controlled trial. Radiother Oncol. Sep 2012; 104(3): 343-8. PMID 22853852
28. Ursino S, D'Angelo E, Mazzola R, et al. A comparison of swallowing dysfunction after three-dimensional conformal and intensity-modulated radiotherapy : A systematic review by the Italian Head and Neck Radiotherapy Study Group. Strahlenther Onkol. Nov 2017; 193(11): 877-889. PMID 28616822
29. Ge X, Liao Z, Yuan J, et al. Radiotherapy-related quality of life in patients with head and neck cancers: a meta-analysis. Support Care Cancer. Jun 2020; 28(6): 2701-2712. PMID 31673782
30. Tandon S, Gairola M, Ahlawat P, et al. Randomized controlled study comparing simultaneous modulated accelerated radiotherapy versus simultaneous integrated boost intensity modulated radiotherapy in the treatment of locally advanced head and neck cancer. J Egypt Natl Canc Inst. Sep 2018; 30(3): 107-115. PMID 29960876
31. Huang TL, Chien CY, Tsai WL, et al. Long-term late toxicities and quality of life for survivors of nasopharyngeal carcinoma treated with intensity-modulated radiotherapy versus non-intensity-modulated radiotherapy. Head Neck. Apr 2016; 38 Suppl 1: E1026-32. PMID 26041548
32. American Thyroid Association. Anaplastic thyroid cancer. https://www.thyroid.org/anaplastic-thyroid-cancer/. Accessed May 20, 2020
33. Bhatia A, Rao A, Ang KK, et al. Anaplastic thyroid cancer: Clinical outcomes with conformal radiotherapy. Head Neck. Jul 2010; 32(7): 829-36. PMID 19885924
34. Schwartz DL, Lobo MJ, Ang KK, et al. Postoperative external beam radiotherapy for differentiated thyroid cancer: outcomes and morbidity with conformal treatment. Int J Radiat Oncol Biol Phys. Jul 15 2009; 74(4): 1083-91. PMID 19095376
35. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology: Head and Neck Cancers. Version 3.2021. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf Accessed July 27, 2021.
36. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology: Thyroid Carcinoma. Version 1.2021. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Accessed July 26, 2021.
37. Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid Association Guidelines for Management of Patients with Anaplastic Thyroid Cancer. Thyroid. Mar 2021; 31(3): 337-386. PMID 33728999

Coding Section

Codes	Number	Description
CPT	77301	Intensity modulated radiotherapy plan, including dose volume histograms for target and critical structure partial tolerance specification
	77338	Multi-leaf collimator (MLC) device(s) for intensity modulated 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 MLC, 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)
ICD-9-CM Diagnosis	140.0-149.9	Malignant neoplasm of lip, oral cavity, and pharynx, code range
	160.00	Malignant neoplasm of nasal cavities
	160.2-160.5	Malignant neoplasm of the accessory sinuses, code range
	161.0-161.9	Malignant neoplasm of larynx
ICD-9-CM Procedure	92.29	Other radiotherapeutic procedure
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-10-CM (effective 10/01/15)	C00.0-C14.8	Malignant neoplasm of lip, oral cavity and pharynx code range
	C30.0	Malignant neoplasm of nasal cavity
	C31.0-C31.9	Malignant neoplasm of accessory sinuses code range
	C32.0-C32.9	Malignant neoplasm of larynx 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 therapy.
	D9000ZZ, D9001ZZ, D9002ZZ, D9010ZZ, D9011ZZ, D9012ZZ, D9030ZZ, D9031ZZ, D9032ZZ, D9040ZZ, D9041ZZ, D9042ZZ, D9050ZZ, D9051ZZ, D9051ZZ, D9060ZZ, D9061ZZ, D9062ZZ, D9070ZZ, D9071ZZ, D9072ZZ, D9080ZZ, D9081ZZ, D9082ZZ, D9090ZZ, D9091ZZ, D9092ZZ, D90B0ZZ, D90B1ZZ, D90B2ZZ, D90D0ZZ, D90D1ZZ, D90D2ZZ, D90F0ZZ, D90F1ZZ, D90F2ZZ	Radiation oncology, ear, nose, mouth and throat, beam radiation, codes by anatomical location and modality (photons < 1 MeV, photons 1-10 MeV and photons > 10 MeV)
	DW010ZZ, DW011ZZ, DW012ZZ	Radiation oncology, anatomical regions, beam radiation, head and neck, codes by modality (photons < 1 MeV, photons 1-10 MeV and photons > 10 MeV)
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     

08/16/2022	Annual review, no change to policy intent.
08/10/2021	Annual review, no change to policy intent. Updating rationale and references.
08/10/2020	Annual review, no change to policy intent. Updating rationale and references.
08/07/2019	Annual review, no change to policy intent. Updating description.
08/27/2018	Annual review, no change to policy intent. Updating background, rationale and references.
08/14/2017	Annual review, no change to policy intent. Updating background, description, rationale and references.
08/03/2016	Annual review, no change to policy intent. Updating background, description, rationale and references.
07/11/2016	Updated Review date to reflect August review date.
08/26/2015	Updated Title to reflect BCA's title.
08/06/2015	Annual review, no change to policy intent. Updated background, description, guidelines, rationale and references. Added regulatory status and coding.
07/23/2014	Annual review.  Added policy verbiage that states: Intensity-modulated radiation therapy is not medically necessary for the treatment of thyroid cancers for all indications not meeting the criteria above. Updated background, description, rationale and references. Added related policies.