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

Summary of Evidence
For individuals who have head and neck cancer who receive intensity-modulated radiotherapy (IMRT), the evidence includes systematic reviews, randomized controlled trials (RCTs) , and nonrandomized comparative studies. Relevant outcomes are overall survival (OS), functional outcomes, quality of life, and treatment-related morbidity. Recently published systematic reviews compared IMRT to 2-dimensional radiotherapy (2D-RT) and 3-dimensional conformal radiotherapy (3D-CRT) in patients with nasopharyngeal carcinoma. Results revealed a significant improvement in clinical oncologic outcomes (e.g., OS, progression-free survival , 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. A 2023 systematic review concluded that local and regional control are similar for patients with early stage glottic cancer treated with IMRT and 2D-RT or 3D-CRT.One RCT compared 2 fractionation schedules of IMRT for locally advanced head and neck cancer and found a survival benefit in using simultaneous modulated accelerated radiotherapy boost over simultaneous integrated boost-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 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 an improvement in the net health outcome.

Additional Information
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
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 to 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 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
Intensity-modulated radiotherapy 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) and Decimal Tissue Compensator (Southeastern Radiation Products), cleared in 2006 and 2004, respectively. FDA product code: IXI. Intensity modulators may be added to standard linear accelerators to deliver IMRT when used with proper treatment planning systems.

Radiotherapy treatment planning systems have also been cleared for marketing by the FDA through the 510(k) process. They include the Prowess Panther (Prowess) cleared in 2003, TiGRT (LinaTech) cleared in 2009, and the Ray Dose (RaySearch Laboratories) cleared in 2008. FDA product code: MUJ.

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

Policy:

• Intensity-modulated 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    

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.
^aTD 5/5, the average dose that results in a 5% complication risk within 5 years. 
^bTD 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 & 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.

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

Head and Neck Cancers
Clinical Context and Therapy Purpose
The purpose of intensity-modulated radiotherapy (IMRT) in individuals who have head and neck cancers is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

Populations
The relevant population of interest is individuals with 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

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

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 

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% confidence interval [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 radiotherapy (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.

Razavian et al. (2023) performed a systematic review and meta-analysis that compared IMRT to 2D-RT or 3D-CRT in patients with early stage squamous cell carcinoma of the glottic larynx.³⁰ A total of 15 studies (14 retrospective, 1 prospective) consisting of 2,083 patients were included. Among the studies (n = 5) that reported outcomes of both treatment modalities (IMRT and 2D-RT/3D-CRT), no significant difference was found in the rate of local failure between the 2 modalities (log odds ratio, -0.48; 95% CI, -1.09 to 0.14; p = .12). Similarly, no significant difference was found in the rate of regional failure between the 2 modalities (log odds ratio, 0.25; 95% CI, -0.66 to 1.16; p = .58). Notably, all 5 studies used for the direct comparison between the 2 treatment techniques were retrospective, and employed different IMRT techniques and heterogeneous methods for treatment volume delineation. Despite these limitations, authors state that pooled outcomes data found that IMRT for early glottis larynx cancer is associated with low rates of local and regional failure, which are in line with historic outcomes of 2D-RT/3D-CRT.

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.³¹ 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 an RCT Comparing SIB-IMRT Versus SMART

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 

NR: not reported; RCT: randomized controlled trial; 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

RCT: randomized controlled trial; 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 

RCT: randomized controlled trial; 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.³² 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. A 2023 systematic review concluded that retrospective data suggest that local and regional control are similar for patients with early stage glottic cancer treated with IMRT and 2D-RT or 3D-CRT.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 individuals who have thyroid cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

Populations
The relevant population of interest is individuals with thyroid cancer in close proximity to organs at risk. Anaplastic thyroid cancer occurs in less than 2% of patients with thyroid cancer.³³

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.³⁴ Thirty-one (58%) patients were irradiated with curative intent. Median radiation dose was 55 Gy (range, 4 to 70). Thirteen (25%) patients received IMRT to a median of 60 Gy (range, 39.9 to 69.0 ). 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.³⁵ 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). Fifty-seven (44%) patients were treated with IMRT to a median dose of 60 Gy (range, 56 to 66 ). Median follow-up was 38 months (range, 0 to 134 ). 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.

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 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 National Comprehensive Cancer Network (NCCN; v1.2023) guideline on head and neck cancers notes that: "Advanced RT [radiation therapy] technologies such as IMRT, tomotherapy, VMAT [volumetric modulated arc therapy] , image-guided RT (IGRT), and PBT [proton beam therapy] 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.³⁶ 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 (v1.2023) guideline for thyroid cancer states, "EBRT [external-beam radiotherapy] 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.³⁷ 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 2021.³⁸ 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: national clinical trial.

References 

1. Misher C. Radiation therapy: which type is right for me? University of Pennsylvania. OncoLink site. Reviewed March 16, 2022. https://www.oncolink.org/print/pdf/5965?print_5938_radiation_therapy_which_type_is_right_for_me.pdf. Accessed May 10, 2023.
2. American Society of Clinical Oncology. Cancer.Net site. Head and neck cancer: statistics. March 2023. https://www.cancer.net/cancer-types/head-and-neck-cancer/statistics. Accessed May 10, 2023.
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 Chuang 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
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23. Bišof V, Rakušić Z, Bibić 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. Razavian NB, D'Agostino RB, Shenker RF, et al. Intensity Modulated Radiation Therapy for Early Stage Squamous Cell Carcinoma of the Glottic Larynx: A Systematic Review and Meta-Analysis. Int J Radiat Oncol Biol Phys. May 06 2023. PMID 37150263
31. 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
32. 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
33. American Thyroid Association. Anaplastic thyroid cancer. https://www.thyroid.org/anaplastic-thyroid-cancer/. 
34. 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
35. 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
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38. 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

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

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

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

History From 2024 Forward 

08/28/2024 Annual review, no change to policy intent. Updating rationale and references 

01012024  NEW POLICY