Medical Policy

Policy Num:       06.001.057
Policy Name:     INTENSITY MODULATED RADIATION THERAPY (IMRT)
Policy ID:          [06.001.057]  [Ac / L / M+ / P+]  [0.00.00]

Last Review:       October 24, 2024
Next Review:      October 20, 2025
 

Related Policies:  None

INTENSITY MODULATED RADIATION THERAPY (IMRT)

Summary

Intensity Modulated Radiation Therapy (IMRT) is a technology for delivering highly conformal external beam radiation to a well-defined treatment volume with radiation beams whose intensity varies across the beam. IMRT is particularly useful for delivering a highly conformal radiation dose to targets positioned near sensitive normal tissues. 

For individuals who have malignant brain tumors who receive IMRT, the evidence includes dose-planning studies, nonrandomized comparison studies, and case series. The relevant outcomes are overall survival, disease-specific survival, morbid events, functional outcomes, and treatment-related morbidity. Case series results have consistently shown with low radiation toxicity but have not demonstrated better tumor control or improved survival with IMRT. Dose-planning studies have shown that IMRT delivers adequate radiation doses to tumors while simultaneously reducing radiation exposure to sensitive brain areas. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have benign brain tumors who receive IMRT, the evidence includes case series. The relevant outcomes are overall survival, disease-specific survival, functional outcomes, and treatment-related morbidity. Case series results have consistently shown low radiation toxicity but have not demonstrated better tumor control or improved survival with IMRT vs other radiotherapy techniques. It is expected that the dose-planning studies evaluating IMRT in patients with malignant tumors should generalize to patients with benign brain tumors because the benefit of minimizing radiation toxicity to sensitive brain areas is identical. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have brain tumor metastases who receive IMRT to avoid hippocampal exposure, the evidence includes nonrandomized comparison studies and case series. The relevant outcomes are overall survival, disease-specific survival, functional outcomes, and treatment-related morbidity. One prospective nonrandomized comparison study using IMRT to avoid hippocampal exposure showed a less cognitive decline with IMRT than with a prespecified historical control. Limitations of the historical control design and other aspects of the study make conclusions uncertain. The role of hippocampal radiation exposure as a cause of cognitive decline is less certain; thus, more definitive studies are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input was obtained in 2012 on the use of IMRT, including its use close to critical structures. There was a near-uniform consensus that use of IMRT in the central nervous system is at least as effective as 3-dimensional conformal radiotherapy and that, given the adverse events that could result if nearby critical structures receive toxic radiation doses, IMRT dosimetric improvements should be accepted as meaningful evidence for its benefit. Input, a strong chain of evidence, and the potential to reduce harms supported a decision that IMRT may be considered medically necessary for the treatment of tumors of the central nervous system that are proximate to organs at risk.

For individuals who have breast cancer who receive IMRT, the evidence includes randomized controlled trials and nonrandomized comparative studies. The relevant outcomes are overall survival, disease-specific survival, quality of life, and treatment-related morbidity. There is modest evidence from randomized controlled trials for a decrease in acute skin toxicity with IMRT compared with 2-dimensional RT for whole-breast irradiation, and dosimetry studies have demonstrated that IMRT reduces inhomogeneity of radiation dose, thus potentially providing a mechanism for reduced skin toxicity. However, because whole-breast RT is now delivered by 3-dimensional conformal radiotherapy (3D-CRT), these comparative data are of limited value. Studies comparing IMRT with 3D-CRT include one randomized controlled trial comparing IMRT with deep inspiration breath hold to 3D-CRT, two nonrandomized comparative studies on whole-breast IMRT, and a few studies on chest wall IMRT. These studies suggest that IMRT require less radiation exposure to nontarget areas and may improve short-term clinical outcomes. The available studies on the chest wall IMRT for postmastectomy breast cancer patients have only focused on treatment planning and techniques. However, when dose-planning studies have indicated that RT will lead to unacceptably high radiation doses, the studies suggest IMRT will lead to improved outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Strong evidence supports the use of IMRT for left-sided breast lesions in which alternative types of RT cannot avoid toxicity to the heart. Based on available evidence, input from clinical vetting, a strong chain of evidence, and the potential to reduce harms, IMRT may be considered medically necessary for whole-breast irradiation when (1) alternative forms of RT cannot avoid cardiac toxicity, and (2) IMRT dose-planning demonstrates a substantial reduction in cardiac toxicity. IMRT for the palliative treatment of lung cancer is considered not medically necessary because conventional radiation techniques are adequate for palliation.

Clinical vetting also provided strong support for IMRT when alternative RT dosimetry exceeds a threshold of 20-gray dose-volume (V20) to at least 35% of normal lung tissue. Based on available evidence, clinical vetting, a strong chain of evidence, and the potential to reduce harms, IMRT may be considered medically necessary for lung cancer when: (1) RT is given with curative intent, (2) alternative RT dosimetry demonstrates radiation dose exceeding V20 for at least 35% of normal lung tissue, and (3) IMRT reduces the V20 of radiation to the lung at least 10% below the V20 of 3D-CRT (eg, 40% reduced to 30%).

For individuals who have localized prostate cancer and are undergoing definitive RT who received IMRT, the evidence includes several prospective comparative studies, retrospective studies, and systematic reviews of these studies. The relevant outcomes are overall survival, disease-free survival, quality of life (QOL), and treatment-related morbidity. Although there are few prospective comparative trials, the evidence has generally shown that IMRT provides tumor control and survival outcomes similar to 3-dimensional conformal radiotherapy (3D-CRT) while reducing gastrointestinal and genitourinary toxicity. These findings are supported by treatment planning studies, which have predicted that IMRT improves target volume coverage and sparing of adjacent organs compared with 3D-CRT. A reduction in clinically significant complications of RT is likely to improve the QOL for treated patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have prostate cancer and are undergoing RT after prostatectomy who receive IMRT, the evidence includes retrospective comparative studies, single-arm phase 2 trials, and systematic reviews of these studies. The relevant outcomes are overall survival, disease-free survival, QOL, and treatment-related morbidity. Although the comparative studies are primarily retrospective, the evidence has generally shown that IMRT provides tumor control and survival outcomes similar to 3D-CRT. Notably, a retrospective comparative study found a significant reduction in acute upper gastrointestinal toxicity with IMRT compared with 3D-CRT, mainly due to better bowel sparing with IMRT. Another retrospective comparative study found a reduction in genitourinary toxicity. A reduction in clinically significant complications of RT is likely to improve the QOL for treated patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

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 (eg, 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 (eg, spinal cord, salivary glands), thus decreasing the risks of adverse events (eg, xerostomia, esophageal stricture).

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

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

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

Input was obtained in 2010 and 2012. It supported the use of IMRT in tumors of the abdomen and pelvis when normal tissues would receive unacceptable doses of radiation. Through a chain of evidence, this reduced toxicity potentially lowers the risk of adverse events (acute and late effects of radiation toxicity). This input and a chain of evidence related to the potential to reduce harms led to the decision that IMRT may be considered medically necessary for the treatment of tumors of the abdomen and pelvis when dosimetric planning with standard 3D-CRT predicts that the radiation dose to an adjacent organ would result in unacceptable normal tissue toxicity.

Objective

This medical policy addresses coverage for Intensity Modulated Radiation Therapy (IMRT).

Policy Statements

IMRT is considered reasonable and medically necessary in instances where sparing the surrounding normal tissue is of added clinical benefit to the patient. Common clinical indications that frequently support the use of IMRT include:

1. Primary, metastatic or benign tumors of the central nervous system.
2. Primary, metastatic tumors of the spine where spinal cord tolerance may be exceeded by conventional treatment.
3. Selected extracranial primary, metastatic or benign lesions.
4. Reirradiation that meets the requirements for medical necessity.

IMRT offers advantages as well as added complexity over conventional or three-dimensional conformal radiation therapy. Before applying IMRT techniques, a comprehensive understanding of the benefits and consequences is required. In addition to satisfying at least one of the four selection criteria noted above, the radiation oncologist’s decision to employ IMRT requires an informed assessment of benefits and risks including:

• Determination of patient suitability for IMRT allowing for reproducible treatment delivery.
• Adequate definition of the target volumes and organs at risk.
• Equipment capability, including ability to account for organ motion when a relevant factor.
• Physician and staff training.
• Adequate quality assurance procedures.

On the basis of the above conditions demonstrating medical necessity, disease sites that may support the use of IMRT include the following:

• Primary, metastatic or benign tumors of the central nervous system including the brain, brain stem and spinal cord.

• Primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with

• conventional treatment or where the spinal cord has previously been irradiated.

• Primary, metastatic, benign or recurrent head and neck malignancies including, but not limited to those involving: 

• Orbits,

• Sinuses,

• Skull base,

• Aero-digestive tract, and

• Salivary glands.

• Thoracic malignancies.

• Abdominal malignancies when dose constraints to small bowel or other normal tissue are exceeded and prevent administration of a therapeutic dose.

• Pelvic malignancies, including prostatic, gynecologic and anal carcinomas.

• Other pelvic or retroperitoneal malignancies.

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

1. Where IMRT does not offer an advantage over conventional or three-dimensional conformal radiation therapy techniques that deliver good clinical outcomes and low toxicity.
2. Clinical urgency, such as spinal cord compression, superior vena cava syndrome or airway obstruction.
3. Palliative treatment of metastatic disease where the prescribed dose does not approach normal tissue tolerances.
4. Inability to accommodate for organ motion, such as for a mobile lung tumor.
5. Inability of the patient to cooperate and tolerate immobilization to permit accurate and reproducible dose delivery.

Policy Guidelines

IMRT Treatment Planning

IMRT treatment plans are tailored to the target volumes and are geometrically more accurate than conventional or three-dimensional conformal radiation therapy plans. IMRT planning defines the necessary field sizes, gantry angles and other beam characteristics needed to achieve the desired radiation dose distribution.

IMRT treatment planning (i.e., inverse treatment planning) is a multi-step process:

1. Imaging: Three-dimensional image acquisition of the target region by simulation employing CT, MR, PET scanners or similar image fusion technology is an essential prerequisite to IMRT treatment planning. If respiratory or other normal organ motion is expected to produce significant movement of the target region during radiotherapy delivery, the radiation oncologist may additionally elect to order multi-phasic treatment planning image sets to account for motion when rendering target volumes.
2. Contouring: Defining the target and avoidance structures is in itself a multi-step process:

• The radiation oncologist reviews the three-dimensional images and outlines the treatment target on each slice of the image set. The summation of these contours defines the Gross Tumor Volume (GTV). For multiple image sets, the physician may outline separate GTVs on each image set to account for the effect of normal organ motion upon target location and shape. Some patients may not have GTVs if they have had previous treatment with surgery or chemotherapy, in which case treatment planning will be based on CTVs as described below.
• The radiation oncologist draws a margin around the GTV to generate a Clinical Target Volume (CTV) which encompasses the areas at risk for microscopic disease (i.e., not visible on imaging studies). Other CTVs may be created based on the estimated volume of residual disease. For multiple image sets, the physician may draw this margin around an aggregate volume containing all image set GTVs to generate an organ-motion CTV, or Internal Target Volume (ITV).
• To account for potential daily patient set-up variation and/or organ and patient motion, a final margin is then added to create a Planning Target Volume (PTV).
• Any combination of the GTV, CTV, ITV or PTV may be contoured depending on the clinical situation and the intent of treatment.
• Nearby normal structures that could potentially be harmed by radiation (i.e., “organs at risk”, or OARs) are also contoured.

3. Radiation Dose Prescribing: The radiation oncologist assigns specific dose requirements for the PTV which typically includes a prescribed dose that must be given to at least 90-95% of the PTV. This is often accompanied by a minimum acceptable point dose within the PTV and a constraint describing an acceptable range of dose homogeneity. Additionally, PTV dose requirements routinely include dose constraints for the OARs (e.g., upper limit of mean dose, maximum allowable point dose and/or a critical volume of the OAR that must not receive a dose above a specified limit). A treatment plan that satisfies these requirements and constraints should maximize the potential for disease control and minimize the risk of radiation injury to normal tissue.
4. Dosimetric Planning and Calculations: The medical physicist or a supervised dosimetrist calculates a multiple static beam and/or modulated arc treatment plan to deliver the prescribed radiation dose to the PTV and simultaneously satisfy the normal tissue dose constraints by delivering significantly lower doses to nearby organs. Dose-volume-histograms are prepared for the PTV and OARs. Here, an arc is defined as a discrete complete or partial rotation of the linear accelerator gantry during which there is continuous motion of the multi-leaf collimator to deliver an optimized radiation dose distribution within the patient. The essential feature of an IMRT plan is that it describes the means to deliver treatment utilizing non-uniform beam intensities. Each radiation beam or arc is, in effect, a collection of numerous “beamlets,” each with a different level of radiation intensity; the summation of these “beamlets” delivers the characteristic highly conformal IMRT dose distribution. The physicist and dosimetrist perform basic dose calculations on each of the modulated beams or arcs. These patient specific monitor unit computations verify through an independent second dose calculation method the accuracy of the calculations.
5. Patient Specific Dose Verification: The calculated beams or arcs are then delivered either to a phantom or a dosimetry measuring device to confirm that the intended dose distribution for the patient is physically verifiable and that the intensity modulated beams or arcs are technically feasible. Additional information can be found in the ASTRO QA White Paper (General Reference #13), which critically evaluates guidance and literature on the safe delivery of IMRT, with a primary focus on recommendations to prevent human error and methods to reduce or eliminate mistakes or machine malfunctions that can lead to catastrophic failures.

Documentation of all aspects of the treatment planning process is essential.

IMRT Treatment Delivery

The basic requirement for all forms of IMRT treatment delivery is that the technology must accurately produce the calculated dose distribution described by the IMRT plan. IMRT treatment delivery may be accomplished via various combinations of gantry motion, table motion, slice-by-slice treatment (tomotherapy) and multi-leaf collimator (MLC) or solid compensators to modulate the intensity of the radiation beams or arcs.

The highly conformal dose distribution produced by IMRT results in sharper spatial dose gradients than conventional or three-dimensional conformal radiation therapy. Consequently, small changes in patient position or target position within the body can cause significant changes in the dose delivered to the PTV and to the organs at risk; thus reproducible patient immobilization is required for precision IMRT. Imaging techniques such as stereoscopic kilovoltage or megavoltage X-ray, ultrasound, or cone beam or megavoltage CT scan (collectively referred to as Image Guided Radiation Therapy or IGRT) may be utilized to account for daily motion of the PTV to accurately deliver the treatment.

Documentation Requirements

Documentation in the patient’s medical records must support:

1. The reasonable and necessary requirements as outlined under the “Policy Statement” section of this policy.
2. The prescription which defines the goals and requirements of the treatment plan, including the specific dose constraints to the target and nearby critical structures.
3. A note of medical necessity for IMRT by the treating physician.
4. Signed IMRT inverse plan that meets prescribed dose constraints for the planning target volume (PTV) and surrounding normal tissue.
5. The target verification methodology must include the following:
   a. Documentation of the clinical treatment volume (CTV) and the planning target volume (PTV). 
   b. Documentation of immobilization and patient positioning.
6. Independent basic dose calculations of monitor units have been performed for each beam before the patient’s first treatment.
7. Documentation of fluence distributions (re-computed and measured in a phantom or dosimetry measuring device) is required.
8. Documentation supporting identification of structures that traverse high-and low-dose regions created by respiration is indicated when billing for respiratory motion management simulation.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

IMRT services may require pre-authorization.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

As IMRT technology was introduced and the appropriate clinical applications were being established, earlier versions of Triple-S IMRT medical policies identified specific disease sites for which IMRT was considered a standard option. The maturation and dissemination of IMRT capabilities with improved clinical outcomes has expanded to the point that a definitive list of “approved sites” driven solely by diagnosis codes (ICD-10) is no longer sufficient. However, it is important to note that normal tissue dose volume histograms (DVHs) or dosimetry must be demonstrably improved with an IMRT plan to validate coverage. Therefore, coverage decisions must extend beyond ICD-10 codes to incorporate additional considerations of clinical scenario and medical necessity with appropriate documentation. For some anatomical sites such as nasopharynx, oropharynx, hypopharynx, larynx (except for early true vocal cord cancer), prostate, anus and central nervous system, IMRT is commonly performed. In all cases, documentation of the medical necessity is required.

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. 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) in 2003, TiGRT (LinaTech) in 2009, and the Ray Dose (RaySearch 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 cleared for marketing by the FDA through the 510(k) process is the Varian IMRT system (Varian Medical Systems). FDA product code: IYE.

Rationale

Population Reference No. 1 

Malignant Brain Tumors

Clinical Context and Therapy Purpose

The purpose of IMRT in patients who have malignant brain tumors 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 treatment with IMRT improve health outcomes in individuals with malignant brain tumors?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with malignant brain tumors.

Interventions

The therapy being considered is IMRT.

Radiotherapy (RT) is an integral component of treating many brain tumors, both benign and malignant. IMRT is a method that allows adequate radiation to the tumor while minimizing the dose to surrounding normal tissues and critical structures. IMRT also allows additional radiation to penetrate specific anatomic areas simultaneously, delivering radiation at a larger target volume.

IMRT is performed by radiation oncologists in an outpatient clinical setting.

Comparators

The following therapy is currently being used: 3D-CRT.

Treatment planning evolved by using 3D images, typically 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 3D-CRT. The standard approach to treat brain tumors depends on the type and location of the tumor. For glioblastoma multiforme, a high-grade malignant tumor, treatment is multimodal, with surgical resection followed by adjuvant RT and chemotherapy.[1]

3D-CRT is performed by radiation oncologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are overall survival (OS), recurrence-free survival (locoregional control), reductions in symptoms, and treatment-related adverse events. A proposed benefit of IMRT is to reduce toxicity to adjacent structures, allowing dose escalation to the target area and fewer breaks in treatment courses due to a reduction in side effects. However, this may come with a loss of locoregional control and OS due to the factors discussed above. The time frame for outcome measures varies from short-term management of toxicity and symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

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

Systematic Reviews

Amelio et al (2010) conducted a systematic review of the clinical and technical issues of using IMRT in newly diagnosed glioblastoma multiforme.^1, Articles were selected through December 2009 and included 17 studies (9 on dosimetric data and technical considerations, 7 on clinical results, 1 on both dosimetric and clinical results) for a total of 204 treated patients and 148 patient datasets used in planning studies. No RCTs were identified, and a meta-analysis was not performed.

For the 6 articles related to planning studies that compared 3D-CRT with IMRT, the report by Fuller et al (2007) showed a noticeable difference between 3D-CRT and IMRT for the planning target volume (PTV; 13% benefit in V95 [volume that received 95% of the prescribed dose] from IMRT, p<0.001)^3,; the remaining studies suggested that IMRT and 3D-CRT provided similar PTV coverage, with differences between 0% and 1%. Target dose conformity was improved with IMRT. The organs at risk in the studies typically were the brainstem, optic chiasm, optic nerves, lens, and retina. In general, IMRT provided better sparing of the organs at risk than 3D-CRT but with considerable variation from study to study.

Of the eight studies that included clinical results, three were retrospective; one was a prospective phase 1 study, andfour were prospective phase 2 single-institution studies. Of these eight studies, two used conventional total dose and dose per fraction, two used a hypofractionated regimen, and the others used a hypofractionated scheme with a simultaneous integrated boost. The median follow-up ranged from 8.8 to 24 months. Almost all patients (96%) completed treatment without interruption or discontinuation due to toxicity. Acute toxicity was reported as negligible, with grade 3 adverse events observed in only 2 studies at rates of 7% and 12%. Grade 4 toxicity was recorded in only one series, with an absolute rate of 3%. Data for late toxicities were available in 6 of 8 studies, with 1 recording grade 4 adverse events with an incidence of 20%. One- and 2-year OS rates varied between 30% and 81.9% and between 0% and 55.6%, respectively. When OS was reported as a median time and ranged from 7 to 24 months. Progression-free survival (PFS) rates ranged from 0% to 71.4% at 1 year from 0% to 53.6% at 2 years. The median PFS ranged from 2.5 to 12 months.

Reviewers also conducted a comprehensive qualitative comparison using data reported in the literature on similar non-IMRT clinical studies, offering the following conclusions. The planning comparisons revealed that 3D-CRT and IMRT provided similar results in terms of target coverage. IMRT was somewhat better than 3D-CRT in reducing the maximum dose delivered to the organs at risk-although the extent varied by case. IMRT was better than 3D-CRT when it came to dose conformity and sparing of the healthy brain tissue at medium to low doses; there were no aspects where IMRT performed worse than 3D-CRT.

This evidence was limited by a number of factors: there was an absence of comparative studies with clinical outcomes; all studies were small in size, from a single institution; most patients (53%) were retrospectively analyzed; chemotherapy administration varied across studies.

Dose-Planning Studies

A representative sample of dose-planning, case series, and comparative studies are discussed next. For example, MacDonald et al (2007) compared the dosimetry of IMRT with 3D-CRT in 20 patients treated for high-grade glioma.^4, Prescription dose and normal tissue constraints were identical for the 3D-CRT and IMRT treatment plans. The IMRT plan yielded superior target coverage compared with the 3D-CRT plan. The IMRT plan reduced the percent volume of brainstem receiving a dose greater than 45 gray (Gy) by 31% (p=0.004) and the percent volume of brain receiving a dose greater than 18 Gy, 24 Gy, and 45 Gy by 10% (p=0.059), 14% (p=0.015), and 40% (p<0.001), respectively. With IMRT, the percent volume of optic chiasm receiving more than 45 Gy was reduced by 30.4% (p=0.047). Compared with 3D-CRT, IMRT significantly increased the tumor control probability (p<0.001) and lowered the normal tissue complication probability for brain and brainstem (p<0.033).

Narayana et al (2006) compared IMRT treatment plans with 3D plans performed in 20 patients of a case series of 58 patients.^5, Regardless of tumor location, IMRT did not improve PTV compared with 3D planning. However, IMRT decreased the maximum dose to the spinal cord, optic nerves, and eye by 16%, 7%, and 15%, respectively.

Nonrandomized Comparison Studies

Paulsson et al (2014) compared treatment failure rates in glioblastomapatients with differing target margins (the size of the region between the tumor and edge of the PTV).^6, In 161 patients, treatment margins were not associated with treatment failure. There was no difference in treatment failure rates between IMRT and 3D-CRT.

Section Summary: Malignant Brain Tumors

Dosimetry studies have demonstrated lower radiation exposure to organs at risk with IMRT treatment plans than with 3D-CRT treatment plans. Limited comparative evidence has shown lower rates of hearing loss with IMRT than with conventional RT. The evidence appears to be consistent in supporting lower neurotoxicity associated with IMRT. No conclusions can be made about the efficacy of IMRT compared with conventional RT.

Summary of Evidence

For individuals who have malignant brain tumors who receive IMRT, the evidence includes dose-planning studies, nonrandomized comparison studies, and case series. The relevant outcomes are OS, disease-specific survival, morbid events, functional outcomes, and treatment-related morbidity. Case series results have consistently shown with low radiation toxicity but have not demonstrated better tumor control or improved survival with IMRT. Dose-planning studies have shown that IMRT delivers adequate radiation doses to tumors while simultaneously reducing radiation exposure to sensitive brain areas. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 2 

Benign Brain Tumors

Clinical Context and Therapy Purpose

The purpose of IMRT in patients who have benign brain tumors is to provide a treatment option that is an alternative to or an improvement on existing therapies.

For benign and low-grade brain tumors, gross total resection remains the primary goal. However, RT may be used in select cases, such as when total resection is not possible, when a more conservative surgical approach may be necessary to achieve long-term treatment goals, and when atypical tumors may need RT even after gross total resection to reduce the risk of local recurrence. Therefore, RT, either definitive or in the postoperative adjuvant setting, remains an integral component in the management of residual, recurrent, and/or progressive benign and low-grade brain tumors for maximizing local control.[2]

The question addressed in this evidence review is: Does treatment with IMRT improve health outcomes in individuals with benign brain tumors?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with benign brain tumors.

Interventions

Radiotherapy is an integral component of treating many brain tumors, both benign and malignant. IMRT is a method that allows adequate radiation to the tumor while minimizing the dose to surrounding normal tissues and critical structures. IMRT also allows additional radiation to penetrate specific anatomic areas simultaneously, delivering radiation at a larger target volume. The therapy being considered is IMRT. IMRT is usually administered by radiation oncologists in an outpatient setting.

Comparators

The following therapy is currently being used: 3D-CRT.

Treatment planning evolved by using 3D images, typically from 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 termed3D-CRT.

The comparator being used in this evidence review is 3D-CRT, which is performed by radiation oncologists.

Outcomes

The general outcomes of interest are OS, recurrence-free survival (locoregional control), reductions in symptoms, and treatment-related adverse events. A proposed benefit of IMRT is to reduce toxicity to adjacent structures, allowing dose escalation to the target area and fewer breaks in treatment courses due to a reduction in side effects. However, this may come with a loss of locoregional control and OS due to the factors discussed above. The time frame for outcome measures varies from short-term management of toxicity and symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

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

Case Series

The evidence for the use of IMRT in patients with benign brain tumors consists mostly of case series. Previously discussed dosimetry studies, which evaluated patients with malignant brain tumors, should be generalizable to patients with benign tumors.

Milker-Zabel et al (2007) reported on results of treatment of complex-shaped meningiomas at the skull base with IMRT.^7, Ninety-four patients received RT as primary treatment (n=26), for residual disease after surgery (n=14), or after local recurrence (n=54). Tumor histology, classified using the World Health Organization, was grade 1 in 54.3%, grade 2 in 9.6%, and grade 3 in 4.2%. Median follow-up was 4.4 years. The overall local tumor control rate was 93.6%. After IMRT, 69 patients had stable disease (by CT or magnetic resonance imaging [MRI]), and 19 had a tumor volume reduction. Six patients had local tumor progression on MRI at a median of 22.3 months after IMRT. In 39.8% of patients, preexisting neurologic deficits improved. Treatment-induced loss of vision was seen in 1 of 53 re-irradiated patients with a grade 3 meningioma 9 months after retreatment with IMRT.

Mackley et al (2007) reported on outcomes of treating pituitary adenomas with IMRT.^8, A retrospective chart review was conducted on 34 patients treated between 1998 and 2003. Median follow-up was 42.5 months. Radiographic local control was 89% and, among patients with secretory tumors, 100% had a biochemical response. One patient required salvage surgery for disease progression, resulting in a clinical PFS of 97%. One patient who received more than 46 Gy experienced optic neuropathy 8 months after radiation.

Sajja et al (2005) reported on outcomes for 35 patients with 37 meningiomas treated with IMRT.^9, Tumor histology was benign in 35 tumors and atypical in 2 tumors. The median CT with MRI follow-up was 19.1 months (range, 6.4-62.4 months). Fifty-four percent of the meningiomas had received surgery or radiosurgery before IMRT, and 46% were treated with IMRT, primarily after diagnosis was established by CT or MRI. Three patients had local failure after treatment. No long-term complications from IMRT were documented among the 35 patients.

Section Summary: Benign Brain Tumors

The evidence on IMRT for treating benign brain tumors includes case series. Case series results have consistently shown with low radiation toxicity but have not demonstrated better tumor control or improved survival with IMRT vs other RT techniques. The dose-planning studies evaluating IMRT in patients with malignant tumors should generalize to patients with benign brain tumors because the benefit of minimizing radiation toxicity to sensitive brain areas is identical.

Summary of Evidence

For individuals who have benign brain tumors who receive IMRT, the evidence includes case series. The relevant outcomes are OS, disease-specific survival, functional outcomes, and treatment-related morbidity. Case series results have consistently shown low radiation toxicity but have not demonstrated better tumor control or improved survival with IMRT vs other radiotherapy techniques. It is expected that the dose-planning studies evaluating IMRT in patients with malignant tumors should generalize to patients with benign brain tumors because the benefit of minimizing radiation toxicity to sensitive brain areas is identical. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 3 

Brain Metastases

IMRT can deliver additional radiation boosts to specific metastases concurrent with whole-brain radiotherapy (WBRT). Clinicians have treated patients using this RT technique rather than treating them separately with WBRT and stereotactic radiosurgery (SRS), the latter having been shown to be more effective than WBRT alone in an RCT.

Clinical Context and Therapy Purpose

The purpose of IMRT to avoid hippocampal exposure in patients who have brain metastases is to provide a treatment option that is an alternative to or an improvement on existing therapies.

Brain metastases occur in up to 40% of adults with cancer and can shorten survival and detract from the quality of life. Many patients who develop brain metastases will die of progressive intracranial disease. Among patients with good performance status, controlled extracranial disease, favorable prognostic features, and solitary brain metastasis, randomized studies have shown that surgical excision followed by WBRT prolongs survival.[3] SRS can replace surgery in certain circumstances, delivering obliteratively high single doses to discrete metastases.[3] For bulky cerebral metastases, level 1 evidence has also shown that delivering a higher radiation dose with an SRS boost is beneficial in addition to standard WBRT. The use of a concomitant boost with IMRT) during WBRT has been attempted to improve overall local tumor control without the use of SRS to avoid additional planned radiation after WBRT ("phase 2" or SRS) and its additional labor and expense.[3] Another indication for the use of IMRT in WBRT is to avoid radiation exposure to the hippocampus. It is thought that avoiding the hippocampus may minimize cognitive decline associated with WBRT.

Patients

The question addressed in this evidence review is: Does treatment with IMRT improve health outcomes in individuals with brain metastases when it is necessary to avoid hippocampal exposure?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with brain metastases.

Interventions

The therapy being considered is IMRT to avoid hippocampal exposure. IMRT is provided by radiation oncologists in an outpatient setting.

Comparators

The following therapy is currently being used: WBRT. WBRT is performed by radiation oncologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are OS, recurrence-free survival, reductions in symptoms, and (locoregional control), reductions in symptoms, and treatment-related adverse events. A proposed benefit of IMRT is to reduce toxicity to adjacent structures, allowing dose escalation to the target area and fewer breaks in treatment courses due to a reduction in side effects. However, this may come with a loss of locoregional control and OS due to the factors discussed above. The time frame for outcome measures varies from short-term management of toxicity and symptoms to long-term procedure-related complications, cancer progression or recurrence, and OS.

Nonrandomized Comparative Studies

Gondi et al (2014) evaluated IMRT as a method to avoid radiation exposure to the hippocampus and prevent adverse cognitive events in patients receiving WBRT.^11, Dosimetry studies had previously established techniques that avoided radiation exposure to this region but still provided coverage and conformality to the remaining brain. Dosimetry studies alone have not been sufficient to establish IMRT as a standard treatment because the toxic effects of radiation on the hippocampus are less well established. The Gondi et al (2014) study was a prospective trial with a prespecified comparison to a historical control group derived from a previously conducted clinical trial. The outcomes were standardized cognitive assessments, and health-related quality of life evaluated at baseline and two-month intervals (out to six months).

Of 100 eligible patients, 42 patients were evaluable at 4 months; 17 patients were alive but did not have cognitive testing, and 41 had died. The mean decline in the primary cognitive endpoint was 7.0%, which was significantly less than the 30% decline in the historical control group (p<0.001). Median survival in the experimental group was 6.8 months and 4.9 months in the historical control group. Although the trial results suggested that hippocampal-sparing WBRT using IMRT is associated with less cognitive decline, the historical control design adds uncertainty to the conclusion. Because the experimental group had survived longer, even though the radiation dose was intended to be equivalent to the historical control, possible unmeasured patient factors associated with better survival may have also caused less cognitive decline. The trial did not provide conclusive evidence that hippocampal-sparing IMRT causes less cognitive decline.

Case Series

A retrospective study by Zhou et al (2014) evaluated the feasibility of WBRT plus simultaneous integrated boost with IMRT for inoperable brain metastases of non-small-cell lung cancer.^12, Twenty-nine non-small-cell lung cancer patients with 87 inoperable brain metastases were included. All patients received WBRT at a dose of 40 Gy and simultaneous integrated boost with IMRT at a dose of 20 Gy concurrent with WBRT in week 4. Prior to each fraction of image-guided IMRT boost, online positioning verification and correction were used to ensure that the set-up errors were within 2 mm by cone beam CT in all patients. The 1-year intracranial control rate, local brain failure rate (BFR), and distant BFR were 63%, 14%, and 19%, respectively. The 2-year intracranial control rate, local BFR, and distant BFR were 42%, 31%, and 36%, respectively. Both the median intracranial PFS and the median OS were 10 months; 6-month, 1-year, and 2-year OS rates were 66%, 41%, and 14%, respectively. Patients had better survival rates when their Score Index for Radiosurgery in Brain Metastases was greater than five, when they had fewer than three intracranial lesions, and when they had a history of epidermal growth factor receptor tyrosine kinase inhibitor treatment. Radiation necrosis was observed in three (3.5%) lesions after RT. Grades 2 and 3 cognitive impairment with grade 2 radiation leukoencephalopathy were observed in 4 (14%) patients. No dosimetric parameters were found to be associated with these late toxicities. Patients who received epidermal growth factor receptor tyrosine kinase inhibitor treatment had higher incidences of grades 2 and 3 cognitive impairment with grade 2 leukoencephalopathy. This evidence would suggest WBRT plus simultaneous integrated boost with IMRT is a tolerable treatment for non-small-cell lung cancer patients with inoperable brain metastases. However, the evidence does not permit conclusions about efficacy.

Section Summary: Brain Metastases

For the treatment of brain metastases, IMRT has been investigated as a technique to avoid hippocampal radiation exposure when delivering WBRT and to deliver additional radiation to specific areas of the brain as a substitute for SRS. For both indications, studies are not definitive regarding improvements in health outcomes.

Summary of Evidence

For individuals who have brain tumor metastases who receive IMRT to avoid hippocampal exposure, the evidence includes nonrandomized comparison studies and case series. The relevant outcomes are OS, disease-specific survival, functional outcomes, and treatment-related morbidity. One prospective nonrandomized comparison study using IMRT to avoid hippocampal exposure showed a less cognitive decline with IMRT than with a prespecified historical control. Limitations of the historical control design and other aspects of the study make conclusions uncertain. The role of hippocampal radiation exposure as a cause of cognitive decline is less certain; thus, more definitive studies are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 4 

Breast Cancer

Clinical Context and Therapy Purpose

The purpose of the use of IMRT in patients who have breast 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 health outcomes in patients with breast cancer?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are women with breast cancer.

Interventions

The therapy being considered is IMRT. Radiotherapy (RT) is an integral component of the treatment of breast cancer. IMRT has been proposed as a method of RT that allows adequate radiation to the tumor while minimizing the radiation dose to surrounding normal tissues and critical structures. IMRT is performed by radiation oncologists in tertiary outpatient clinical settings.

Comparators

The following therapy is currently being used to make decisions about breast cancer: 2D and 3D-CRT. 3D-CRT is performed by radiation oncologists in tertiary outpatient clinical settings.

Outcomes

The general outcomes of interest are overall survival (OS), recurrence-free survival (locoregional control), and treatment-related adverse events (eg, radiation dermatitis).

The grading of acute radiation dermatitis is relevant to studies of IMRT for the treatment of breast cancer. Acute radiation dermatitis is graded on a scale of 0 (no change) to 5 (death). Grade 2 is moderate erythema and patchy moist desquamation, mostly in skin folds; grade 3 is moist desquamation in other locations and bleeding with minor trauma. Publications have also reported on the potential for IMRT to reduce radiation to the heart (left ventricle) in patients with left-sided breast cancer and unfavorable cardiac anatomy.^3, This is a concern because of the potential development of late cardiac complications (eg, coronary artery disease) following FRT to the left breast.

In addition, IMRT may reduce toxicity to structures adjacent to tumors, allowing dose escalation to the target area and fewer breaks in treatment courses due to a reduction in side effects. However, this may come with a loss of locoregional control and OS. Thus, outcomes of interest are toxicity, QOL, locoregional recurrence, and OS.

Follow-up after IMRT varies by the staging of breast cancer and patient age at diagnosis. Five-year to ten-year follow-up to monitor for recurrence have been recommended.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

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

Whole-Breast Irradiation With IMRT vs 2-Dimensional Radiotherapy

Systematic Reviews

Dayes et al (2012) conducted a systematic review of the evidence for IMRT for whole-breast irradiation in the treatment of breast cancer to quantify its potential benefits and to make recommendations for radiation treatment programs.^4, Based on a review of 6 studies (total n=2012 patients) published through March 2009 (1 RCT, 3 retrospective cohort studies, 1 historically controlled trial, 1 prospective cohort), reviewers recommended IMRT over conventional RT after breast-conserving surgery to avoid acute adverse events associated with radiation. There were insufficient data to recommend IMRT over conventional RT based on oncologic outcomes or late toxicity. The RCT included in this review was the Canadian multicenter trial by Pignol et al (2008), reported next.^5, In this RCT, IMRT was compared with2D-RT. Computed tomography scans were used in treatment planning for both arms of the study. The types of conventional RT regimens used in the other studies were not reported.

Randomized Controlled Trials

The multicenter, double-blind RCT by Pignol et al (2008, 2016) evaluated whether breast IMRT would reduce the rate of acute skin reaction (moist desquamation), decrease pain, and improve QOL compared with 2D-RT using wedges.^5,6, Patients were assessed each week up to six weeks after RT and then at eight to ten years. A total of 358 patients were randomized between 2003 and 2005 at 2 Canadian centers, and 331 were analyzed. Of these, 241 patients were available for long-term follow-up. The trialists noted that breast IMRT significantly improved the dose distribution compared with 2D-RT. They also noted a lower proportion of patients with moist desquamation during or up to 6 weeks after RT (31% with IMRT vs 48% with standard treatment; p=0.002). A multivariate analysis found the use of breast IMRT and smaller breast size were significantly associated with a decreased risk of moist desquamation. The presence of moist desquamation significantly correlated with pain and a reduced QOL. At a median follow-up of 9.8 years, there was no significant difference in chronic pain between treatment arms. Young age (p=0.013) and pain during RT (p<0.001) were associated with chronic pain. Poorer self-assessed cosmetic outcome (p<0.001) and QOL (p<0.001) were also associated with pain during RT.

Donovan et al (2002) reported on an RCT comparing outcomes for 2D-RT using wedged, tangential beams with IMRT in 300 breast cancer patients.^7, In a 2007 abstract, investigators reported interim cosmetic outcomes at 2 years postrandomization for 233 evaluable patients. Donovan et al (2007) reported subsequently on this trial.^8, Enrolled patients had "higher than average risk of late radiotherapy-adverse effects," which included patients with larger breasts. Trialists stated that while breast size was not particularly good at identifying women with dose inhomogeneity falling outside current International Commission on Radiation Units and Measurements guidelines, their trial excluded women with small breasts (≤500 cm³), who generally have fairly good dosimetry with standard 2D compensators. All patients were treated with 6 or 10 megavolt photons to a dose of 50 gray (Gy) in 25 fractions in 5 weeks followed by an electron boost to the tumor bed of 11.1 Gy in 5 fractions. The primary endpoint (change in breast appearance) was scored from serial photographs taken before RT and at 1-, 2-, and 5-year follow-ups. Secondary endpoints included patient self-assessments of breast discomfort, breast hardness, QOL, and physician assessments of breast induration. Two hundred forty (79%) patients with 5-year photographs were available for analysis. Change in breast appearance was identified in 71 (58%) of 122 allocated standard 2D treatment compared with 47 (40%) of 118 patients allocated IMRT. Significantly fewer patients in the IMRT group developed palpable induration assessed clinically in the center of the breast, pectoral fold, inframammary fold, and at the boost site. No significant differences between treatment groups were found in patient-reported breast discomfort, breast hardness, or QOL. The authors concluded that minimization of unwanted radiation dose inhomogeneity in the breast reduced late adverse events. While the change in breast appearance differed statistically, a beneficial effect on QOL was not demonstrated.

Barnett et al (2009) published baseline characteristics and dosimetry results of a single-center RCT assessing IMRT for early breast cancer after breast-conserving surgery.^9, Subsequently, Barnett et al (2012) reported on the 2-year interim results of their RCT.^10, In this trial, 1145 patients with early breast cancer were evaluated for external-beam radiotherapy. Twenty-nine percent had adequate dosimetry with standard RT. The other 815 patients were randomized to IMRT or 2D-RT. Inhomogeneity occurred most often when the dose-volume was greater than 107% (V107) of the prescribed dose to a breast volume greater than 2 cm³ with conventional RT. When breast separation was 21 cm or more, 90% of patients had received greater than V107 of the prescribed dose to greater than 2 cm³ with standard radiation planning. The incidence of acute toxicity did not differ significantly between groups. Additionally, photographic assessment scores for breast shrinkage did not differ significantly between groups. The authors noted overall cosmesis after 2D-RT and IMRT was dependent on surgical cosmesis, suggesting breast shrinkage and induration were due to surgery rather than radiation, thereby masking the potential cosmetic benefits of IMRT.

Whole-Breast Irradiation With IMRT vs 3D-CRT

Randomized Controlled Trials

In their RCT, Jagsi et al (2018) assess whether IMRT with deep inspiration breath hold (DIBH) reduces cardiac or pulmonary toxicity of breast RT compared to 3D-CRT, the current standard RT. The study included 62 women with node-positive breast cancer in whom RT was indicated for treating the left breast or chest-wall and the internal mammary, infraclavicular and supraclavicular nodal regions. The primary outcome was the percentage decrease in heart perfusion at one year post-treatment compared to baseline, measured using attenuation corrected single-photon emission computed tomography. A secondary outcome was a change in left ventricular ejection fraction. The 3D-CRT group received ≥ 5 Gy to 15.8% of the left ventricle; the IMRT-DIBH group received 5.6% to the left ventricle (P < 0.001). At one year, no differences in perfusion of the heart were detected; however, significant differences were found in left ventricular ejection fraction . In the 3D-CRT arm, six patients had > 5% changes in left ventricular ejection fraction , and the IMRT-DIBH arm had one patient with > 5% change. The authors contend that their study is important because it demonstrates that the IMRT-DIBH technique’s reduction in cardiac dose could be associated with better preservation of cardiac left ventricle function—a potentially clinically meaningful finding. One limitation of this study is its small size, and only one follow-up scan was conducted at one year due to resource constraints. A six-month scan might have shown greater differences between the two arms.

Nonrandomized Comparative Studies

Hardee et al (2012) compared the dosimetric and toxicity outcomes after treatment with IMRT or 3D-CRT for whole-breast irradiation in 97 consecutive patients with early-stage breast cancer, who were assigned to either approach after partial mastectomy based on insurance carrier approval for reimbursement for IMRT.^11, IMRT significantly reduced the maximum radiation dose to the breast (Dmax median, 110% for 3D-CRT vs 107% for IMRT; p<0.001) and improved median dose homogeneity (median, 1.15 for 3D-CRT vs 1.05 for IMRT; p<0.001) compared with 3D-CRT. These dosimetric improvements were seen across all breast volume groups. Grade 2 dermatitis occurred in 13% of patients in the 3D-CRT group and in 2% in the IMRT group. IMRT moderately decreased rates of acute pruritus (p=0.03) and grade 2 and 3 subacute hyperpigmentation (p=0.01). With a minimum of six months of follow-up, the treatment was reported to be similarly well-tolerated by both groups, including among women with large breast volumes.

Guttmann et al (2018) published a single-center retrospective analysis of 413 women who received tangential whole-breast irradiation between 2011 and 2015 (see Table 1).^12, Of the patients, 212 underwent IMRT and 201 received 3D-CRT. The main endpoint was a comparison of acute radiation dermatitis (grade 2+), and secondary endpoints were acute fatigue and breast pain. Grade 2+ radiation dermatitis was experienced by 59% of 3D-CRT patients and 62% of IMRT (p=0.09). There was also no significant difference between 3D-CRT and IMRT for breast pain (grade 2+, 18% vs 18%, respectively; p=0.33) or fatigue (grade 2+, 18% vs 25.5%, respectively; p=0.24) (see Table 2). A study limitation was that follow-up varied across patients because those treated with IMRT completed treatment one week sooner than those treated with 3D-CRT.

Table 1. Summary of Key Nonrandomized Trials Characteristics

FU: follow-up; 3D-CRT: 3-dimensional conformal radiotherapy; IMRT: intensity-modulated radiotherapy.

Table 2. Summary of Key Nonrandomized Trials Results

Chest Wall Irradiation

A few studies have examined the use of IMRT for chest wall irradiation in postmastectomy breast cancer patients. Available studies have focused on treatment planning and techniques to improve dose distributions to targeted tissues while reducing radiation to normal tissue and critical surrounding structures (eg, heart, lung). An example is a study by Rudat et al (2011), in which treatment planning for chest wall irradiation with IMRT was compared with 3D-CRT in 20 postmastectomy patients.^13, The authors reported IMRT significantly decreased heart and lung high-dose volume with a significantly improved conformity index compared with 3D-CRT. However, there were no significant differences in the homogeneity index. The authors noted longer-term prospective studies are needed to further assess cardiac toxicity and secondary lung cancer risk with multifield IMRT, which while reducing high-dose volume, increases mean heart and lung dose. As noted, health outcomes were not reported in this study.

Ho et al (2019) published the long-term pulmonary outcomes of a feasibility study of inverse-planned, multibeam intensity modulated radiation therapy in node-positive breast cancer patients receiving regional nodal irradiation.^14, While the authors' primary endpoint was feasibility, they also observed the incidence of radiation pneumonitis grade 3 or greater and changes in pulmonary function. The later endpoints were measured with the Common Terminology Criteria for Adverse Events and pulmonary function tests and community-acquired pneumonia questions. Of 104 completed follow-up procedures, the overall rate of respiratory toxicity was  10.6%, with 1 grade 3 radiation pneumonitis event.

Rastogi et al (2018) published a retrospective study of 107 patients receiving RTpostmastectomy to the left chest wall.^15, Patients were treated with3D-CRT (n=64) or IMRT (n=43). The planning target volume, homogeneity index, and conformity index for both groups were compared. IMRT had a significantly improved conformity index score (1.127) compared with 3D-CRT (1.254; p<0.001), while results for both planning target volume (IMRT, 611.7 vs 3D-CRT, 612.2; p=0.55) and homogeneity index (IMRT, 0.094 vs 3D-CRT, 0.096; p=0.83) were comparable. Furthermore, secondary analyses showed that IMRT differed had significantly lower mean- and high-dose volumes to the heart and ipsilateral lung (p<0.001 and p<0.001, respectively), while 3D-CRT had superior low-dose volume (p<0.001). The study was limited by its small population size and short follow-up.

Section Summary: Breast Cancer

There is modest evidence from RCTs that IMRT decreases acute skin toxicity more than 2D-RT for whole-breast irradiation. One RCT reported improvements in moist desquamation of skin but did not find differences in grade 3 or 4 skin toxicity, pain symptoms, or QOL. Another RCT found a change in breast appearance but not QOL. A third RCT reported no differences in cosmetic outcomes at two years for IMRT or 2D-RT. Dosimetry studies have demonstrated that IMRT reduces inhomogeneity of radiation dose, thus potentially providing a mechanism for reduced skin toxicity. However, because whole-breast RT is now delivered by 3D-CRT, these comparison data are of limited value. Studies comparing IMRT with 3D-CRT include one RCT comparing IMRT with DIBH to 3D-CRT, two nonrandomized comparative assessments of whole-breast IMRT, and studies on treatment planning for chest wall IMRT. These studies have suggested that IMRT might improve short-term clinical outcomes. No studies have reported on health outcomes after IMRT for chest wall irradiation in breast cancer patients postmastectomy. Available studies have only focused on treatment planning and techniques. The risk of secondary lung cancers needs further evaluation. Additionally, cardiac and pulmonary toxicity needs further evaluation. Despite this, strong evidence supports the use of IMRT for left-sided breast lesions in which alternative types of RT cannot avoid toxicity to the heart and lungs.

Summary of Evidence

For individuals who have breast cancer who receive IMRT, the evidence includes RCTs and nonrandomized comparative studies. The relevant outcomes are OS , disease-specific survival, QOL, and treatment-related morbidity. There is modest evidence from RCTs for a decrease in acute skin toxicity with IMRT compared with 2D-RT for whole-breast irradiation, and dosimetry studies have demonstrated that IMRT reduces inhomogeneity of radiation dose, thus potentially providing a mechanism for reduced skin toxicity. However, because whole-breast RT is now delivered by 3D-CRT, these comparative data are of limited value. Studies comparing IMRT with 3D-CRT include one RCT comparing IMRT with DIBH to 3D-CRT, two nonrandomized comparative studies on whole-breast IMRT, and a few studies on chest wall IMRT. These studies suggest that IMRT requires less radiation exposure to nontarget areas and may improve short-term clinical outcomes. The available studies on chest wall IMRT for postmastectomy breast cancer patients have only focused on treatment planning and techniques. However, when dose-planning studies have indicated that RT will lead to unacceptably high radiation doses, the studies suggest IMRT will lead to improved outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Strong evidence supports the use of IMRT for left-sided breast lesions in which alternative types of RT cannot avoid toxicity to the heart. Based on available evidence, input from clinical vetting, a strong chain of evidence, and the potential to reduce harms, IMRT may be considered medically necessary for whole-breast irradiation when (1) alternative forms of RT cannot avoid cardiac toxicity, and (2) IMRT dose-planning demonstrates a substantial reduction in cardiac toxicity. IMRT for the palliative treatment of lung cancer is considered not medically necessary because conventional radiation techniques are adequate for palliation.

Population Reference No. 5 

Lung Cancer

Clinical Context and Therapy Purpose

The purpose of IRMT in patients who have lung 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 health outcomes in patients with lung cancer?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with lung cancer.

Interventions

The therapy being considered is IMRT. RT is an integral component of the treatment of lung cancer. IMRT has been proposed as a method of RT that allows adequate radiation to the tumor while minimizing the radiation dose to surrounding normal tissues and critical structures. IMRT is performed by radiation oncologists in tertiary outpatient clinical settings.

Comparators

The following therapy is currently being used to make decisions about lung cancer: 3D-CRT. 3D-CRT is performed by radiation oncologists in tertiary outpatient clinical settings.

Outcomes

The general outcomes of interest are OS, recurrence-free survival, and treatment-related adverse events.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

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

Systematic Reviews

Bezjak et al (2012) conducted a systematic review that examined the evidence on the use of IMRT for the treatment of lung cancer to quantify its potential benefits and make recommendations for RT programs considering adopting this technique in Ontario, Canada.^16, This review consisted of 2 retrospective cohort studies (through March 2010) reporting on cancer outcomes, which was considered insufficient evidence on which to make evidence-based recommendations. These 2 cohort studies reported on data from the same institution; the study by Liao et al (2010; reported below)^17, indicated that patients assessed in their cohort (n=409) were previously reported in the cohort by Yom et al (2010), (n=290) but it is not clear exactly how many patients were added in the second report. However, due to the known dosimetric properties of IMRT and extrapolating from clinical outcomes from other disease sites, reviewers recommended that IMRT be considered for lung cancer patients when the tumor is proximate to an organ at risk, where the target volume includes a large volume of an organ at risk, or where dose escalation would be potentially beneficial while minimizing normal tissue toxicity.^16,

Nonrandomized Comparative Studies

Chun et al (2017) reported on a secondary analysis of a trial that assessed the addition of cetuximab to a standard chemotherapy regimen and radiation dose escalation.^18, Use of IMRT or 3D-CRT was a stratification factor in the 2´2 design. Of 482 patients in the trial, 53% were treated with 3D-CRT and 47% were treated with IMRT, though treatment allocation was not randomized. Compared with the 3D-CRT group, the IMRT group had larger planning treatment volumes (486 mL vs 427 mL, p=0.005), larger planning treatment volume/volume of lung ratio (median, 0.15 vs 0.13; p=0.13), and more stage IIIB breast cancer patients (38.6% vs 30.3%, p=0.056). Even though there was an increase in treatment volume, IMRT was associated with less grade 3 or greater pneumonitis (3.5% vs 7.9%, p=0.039) and a reduced risk (odds ratio, 0.41; 95% confidence interval, 0.171 to 0.986; p=0.046), with no significant differences between the groups in 2-year OS, progression-free survival, local failure, or distant metastasis-free survival.

The nonrandomized comparative study by Liao et al (2010) compared patients who received RT, along with chemotherapy, for inoperable non-small-cell lung cancer (NSCLC) at a single institution.^17, This study retrospectively compared 318 patients who received computed tomography plus 3D-CRT and chemotherapy from 1999 to 2004 (mean follow-up, 2.1 years) with 91 patients who received 4-dimensional computed tomography plus IMRT and chemotherapy from 2004 to 2006 (mean follow-up, 1.3 years). Both groups received a median dose of 63 Gy. Disease endpoints were a locoregional progression, distant metastasis, and OS. Disease covariates were gross tumor volume, nodal status, and histology. The toxicity endpoint was grade 3, 4, or 5 radiation pneumonitis; toxicity covariates were gross tumor volume, smoking status, and dosimetric factors. Using Cox proportional hazards models, the hazard ratios (HRs) for IMRT were less than one for all disease endpoints; the difference was significant only for OS. The median survival was 1.40 years for the IMRT group and 0.85 years for the 3D-CRT group. The toxicity rate was significantly lower in the IMRT group than in the 3D-CRT group. The volume of the lung receiving 20 Gy was higher in the 3D-CRT group and was a factor in determining toxicity. Freedom from distant metastasis was nearly identical in both groups. The authors concluded that treatment with 4-dimensional computed tomography plus IMRT was at least as good as that with 3D-CRT in terms of the rates of freedom from locoregional progression and metastasis. This retrospective study found significant reductions in toxicity and improvement in survival. The nonrandomized, retrospective aspects of this study from a single-center limit the ability to draw definitive treatment conclusions about IMRT.

Harris et al (2014) compared the effectiveness of IMRT, 3D-CRT, or 2D-RT in treating stage III NSCLC using a cohort of patients from the Surveillance, Epidemiology, and End Results-Medicare database treated between 2002 and 2009.^19, OS was better with IMRT and 3D-CRT than with 2D-CRT. In univariate analysis, improvements in OS (HR=0.90, p=0.02) and cancer-specific survival (HR=0.89, p=0.02) were associated with IMRT. However, IMRT was similar to 3D-CRT after controlling for confounders in OS (HR=0.94, p=0.23) and cancer-specific survival (HR=0.94, p=0.28). On multivariate analysis, toxicity risks with IMRT and 3D-CRT were also similar. Likewise, results were similar for the propensity score-matched models and the adjusted models.

Shirvani et al (2013) reported on a U.S. cancer center study that assessed the use of definitive IMRT in limited-stagesmall-cell lung cancer treated with definitive RT.^20, In this study of 223 patients treated from 2000 to 2009, 104 received IMRT and 119 received 3D-CRT. Median follow-up times were 22 months (range, 4-83 months) for IMRT and 27 months (range, 2-147 months) for 3D-CRT. In both multivariable and propensity score-matched analyses, OS and disease-free survival did not differ between IMRT and 3D-CRT. However, rates of esophagitis-related percutaneous feeding tube placements were lower with IMRT (5%) than with 3D-CRT (17%; p=0.005).

Ling et al (2016) compared IMRT with 3D-CRT in patients who had stage III NSCLC treated with definitive RT.^21, In this study of 145 consecutive patients treated between 1994 and 2014, the choice of treatment was at the treating physician's discretion but all IMRT treatments were performed in the last 5 years. The authors found no significant differences between the groups for any measure of acute toxicity (grade ≥2 esophagitis, grade ≥2 pneumonitis, percutaneous endoscopic gastrostomy, narcotics, hospitalization, or weight loss). There were no significant differences in oncologic and survival outcomes.

Koshy et al (2017) published a retrospective cohort analysis of patients with stage III NSCLC, comparing those treated with IMRT and with non-IMRT.^22, Using the National Cancer Database, 7493 patients treated between 2004 and 2011 were assessed. Main outcomes were OS and the likelihood and effects of radiation treatment interruption, defined as a break in the treatment of four or more days. OS for non-IMRT and IMRT patients, respectively, were 18.2 months and 20 months (p<0.001) (see Table 4). Median survival with and without a radiation treatment interruption was 16.1 and 19.8 months, respectively (p<0.001), and IMRT significantly reduced the likelihood of a radiation treatment interruption (odds ratio, 0.84; p=0.04). The study was limited by unavailable information regarding radiation treatment planning and potential mechanisms affecting survival, and by a possible prescription, bias causing patients with better performance status to be given IMRT.

Table 3. Summary of Key Observational Comparative Study Characteristics

FU: follow-up; IMRT: intensity-modulated radiotherapy.

Table 4. Summary of Key Observational Comparative Study Results

Section Summary: Lung Cancer

For the treatment of lung cancer, no RCTs were identified that compared IMRT with 3D-CRT. Dosimetry studies have reported that IMRT can reduce radiation exposure to critical surrounding structures, especially for large lung tumors. Based on nonrandomized comparative studies, IMRT appears to produce survival outcomes comparable with those of 3D-CRT, with a reduction in adverse events.

Summary of Evidence

For individuals who have lung cancer who receive IMRT, the evidence includes nonrandomized, retrospective, comparative studies. The relevant outcomes are OS , disease-specific survival, QOL, and treatment-related morbidity. Dosimetry studies have shown that IMRT can reduce radiation exposure to critical surrounding structures, especially in large lung tumors. Based on nonrandomized comparative studies, IMRT appears to produce survival outcomes comparable to those of 3D-CRT and reduce toxicity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Clinical vetting also provided strong support for IMRT when alternative RT dosimetry exceeds a threshold of V20 to at least 35% of normal lung tissue. Based on available evidence, clinical vetting, a strong chain of evidence, and the potential to reduce harms, IMRT may be considered medically necessary for lung cancer when(1) RT is given with curative intent, (2) alternative RT dosimetry demonstrates radiation dose exceeding V20 for at least 35% of normal lung tissue, and (3) IMRT reduces the V20 of radiation to the lung at least 10% below the V20 of 3D-CRT (eg, 40% reduced to 30%).

Population Reference No. 6 

IMRT for Primary (Definitive) Therapy for Localized Prostate Cancer

Clinical Context and Test Purpose

The purpose of IMRT in patients who have localized prostate cancer and undergoing definitive radiotherapy (RT 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 IMRT improve the net health outcome for individuals who have localized prostate cancer and are undergoing definitive therapy?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals who have localized prostate cancer and are undergoing definitive therapy.

Interventions

The test being considered is IMRT.

RT is an integral component of prostate cancer treatment. IMRT has been proposed as a method of external-beam radiotherapy that delivers adequate radiation to the tumor volume while minimizing the radiation dose to surrounding normal tissues and structures.

IMRT is performed by radiation oncologists in an outpatient clinical setting.

Comparators

The following test is currently being used to make decisions about the treatment of localized prostate cancer: 3D-CRT.

Treatment planning evolved by using 3D 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 3D-CRT.

3D-CRT is performed by radiation oncologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are overall survival (OS), locoregional recurrence, QOL, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

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

Systematic Reviews

A meta-analysis by Yu et al (2016) included 23 studies (total n=9556 patients) that compared IMRT with 3D-CRT for gastrointestinal (GI), genitourinary (GU), and rectal toxicity, biochemical control, and OS.^5, Reviewers included 16 retrospective comparisons and 5 prospective cohort studies published before July 2015. The relative risk for the pooled analysis was considered significant if the 95% confidence intervals did not overlap at 1 at the p<0.05 level. IMRT resulted in less acute and late GI toxicity, less rectal bleeding, and improved biochemical control (see Table 1). There was a modest increase in acute GU toxicity, and no significant differences between the treatments in acute rectal toxicity, late GU toxicity, and OS.

Table 1. Outcomes for IMRT Compared With 3D-CRT

CI: confidence interval; GI: gastrointestinal, grade 2-4 toxicity; GU: genitourinary, grade 2-4 toxicity; IMRT: intensity-modulated radiotherapy; RR: relative risk; 3D-CRT: 3-dimensional conformal radiotherapy.

Bauman et al (2012) published a systematic review assessed IMRT in the treatment of prostate cancer to quantify its potential benefits and to make recommendations for RT programs considering adopting this technique within Ontario, Canada.^6, Based on a review of 11 published reports through March 2009 (9 retrospective cohort studies, 2 RCTs) including 4559 patients, reviewers recommended IMRT over 3D-CRT for aggressive treatment of localized prostate cancer where an escalated radiation (>70 gray [Gy]) dose would be required. Four studies (three retrospective cohort studies, one RCT) reported differences in adverse events between IMRT and 3D-CRT. The RCT (n=78 patients) reported significantly less frequent acute GI toxicity in the IMRT group than in the 3D-CRT group. This was true for grade 2, 3, or 4 toxicity (20% vs 61%, p=0.001), grade 3 or 4 toxicity (0% vs 13%, p=0.001), and for acute proctitis (15% vs 38%, p=0.03). A second RCT included in this systematic review reported no differences in toxicity between IMRT and 3D-CRT.

For late GI toxicity, 4 of 9 studies, all retrospective cohort studies (total n=3333 patients), reported differences between IMRT and 3D-CRT. One RCT, reporting on late GI toxicity, did not find any differences between IMRT and 3D-CRT. Five of nine studies reported on late GU effects: only one reported a difference in late GU effects in favor of 3D-CRT. Two retrospective cohort studies reported mixed findings on QOL outcomes.^6,

A systematic review by Hummel et al (2010) conducted for the Health Technology Assessment Programme evaluated the clinical effectiveness of IMRT for the radical treatment of prostate cancer.^7, The literature search through May 2009 identified 8 nonrandomized studies comparing IMRT with 3D-CRT. Clinical outcomes were OS, biochemical (prostate-specific antigen [PSA]) relapse-free survival, toxicity, and health-related QOL. The biochemical relapse-free survival was not affected by treatment received, except when doses differed between groups; in those cases, a higher dose with IMRT was favored over lower doses with 3D-CRT. There was some indication that GU toxicity was worse for patients treated with dose-escalated IMRT. However, any group difference resolved by six months after treatment. Data comparing IMRT with 3D-CRT supported the theory that higher doses (up to 81 Gy) can improve biochemical survival for patients with localized prostate cancer. Most studies reported an advantage for IMRT in GI toxicity, particularly for the volume of the rectum treated, because toxicity can be reduced by increasing conformality of treatment.

Randomized Controlled Trials

Studies not included in the Yu et al (2016) meta-analysis^5,are described next.

Viani et al (2016) reported on a pseudorandomized trial (sequential allocation) that compared toxicity levels between IMRT and 3D-CRT in 215 men who had localized prostate cancer.^8, Treatment consisted of hypofractionatedRT at a total dose of 70 Gy in 2.8 Gy per fraction for either IMRT or 3D-CRT. The primary endpoint was toxicity, defined as any symptoms up to six months after treatment (acute) or that started six months after treatment (late). QOL was assessed with a prostate-specific module. The trial was adequately powered, and the groups were comparable at baseline. However, blinding of patients and outcome assessors were not reported. As shown in Table 2, the 3D-CRT group reported significantly more incidence of acute and late GI and GU toxicity, with similar rates of biochemical control (PSA nadir + 2 ng/mL). The combined incidence of acute GI and GU toxicity was 28% for the 3D-CRT group compared with 11% for the IMRT group. Prostate-specific QOL was reported to be worse in the 3D-CRT group at 6, 12, and 24 months but not at 36 months posttreatment.

Table 2. Acute and Late Toxicity Rates With 3D-CRT and IMRT

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

Nonrandomized Studies

Sujenthiran et al (2017) published a retrospective cohort study evaluating 23222 men who were treated for localized prostate cancer with IMRT (n=6933) or 3D-CRT (n=16289) between January 2010 and December 2013 and whose data were available in various databases within the English National Health Service.^9, Dosage was similar between treatment types: patients in both groups received a median of 2 Gy per fraction for a median total dose of 74 Gy. GI and GU toxicities were categorized as grade 3 or above using National Cancer Institute Common Terminology Criteria. On average, patients in the IMRT group experienced fewer GI toxic events per 100 person-years (4.9) than patients in the 3D-CRT group, who saw an average 6.5 GI events per 100 person-years (adjusted hazard ratio, 0.66; 95% confidence interval , 0.61 to 0.72; p<0.01). The rate of GU toxicity events was similar between treatment groups (IMRT, 2.3 GU events per 100 person-years vs 3D-CRT, 2.4 GU events per 100 person-years; hazard ratio, 0.94; 95% confidence interval , 0.84 to 1.06; p=0.31). The most commonly diagnosed GI toxicity events were radiation proctitis (n=5962 [68.5%] of 8701 diagnoses). Of 4061 GU toxicity diagnoses, the most common was hematuria (1265 [31.1%]). Study limitations included therapeutic differences and baseline GI and GU symptoms unaccounted for in the analysis, as well as limited follow-up on GI and GU toxicity. Reviewers concluded that IMRT showed a significant reduction in GI toxicity severity over 3D-CRT and similar levels of GU toxicity severity.

Michalski et al (2013) reported on comparative data for IMRT and 3D-CRT from the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial.^10, In this trial, the initial protocol only included 3D-CRT, but during the trial, the protocol was amended to include IMRT. As a result, 491 patients were treated with 3D-CRT and 257 were treated with IMRT. Patients treated with 3D-CRT received 55.8 Gy to the prostate and seminal vesicles and then 23.4 Gy to the prostate only. All IMRT patients received 79.2 Gy to the prostate and seminal vesicles. Radiation exposure for the bladder and rectum were significantly reduced with IMRT. There was a significant decrease in the incidence of grades 2, 3, and 4 late GI toxicity for IMRT on univariate analysis (p=0.039). On multivariate analysis, there was a 26% reduction in grade 2, 3, and 4 GI toxicity for the IMRT group but this difference was not statistically significant (p=0.099). There were no differences in early or late GU toxicity between groups.

Vora et al (2013) reported on 9-year tumor control and chronic toxicities observed in 302 patients treated with IMRT for clinically localized prostate cancer at a single institution.^11, Median dose delivered was 76 Gy (range, 70-77 Gy), and 35% of patients received androgen deprivation therapy. Local and distant recurrence rates were 5% and 8.6%, respectively. At 9 years, biochemical control rates were 77% for low-risk, 70% for intermediate-risk, and 53% for high-risk patients (p=0.05). At last follow-up, none had persistent GI and only 0.7% had persistent GU toxicities of grade 3 or 4. The high-risk group was associated with a higher distant metastasis rate (p=0.02) and death from prostate cancer (p=0.001).

Wong et al (2009) reported on a retrospective study of radiation dose escalation in 853 patients with localized (T1c-T3N0M0) prostate cancer.^12, RTs used included conventional dose (71 Gy) 3D-CRT (n=270), high-dose (75.6 Gy) IMRT (n=314), permanent transperineal brachytherapy (n=225), and external-beam radiotherapy plus brachytherapy boost (n=44). All patients were followed for a median of 58 months (range, 3-121 months). The 5-year OS rate for the entire group was 97%. The 5-year biochemical no evidence of disease rates, local control rates, and distant control rates were 74%, 93%, and 96%, respectively, for 3D-CRT; 87%, 99%, and 97%, respectively, for IMRT; 94%, 100%, and 99%, respectively, for brachytherapy alone; and 94%, 100%, and 97%, respectively, for external-beam radiotherapy plus brachytherapy.

Dosing for Low-Risk vs Intermediate- to High-Risk Prostate Cancer

The National Comprehensive Cancer Network (NCCN) has made recommended use of RT for patients with prostate cancer based on risk stratification by clinical and pathologic findings. These recommendations are based on studies that did and did not include IMRT as the mode of RT.

In 1993, a U.S. cancer research center initiated an RCT comparing toxicity levels with outcomes after 3D-CRT (at 78 Gy) and 2-dimensional RT (at 70 Gy) in patients with localized prostate cancer. The long-term results were reported by Kuban et al (2008).^13, The trial included 301 patients with stage T1b to T3 disease who received 70 Gy (n=150) or 78 Gy (n=151). Median follow-up was 8.7 years. Patient risk levels in the 70- and 78-Gy groups were low (n=31 and n=30), intermediate (n=71 and n=68), and high (n=48 and n=53), respectively. When analyzed by risk group, patients with low-risk disease treated to 78 Gy vs 70 Gy, had freedom from abiochemical or clinical failure of 88% and 63%, respectively (p=0.042). The intermediate-risk patients showed no statistically significant difference in freedom from biochemical or clinical failure based on dose level (p=0.36). Patients with high-risk disease showed a significant difference in freedom from biochemical or clinical failure based on dose (63% vs 26%, p=0.004), although when these high-risk patients were stratified by PSA level, only those patients with a PSA level greater than 10 ng/mL showed a difference in freedom from biochemical or clinical failure.

The NCCN guidelines also cite the Kuban et al (2008) study as evidence for a dose of 75.6 to 79.2 Gy (with or without the inclusion of the seminal vesicles) as appropriate for patients with low-risk cancers and that the conventional dose of 70 Gy is no longer considered adequate.

For patients with intermediate- and high-risk prostate cancer, the NCCN has cited the following studies. For example, Xu et al (2011) reported on a toxicity analysis of dose escalation from 75.6 to 81.0 Gy in 189 patients receiving definitive RT for prostate cancer.^14, Patients were at high-, intermediate-, and low-risk according to the NCCN definitions, and were dosed at physician discretion. A total of 119 patients received 75.6 Gy and 70 received 81.0 Gy. Patients were followed at intervals of three to six months for five years and yearly after that (median follow-up, three years). The 81.0-Gy group had higher rates of grade 2 acute GU toxicity (p<0.001), late GU toxicity (p=0.001), and late GI toxicity (p=0.082) but a lower rate of acute GI toxicity (p=0.002). There were no notable differences in final GU (p=0.551) or final GI (p=0.194) toxicity levels compared with the 75.6-Gy group.

Eade et al (2007) reported on the results of 1530 consecutive patients treated for localized prostate cancer with 3D-CRT between 1989 and 2002.^15, Patients were grouped by dose level: less than 70 Gy (n=43), 70 to 74.9 Gy (n=552), 75 to 79.9 Gy (n=568), and 80 Gy or more (n=367). Median follow-up ranged from 46 to 86 months, with the group receiving 80 Gy or more having a median follow-up of 45.6 months. Adjusted 5-year estimates of freedom from biochemical failure for the 4 groups were 60%, 68%, 76%, and 84% using the American Society for Radiation Oncology criteria and 70%, 81%, 83%, and 89% using Phoenix criteria, respectively. Adjusted 5- and 10-year estimates of freedom from distant metastases for the 4 groups were 96% and 93%, 97% and 93%, 99% and 95%, and 98% and 96%, respectively. The authors concluded that a pronounced RT dose-response by freedom from biochemical failure was seen after adjusting for pretreatment PSA level, Gleason score, and tumor stage and that the vast majority of patients should receive 80 Gy or more, although a subgroup of patients might be adequately treated with radiation lower dose.

Section Summary: IMRT for Primary (Definitive) RT for Localized Prostate Cancer

The evidence on IMRT for definitive treatment of localized prostate cancer includes several prospective comparative studies, retrospective comparative studies, and systematic reviews of these studies. Results generally showed that IMRT provides tumor control and survival outcomes similar to 3D-CRT, with reductions in GI and GU toxicity. A reduction in clinically significant complications of RT is likely to improve the QOL for treated patients.

Summary of Evidence

For individuals who have localized prostate cancer and are undergoing definitive RT who received IMRT, the evidence includes several prospective comparative studies, retrospective studies, and systematic reviews of these studies. The relevant outcomes are OS, disease-free survival, QOL, and treatment-related morbidity. Although there are few prospective comparative trials, the evidence has generally shown that IMRT provides tumor control and survival outcomes similar to 3D-CRT while reducing gastrointestinal and genitourinary toxicity. These findings are supported by treatment planning studies, which have predicted that IMRT improves target volume coverage and sparing of adjacent organs compared with 3D-CRT. A reduction in clinically significant complications of RT is likely to improve the QOL for treated patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 7 

IMRT for Prostate Cancer After Prostatectomy

Clinical Context and Test Purpose

The purpose of IMRT in patients who have prostate cancer and are undergoing RT after prostatectomy 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 IMRT improve the net health outcome in patients who have prostate cancer and are undergoing RT after prostatectomy?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals who have prostate cancer and are undergoing RT after prostatectomy.

Interventions

The test being considered is IMRT. IMRT is performed by radiation oncologists in an outpatient clinical setting.

Comparators

The following tool is currently being used to make decisions about the treatment of localized prostate cancer after prostatectomy: 3D-CRT.

Outcomes

The general outcomes of interest are OS, locoregional recurrence, QOL, and treatment-related morbidity.

Systematic Reviews

The Bauman et al (2012) systematic review (discussed earlier) found insufficient data to recommend IMRT over 3D-CRT as adjuvant therapy after prostatectomy.^6,

The joint American Urological Association and the American Society for Radiation Oncology (2013) guidelines on the use of adjuvant and salvage RT after prostatectomy was based on a systematic review conducted by Thompson et al (2013) who searched the literature from 1990 to 2012 and selected 294 articles.^4, Reviewers attempted to determine which RT technique and doses produced optimal outcomes, but found it impossible to answer these questions because most available data came from observational studies and approximately one-third treated patients with conventional 2-dimensional external-beam modalities. Of the literature assessed in the review, less than 5% of studies reported using IMRT. Reviewers stated that 64 to 65 Gy is the minimum dose that should be delivered after prostatectomy but that dosage should be individualized to the patient.

Nonrandomized Comparative Studies

Alongi et al (2009) reported on acute toxicity results of whole pelvis irradiation for 172 consecutive patients with clinically localized prostate cancer treated with IMRT or 3D-CRT as adjuvant (n=100) or salvage (n=72) therapy after radical prostatectomy and pelvic lymph node dissection.^16, Whole pelvis radiation was considered in patients with a limited lymphadenectomy and/or in the presence of a high-risk of nodal involvement, in patients with positive lymph nodes and/or in the presence of adverse prognostic factors (Gleason score >7 and/or preoperative PSA level >10 ng/mL). Eighty-one patients underwent 3D-CRT, and 91 underwent IMRT. No grade 3 or 4 acute GU or lower GI side effects were observed. Acute grade 2 GU and acute lower GI grade 2 events did not differ significantly between treatment groups (see Table 3). There was a higher incidence of acute upper GI grade 2, 3, and 4 toxicity, in the 3D-CRT group. The authors concluded that acute toxicity following postoperative whole pelvis irradiation was reduced with IMRT compared with 3D-CRT; this effect was most significant for upper GI symptoms, owing mainly to better bowel sparing with IMRT.

Table 3. Acute and Late Toxicity Rates With 3D-CRT and IMRT

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

Massaccesi et al (2013) reported preliminary acute toxicity results from a phase 2 trial of hypofractionated IMRT with a simultaneous integrated boost to the pelvic nodes and prostate bed after prostatectomy.^17, Between 2008 and 2012, 49 patients considered to be at a high-risk of relapse after radical prostatectomy or who had biochemical relapse received 45 Gy in 1.8-Gy fractions to the whole pelvis and 62.5 Gy in 2.5-Gy fractions (equivalent dose, 68.75 Gy) to the prostate bed. The toxicity findings were compared with those of 52 consecutive patients selected from an electronic database who underwent adjuvant or salvage 3D-CRT with standard 2-Gy fractionation to the prostatic bed and regional pelvic nodes. Grade 1, 2, 3, and 4 acute GU toxicity occurred in 71.2% of all patients without a significant difference between the groups (hypofractionated IMRT vs conventionally fractionated 3D-CRT; p=0.51). Grade 2 acute GU toxicity, reported in 19.8% of all patients, was less frequent in patients in the IMRT group (9.6% vs 28.8%, p=0.02). There were no cases of grade 3 acute GU toxicity. Thirty (29.7%) patients developed grade 2 acute GI toxicity; the difference between groups was not statistically significant. No cases of grade 3 acute GI toxicity were reported. The study concluded that the acute toxicity profile for hypofractionated high-dose simultaneous integrated boost IMRT after prostatectomy compared favorably with that of conventionally fractionated high-dose 3D-CRT.

Single-Arm Studies

Several prospective single-arm,phase 2 studies have evaluated the safety and efficacy of different methods of delivering IMRT (eg, integrated boost, hypofractionation).

PLATIN 3 Trial

Initial results of the phase 2, Prostate and Lymph Node Irradiation With Integrated Boost-IMRT After Neoadjuvant Antihormonal Treatment trial were published by Katayama et al (2014).^18, This trial evaluated the safety and feasibility of irradiating the pelvic lymph nodes simultaneously with a boost to the prostate bed in 40 patients with high-risk features or inadequate lymphadenectomy after radical prostatectomy. Treatment consisted of 2 months of antihormonal treatment before IMRT of the pelvic lymph nodes (51.0 Gy) with a simultaneous integrated boost to the prostate bed (68.0 Gy). No incidence of acute grade 3 or 4 toxicity occurred. Nearly 23% of patients experienced acute grade 2 GI and GU toxicity, 10% late grade 2 GI toxicity, and 5% late grade 2 GU toxicity. One patient developed late grade 3 proctitis and enteritis. At a median of 24 months, 89% of patients were free of a PSA recurrence.

PRIAMOS1 Trial

Acute toxicity results from the Hypofractionated RT of the Prostate Bed With or Without the Pelvic Lymph Nodes trial were reported by Katayama et al (2014).^19, This prospective phase 2 trial assessed the safety and toxicity of hypofractionated RT of the prostate bed with IMRT as a basis for further prospective trials. Forty patients with indications for adjuvant or salvage therapy (pathologic stage T3 and/or R1/2 or with a PSA recurrence after prostatectomy) were enrolled from February to September 2012; 39 were evaluated. All patients received a total dose of 54.0 Gy to the prostate bed, 28 for salvage and 11 in the adjuvant setting. Based on preoperative staging, patients were risk-stratified as low (n=2), intermediate (n=27), or high (n=10). Ten weeks after completing therapy, there were no adverse events exceeding grade 3. Acute GI toxicity rates were 56.4% and 17.9% for grade 1 and 2, respectively, and acute grade 1 GU toxicity was recorded in 35.9% of patients.

Corbin et al (2013) reported on the adverse events in men at high-risk of recurrence 2 years after prostatectomy and IMRT.^20, Between 2007 and 2010, 78 consecutive men received adjuvant RT (n=17 [22%]) or salvage RT (n=61 [78%]). The median IMRT dose was 66.6 Gy (range, 60-72 Gy). QOL data was collected prospectively at 2, 6, 12, 18, and 24 months, and included urinary incontinence, irritation or obstruction, bowel or rectal function, and sexual function. No significant changes were observed from baseline through 2-year follow-up, with global urinary irritation or obstruction scores unchanged or improved over time from baseline, global urinary incontinence improved from baseline to 24 months in the subset of patients receiving adjuvant therapy, and global bowel and sexual domain scores improved or were unaffected over follow-up (though initially lower at 2 months).

Section Summary: IMRT for Prostate Cancer After Prostatectomy

The evidence on the use of IMRT for prostate cancer after prostatectomy includes nonrandomized comparative studies, single-arm phase 2 trials, retrospective series, and systematic reviews of these studies. Although the comparative studies are primarily retrospective, the evidence has generally shown that IMRT provides tumor control and survival outcomes similar to 3D-CRT. Notably, a retrospective comparative study found a significant reduction in acute GI toxicity with IMRT compared with 3D-CRT, mainly due to better bowel sparing with IMRT. Another retrospective comparative study found a reduction in GU toxicity. A reduction in clinically significant complications of RT is likely to improve the QOL for treated patients.

Summary of Evidence

For individuals who have prostate cancer and are undergoing RT after prostatectomy who receive IMRT, the evidence includes retrospective comparative studies, single-arm phase 2 trials, and systematic reviews of these studies. The relevant outcomes are OS, disease-free survival, QOL, and treatment-related morbidity. Although the comparative studies are primarily retrospective, the evidence has generally shown that IMRT provides tumor control and survival outcomes similar to 3D-CRT. Notably, a retrospective comparative study found a significant reduction in acute upper GI toxicity with IMRT compared with 3D-CRT, mainly due to better bowel sparing with IMRT. Another retrospective comparative study found a reduction in GU toxicity. A reduction in clinically significant complications of RT is likely to improve the QOL for treated patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 8 

Head and Neck Cancers

Clinical Context and Test 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 PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with head and neck cancers. Head and neck cancers account for 3% to 5% of cancer cases in the U. S. 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.

IMRT is performed by radiation oncologists in an outpatient clinical setting.

Comparators

The following practices are currently being used to make decisions about the treatment of head and neck cancers: 3-dimensional conformal radiotherapy (3D-CRT) and 2-dimensional radiotherapy (2D-RT).

3D-CRT and 2D-RT are performed by radiation oncologists in an outpatient clinical setting.

Outcomes

The general outcomes of interest are locoregional control, overall survival (OS), and treatment-related morbidity. Evaluation of patient-reported outcomes and QOL measures are also of interest.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

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

Systematic Reviews

Ursino et al (2017) published a systematic review of 22 studies (totaln=1311 patients) evaluating swallowing outcomes in patients treated with 3D-CRT or IMRT for head and neck cancer.^1, 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.

Marta et al (2014) reported on a systematic review and meta-analysis of 5 prospective phase 3 randomized trials comparing IMRT with 2D-RT or 3D-CRT for head and neck cancer.^2, A total of 871 patients were randomized to IMRT (n=434) or to 2D-RT or 3D-CRT (n=437). Xerostomia grades 2, 3, or 4 were found to be significantly lower in patients treated with IMRT than with 2D-RT and 3D-CRT for all studies (hazard ratio, 0.76; 95% confidence interval, 0.66 to 0.87; p<0.001). Locoregional control and OS were similar across all three technologies.

A comparative effectiveness review on radiotherapy for head and neck cancers was published by Samson et al (2010) for the Agency for Healthcare Research and Quality.^3, This report noted that, based on moderate strength evidence, IMRT reduced late xerostomia and improved QOL domains related to xerostomia compared with 3D-CRT. Reviewers also found that no conclusions on tumor control or survival could be drawn from the evidence. An update, published by Ratko et al (2014), was consistent with and strengthened the findings of the original review on late xerostomia.^4,

Randomized Controlled Trials

I, 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, progression-free survival (PFS), and OSoverall survival. Sixty patients with locally advanced head and neck cancer were randomized to either SIB-IMRT (control arm) or SMART (study arm).^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 = 0.038). At 2 years post-treatment, PFS was 53.3% and 80.0% (P = 0.028) for the SIB-IMRT and SMART groups, respectively. Two-year OS was also higher for the SMART group, with rates of 60.0% vs 86.7% (P = 0.020) for SIB-IMRT and SMART, respectively. 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 status was not part of the pretreatment workup; the treatment response and prognosis for human papillomavirus -positive tumors are considerably different compared to human papillomavirus -negative tumors, but this factor could not be included in the analysis.

Of the 5 phase 3 RCTs included in the Marta et al  (2014) meta-analysis, only 1 trial (Gupta et al [2012]^6,) compared IMRT with 3D-CRT. Long-term results from this trial were published by Ghosh-Laskar et al (2016).^7, This trial included 60 patients with squamous cell carcinoma of the head and neck and was powered to detect a 35% difference in toxicity between treatments (85% vs 50%). The proportion of patients with salivary gland toxicity was lower in the IMRT group (59%) than in the 3D-CRT group (89%; p=0.009). The percentage of patients with substantial weight loss was significantly lower in the IMRT group at one and two years. There were no significant differences between the two groups for acute dysphagia, mucositis, dermatitis, or requirements for tube feeding. Xerostomia decreased over follow-up in both groups, but significant differences in late salivary toxicity persisted through five years. At 2 years posttreatment, grade 2 or worse xerostomia was 0% in the IMRT group compared with 28% following 3D-CRT (p=0.017). At 5 years, salivary toxicity was 0% in the IMRT group compared with 17% following 3D-CRT (p=0.041). Locoregional control and OS did not differ significantly between groups.

The other 4 RCTs reviewed by Marta et al (2014) compared IMRT with 2D-RT. An RCT by Pow et al (2006) on IMRT for nasopharyngeal carcinoma (NPC) included only 45 patients.^8,Nutting et al (2011) reported on the Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer, a randomized phase 3 trial, which also compared conventional RT with parotid-sparing IMRT in 94 patients with T1, T2, T3, or T4 tumor stage, and N0, N1, N2, or N3, and M0nodal stage pharyngeal squamous cell carcinoma.^9, One year after treatment, grade 2 or worse xerostomia was reported in 38% of patients in the IMRT group, which was significantly lower than the reported 74% in the conventional RT group. Xerostomia rates continued to be significantly lowered 2 years posttreatment in the IMRT group (29% vs 83%, respectively). At 24 months, rates of locoregional control, nonxerostomia late toxicities, and OS did not differ significantly between treatment groups.

Peng et al (2012) compared IMRT with 2D-RT in 616 patients with NPC.^10, At a median follow-up of 42 months (range, 1-83 months), patients in the IMRT group had significantly lower radiation-induced toxicities. The 5-year OS rate was 80% in the IMRT group and 67% in the 2D-CRT group.

Nonrandomized Comparative Studies

Several nonrandomized comparative studies have evaluated late toxicities and QOL 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.^11, 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, 0.30; 95% confidence interval, 0.12 to 0.78; p=0.007), as well as the 5-year disease-free survival rate (85.7% vs 71.2%, respectively; hazard ratio, 0.47; 95% confidence interval, 0.23 to 0.94; p=0.029). Grade 2, 3, and 4 xerostomia (52.7% vs 34%, respectively; p=0.015) and hearing loss (40.5% vs 22.5%, respectively; p=0.01) 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.^12, 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 five years posttreatment; then, at 6-month intervals thereafter. Late toxicities (eg, 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 QOL, 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, 0.47-0.53). Late toxicities were less severe in the IMRT group, with adjusted odds ratios 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.

Vergeer et al (2009) compared IMRT with 3D-CRT for patient-rated acute and late xerostomia and health-related quality of life (HRQOL) among patients with head and neck squamous cell carcinoma.^13, The study included 241 patients with head and neck squamous cell carcinoma (cancers arising from the oral cavity, oropharynx, hypopharynx, nasopharynx, or larynx and those with neck node metastases from squamous cell cancer of unknown primary) treated with bilateral irradiation with or without chemotherapy. All patients were included in a program that prospectively assessed acute and late morbidity and HRQOL at regular intervals. Before October 2004, all patients were treated with 3D-CRT (n=150); starting that October, 91 patients received IMRT. The use of IMRT significantly reduced the mean dose to the parotid glands (27Gyvs 43 Gy; p<0.001). During radiation, grade 3 or higher xerostomia at 6 weeks was significantly less common with IMRT (20%) than after 3D-CRT (45%). At 6 months, the prevalence of grade 2 or higher xerostomia was significantly lower after IMRT (32%) than with 3D-CRT (56%). Treatment with IMRT also had a positive effect on several general and head and neck cancer-specific HRQOL measures.

Rusthoven et al (2008) assessed outcomes for IMRT and 3D-CRT in patients who had oropharyngeal cancer.^14, In this study, which treated 32 patients with IMRT and 23 with 3D-CRT, late xerostomia occurred in 15% of the IMRT patients and in 94% of the 3D-CRT patients.

Section Summary: Head and Neck Cancer

The literature on IMRT for head and neck cancer includes 4 systematic reviews, including 2 meta-analyses of RCTs, as well as RCTs and nonrandomized comparative studies. Most RCTs have compared IMRT with 2D-RT, which has been replaced by 3D-CRT. One RCT that compared IMRT with 3D-CRT found a significant benefit of IMRT for reduced xerostomia that persisted through five years. Oncologic outcomes did not differ significantly between treatments. 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. HRQOL was also improved with IMRT compared with 3D-CRT with 2D-RT plus 3D-CRT boost. Comparators in these nonrandomized studies were generally older technologies (eg, 2D-RT) with older treatment protocols, both of which limit interpretation of the results. However, more recent evidence has also supported the conclusions of the comparative effectiveness review that treatment of head and neck cancers with IMRT reduces xerostomia compared with other external-beam radiotherapy techniques. For the outcomes of PFS and OS, another RCT compared two fractionation schedules of IMRT and found SMART superior to SIB-IMRT in the areas of two-year PFS and OS. And an additional nonrandomized study concluded that IMRT followed by chemotherapy as opposed to IMRT alone led to better OS rates for high-risk patients. However, the evidence permits no conclusions on tumor control or survival.

Summary of Evidence

For individuals who have head and neck cancer who receive IMRT, the evidence includes systematic reviews, RCTs , and nonrandomized comparative studies. The relevant outcomes are OS, functional outcomes, QOL, and treatment-related morbidity. One RCT that compared IMRT with 3D-CRT found a significant benefit of IMRT on xerostomia that persisted through five years. Oncologic outcomes did not differ significantly between treatments. Another RCT compared two fractionation schedules of IMRT for locally advanced head and neck cancer and found a 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, the evidence has shown that IMRT significantly and consistently reduces both early and late xerostomia and improves QOL domains related to xerostomia compared with 3D-CRT. For the outcomes of PFS and OS, another RCT compared two fractionation schedules of IMRT and found SMART superior to SIB-IMRT in the areas of two-year PFS and OS. And an additional nonrandomized study concluded that IMRT followed by chemotherapy as opposed to IMRT alone led to better OS rates for high-risk patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 9 

Thyroid Cancer

Clinical Context and Test 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 PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are patients with thyroid cancer in close proximity to organs at risk. Anaplastic thyroid cancer occurs in less than 5% of thyroid cancers.

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. IMRT is delivered in tertiary oncology care settings where complex imaging, radiation physics, and treatment planning resources are available.

Comparators

The following practices are currently being used to make decisions about the treatment of thyroid cancer: 3-D 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 locoregional control, OS, and treatment-related morbidity. Evaluation of patient-reported outcomes and QOL measures are also of interest. Locoregional control and OS should be assessed at one and five years.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

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

Case Series

The best available evidence for this indication consists of case series. For example, the largest series comparing IMRT with 3D-CRT was published by Bhatia et al (2010).^15, This series reviewed institutional outcomes for anaplastic thyroid cancer treated with 3D-CRT or IMRT in 53 consecutive patients. Thirty-one (58%) patients were irradiated with curative intent. Median radiation dose was 55 Gy (range, 4-70 Gy). Thirteen (25%) patients received IMRT to a median of 60 Gy (range, 39.9-69.0 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 radiotherapy.^16, 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, 38-72 Gy). Fifty-seven (44%) patients were treated with IMRT to a median dose of 60 Gy (range, 56-66 Gy). Median follow-up was 38 months (range, 0-134 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. IMRT 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 nonrandomized, retrospective studies. High-quality studies that differentiate the superiority of any type of external-beam radiotherapy 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 (eg, OS vsPFS 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 (eg, anaplastic thyroid carcinoma) or for thyroid tumors located near critical structures (eg, 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 thyroid cancer in close proximity to organs at risk who receive IMRT, the evidence includes nonrandomized, retrospective studies. The relevant outcomes include OS, functional outcomes, QOL, 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 (eg, 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.

Population Reference No. 10

Intensity-Modulated Radiotherapy for Cancers of the Abdomen and Pelvis

Multiple-dose planning studies generate 3-dimensional conformal radiotherapy (3D-CRT) andIMRT treatment plans from the same scans and then compare predicted dose distributions within the target area and adjacent organs. Results of such planning studies have shown that IMRT is better than 3D-CRT with respect to conformality to the target and dose homogeneity within the target. Results have also demonstrated that IMRT delivers less radiation to nontarget areas. Dosimetry studies using stationary targets generally confirm these predictions. However, because patients move during treatment, dosimetry with stationary targets only approximate actual radiation doses received. Based on these dosimetry studies, radiation oncologists expect IMRT to improve treatment outcomes compared with those of 3D-CRT.

Comparative studies of radiation-induced adverse events from IMRT vs alternative radiation delivery would constitute definitive evidence of establishing the benefit of IMRT. Single-arm series of IMRT can give insights into the potential for benefit, particularly if an adverse event expected to occur at high rates is shown to decrease significantly. Studies of treatment benefit are also important to establish that IMRT is at least as good as other types of delivery, but absent such comparative trials, it is likely that benefit from IMRT is at least as good as with other types of delivery.

In general, when the indication for IMRT is to avoid radiation to sensitive areas, dosimetry studies have been considered sufficient evidence to demonstrate that harm would be avoided using IMRT. For other indications, such as using IMRT to provide better tumor control, comparative studies of health outcomes are needed to demonstrate such a benefit.

Clinical Context and Test Purpose

The purpose of IMRT in patients who have abdominal or pelvic cancers is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

The following PICOTS were used to select literature to inform this review.

Patients

The relevant populations of interest are patients with gastrointestinal cancers (eg, stomach, hepatobiliary, and pancreatic cancers), gynecologic cancers (eg, cervical and endometrial cancers), and anorectal cancers who are recommended for radiotherapy (RT).

Interventions

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

Comparators

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

Outcomes

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

Timing

Toxicity and recurrence can be assessed acutely and long-term.

Setting

IMRT is usually administered in a hospital or free-standing facility.

Population Reference No. 10 Policy Statement

Gastrointestinal Tract Cancers

Stomach

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

Table 1. Outcomes for Intensity-Modulated Radiotherapy With Capecitabine Plus Oxaliplatin vs 3-Dimensional Conformal Radiotherapy With 5-FU Plus FA for Stomach Cancer

Adapted from Boda-Heggemann et al (2009, 2013).^1,2,
FA: folinic acid; 5-FU: 5-fluorouracil.

Hepatobiliary

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

Pancreatic

Literature searches have identified a few comparative studies and case series on IMRT for pancreatic cancer. For example, Lee et al (2016) reported on a prospective comparative study of GI toxicity in patients treated with concurrent chemoradiotherapy plus IMRT or 3D-CRT for treatment of borderline resectable pancreatic cancer.^4, Treatment selection was by patient choice after consultation with a radiation oncologist. Symptoms of dyspepsia, nausea or vomiting, and diarrhea did not differ between groups. Upper endoscopy revealed more patients with gastroduodenal ulcers in the 3D-CRT group than in the IMRT group (see Table 2). OS was longer in the IMRT group than in the 3D-CRT group but the interpretation of survival results was limited by the risk of bias in this nonrandomized study.

Prasad et al (2016) retrospectively reviewed charts of patients with locally advanced pancreatic cancer who were treated with IMRT (n=134) or 3D-CRT (n=71).^5, Propensity score analysis was performed to account for potential confounding variables, including age, sex, radiation dose, RT field size, and concurrent RT. Grade 2 GI toxicity occurred in significantly more patients treated with 3D-CRT than with IMRT (propensity score odds ratio, 1.26; 95% confidence interval, 1.08 to 1.45; p=0.001; see Table 2). Hematologic toxicity and median survival were similar in the two groups.

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

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

Section Summary: GI Tract Cancers

The evidence on IMRT for GI tract cancers includes nonrandomized comparative studies. IMRT has been compared with 3D-CRT for the treatment of stomach, hepatobiliary, and pancreatic cancers, with some studies reporting longer OS and decreased toxicity with IMRT. For the treatment of stomach cancer, IMRT improved survival compared with 3D-CRT. However, this study also used different chemotherapy regimens, confounding the results. The evidence on hepatobiliary cancer includes a series of historical controls that found an increase in median survival with no difference in toxicity. Two comparative studies (one prospective, one retrospective) were identified on IMRT for pancreatic cancer. The prospective comparative study found an increase in survival with a reduction in GI toxicity, while the retrospective study found a decrease in GI toxicity. Although most studies were limited by their retrospective designs and changes in practice patterns over time, the available evidence would suggest that IMRT improves survival and decreases toxicity better than 3D-CRT in patients with GI cancers.

Summary of Evidence

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

Population Reference No. 11 

Gynecologic Cancers

Randomized Controlled Trials

A trial by Naik et al (2016) randomized 40 patients with cervical cancer to IMRT or to 3D-CRT.^6, Both arms received concurrent chemotherapy (cisplatin) plus RT at 50 Gy in 25 fractions. Dosimetric planning showed higher conformality and lower doses to organs at risk with IMRT. With follow-up through 90 days, posttreatment, vomiting and acute GI and genitourinary (GU) toxicity were significantly higher in the 3D-CRT group (see Table 3).

Gandhi et al (2013) reported on a prospective randomized study that compared whole-pelvis IMRT with whole-pelvis 2-dimensional RT in 44 patients with locally advanced cervical cancer.^7, Each treatment arm had 22 patients. The OS rate at 27 months was 88% with IMRT and 76% with 2-dimensional RT (p=0.645). However, fewer grade 2, 3, or 4 GI toxicities were experienced in the IMRT group than in the conventional RT group (see Table 3).

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

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

Nonrandomized Comparative Studies

Shih et al (2016) conducted a retrospective comparison of bowel obstruction following IMRT (n=120) or 3D-CRT (n=104) after hysterectomy for endometrial or cervical cancer.^8, Groups were generally comparable, except more patients in the 3D-CRT group had open hysterectomy (81% vs 47%, p<0.001). Patients received regular examinations throughout a median follow-up of 67 months, and the 5-year rate of bowel obstruction was 0.9% in the IMRT group compared with 9.3% in the 3D-CRT group (p=0.006). A body mass index of 30 kg/m² or more was also associated with less bowel obstruction. However, on multivariate analysis, the only significant predictor of less bowel obstruction was IMRT (p=0.022).

Chen et al (2014) reported on 101 patients with endometrial cancer treated with hysterectomy and adjuvant RT.^9, No significant differences between IMRT patients (n=65) and CRT patients (n=36) were found in 5-year OS (82.9% vs 93.5%; p=0.26), local failure-free survival (93.7% vs 89.3%; p=0.68), or disease-free survival (88.0% vs 82.8%; p=0.83). However, IMRT patients experienced fewer acute and late toxicities.

Chen et al (2007) examined the use of posthysterectomy RT in 68 women with high-risk cervical cancer.^10, The initial 35 cases received 2-dimensional RT delivered to the whole pelvis; the next 33 patients underwent IMRT. All patients received RT at 50.4 Gy in 28 fractions and 6 Gy of high-dose rate vaginal cuff intracavitary brachytherapy in 3 insertions; chemotherapy (cisplatin) was administered concurrently to all patients. All patients completed the planned course of treatment. At a median follow-up of 34.6 months (range, 12-52 months) in 2-dimensional RT recipients and 14 months (range, 6-25 months) in IMRT recipients, the 1-year locoregional control rate was 94% for 2-dimensional RT and 93% for IMRT. Grade 1 or 2 acute GI toxicities were noted in 36% and 80% of IMRT and 2-dimensional RT recipients, respectively (p<0.001), while acute grade 1 or 2 GU toxicities occurred in 30% and 60%, respectively (p=0.022). There was no significant difference between IMRT and 2-dimensional RT in the incidence of acute hematologic toxicities. Overall, the IMRT patients had lower rates of chronic GI toxicities (p=0.002) than the 2-dimensional RT patients.

Section Summary: Gynecologic Cancers

The evidence on IMRT for gynecologic cancers includes 2 small RCTs (<50 patients each) and several nonrandomized comparative studies. There is limited comparative evidence on survival outcomes following IMRT or 3D-CRT. However, available results have generally been consistent that IMRT reduces GI and GU toxicity. Based on evidence with other cancers of the pelvis and abdomen in close proximity to organs at risk, it is expected that OS with IMRT would be at least as good as 3D-CRT, with a decrease in toxicity.

Summary of Evidence

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

Population Reference No. 12 

Anorectal Cancer

Randomized Controlled Trials

Rattan et al (2016) conducted a small (n=20) RCT assessing IMRT for the treatment of anal canal cancer.^11, Grade 3 GI toxicity during treatment was not observed in any patients in the IMRT group but was seen in 60% of patients treated with 3D-CRT (p=0.010). Hematologic grade 3 toxicity was not seen in any patients treated with IMRT but was noted in 20% of patients treated with 3D-CRT (p=0.228). Other parameters indicating better tolerance to treatment with IMRT were reduced need for parenteral fluid (10% vs 60%, p=0.019) and blood transfusion (0% vs 20%, p=0.060).

Nonrandomized Comparative Studies

Sun et al (2017) reported on a comparative analysis of the National Cancer Database of IMRT with 3D-CRT for the treatment of rectal adenocarcinoma.^12, A total of 7386 patients with locally advanced rectal carcinoma were treated with neoadjuvant chemoradiotherapy (45 to 54 Gy) from 2006 to 2013; 3330 (45%) received IMRT and 4065 (55%) received 3D-CRT. Use of IMRT increased from 24% in 2006 to 50% in 2013. Patient age, race, insurance status, Charlson-Deyo comorbidity score, hospital type, income and educations status, and clinical disease stage were not predictive of which RT was used. The mean radiation dose was higher with IMRT (4735 centigray vs 4608 centigray, p<0.001) and the occurrence of sphincter loss surgery was higher in the IMRT group (see Table 4). However, patients treated with IMRT had a higher risk of positive margins. Multivariate analysis found no significant differences between the treatments for pathologic downstaging, unplanned readmission, 30-day mortality, or long-term survival. This study used unplanned readmission as a surrogate measure of adverse events but could not assess acute or late toxicity.

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

Adapted from Sun et al (2017).^12,
CI: confidence interval; IMRT: intensity-modulated radiotherapy; 3D-CRT: 3-dimensional conformal radiotherapy.

Huang et al (2017) reported on a retrospective comparison of outcomes and toxicity for preoperative image-guided IMRT and 3D-CRT in locally advanced rectal cancer.^13, A total of 144 consecutive patients treated between 2006 and 2015 were analyzed. The 3D-CRT group was treated with 45 Gy in 25 fractions while the IMRT group was treated with 45 Gy in 25 fractions with a simultaneous integrated boost of 0.2 Gy per day for the primary tumor up to a total dose of 50 Gy. Statistical analysis was performed for grade 0, 1, 2, 3, or 4 toxicity and was significant only for acute GI toxicity (p=0.039; see Table 5). Four-year OS and disease-free survival did not differ between the two groups. Multivariate analysis found IMRT to be an independent predictor of local failure-free survival (hazard ratio, 0.35; 95% confidence interval, 0.11 to 0.95; p=0.042).

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

Adapted from Huang et al (2017).^13,
IMRT: intensity-modulated radiotherapy; 3D-CRT: 3-dimensional conformal radiotherapy.

In a retrospective review of 89 consecutive patients (52 IMRT, 37 3D-CRT), Chuong et al (2013) found that 3-year OS, progression-free survival, locoregional control, and colostomy-free survival did not differ significantly between patients treated with IMRT or with 3D-CRT (p>0.1).^14, Adverse events with 3D-CRT were more frequent and severe and required more treatment breaks than IMRT (11 days vs 4 days; p=0.006) even though the median duration of treatment breaks did not differ significantly (12.2 days vs 8.0 days; p=0.35). IMRT patients had fewer acute grade 3 or 4 nonhematologic toxicity (p<0.001), improved late grade 3 or 4 GI toxicity (p=0.012), and fewer acute grade 3 or 4 skin toxicity (p<0.001) than 3D-CRT patients.

Dasgupta et al (2013) retrospectively reviewed 223 patients (45 IMRT, 178 CRT) to compare outcomes for anal cancer.^15, They reported that two-year OS, distant metastases-free survival, and locoregional recurrence-free survival did not differ significantly between patients in the IMRT and CRT groups.

Dewas et al (2012) retrospectively reviewed 51 patients with anal cancer treated with IMRT (n=24) or with 3D-CRT (n=27).^16, Outcomes also did not differ significantly between patients in the IMRT and 3D-CRT groups in two-year OS, locoregional relapse-free survival, and colostomy-free survival. Grade 3 acute toxicity occurred in 11 IMRT patients and in 10 3D-CRT patients.

Case Series

A GI toxicity study by Devisetty et al (2009) reported on 45 patients who received concurrent chemotherapy plus IMRT for anal cancer.^17, IMRT was administered to a dose of 45 Gy in 1.8-Gy fractions, with areas of gross disease subsequently boosted with 9 to 14.4 Gy. Acute GU toxicity was grade 0 in 25 (56%) cases, grade 1 in 10 (22%) patients, grade 2 in 5 (11%) patients, with no grade 3 or 4 toxicities reported; 5 (11%) patients reported no GU tract toxicities. Grades 3 and 4 leukopenia were reported in 26 (56%) cases, neutropenia in 14 (31%), and anemia in 4 (9%). Acute GI toxicity included grade 0 in 2 (4%) patients, grade 1 in 11 (24%), grade 2A in 25 (56%), grade 2B in 4 (9%), grade 3 in 3 (7%), and no grade 4 toxicities. Univariate analysis of data from these patients suggested a statistical correlation between the volume of bowel that received 30 Gy or more of radiation and the risk for clinically significant (grade ≥2) GI toxicities.

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

Section Summary: Anorectal Cancer

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

Summary of Evidence

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

Population Reference No. 13 

For individuals with other primary, metastatic or benign tumors IMRT may be considered medically necessary if submitted documentation demonstrates a benefit over conventional 3-dimensional conformal radiotherapy.

Supplemental Information

N/A

Practice Guidelines and Position Statements

N/A

Medicare National Coverage

There is no national coverage determination. Local coverage determination of IMRT applicable to PR is discussed in the LCD L36773.

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