Medical Policy



Subject: Intensity Modulated Radiation Therapy (IMRT)
Document #: THER-RAD.00007 Current Effective Date:    06/28/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses intensity modulated radiation therapy (IMRT) which refers to a technique of external conformal radiation planning and delivery, in which non-uniform intensity beams produce unique radiation dose distributions that are intended to better target the lesion with better sparing of surrounding normal tissue than with conventional radiation therapy (RT), thereby limiting side effects. IMRT also allows for dose escalation, when clinically appropriate, which can potentially improve local control of a tumor.

Note:   For information related to additional documents regarding radiation therapy, please see:

Position Statement

Medically Necessary:

IMRT of the prostate is considered medically necessary in individuals who meet either of the following:

  1. Localized prostate cancer; or
  2. Post-prostatectomy for dose escalation greater than or equal to 64 Gy, when:
    1. PSA remains detectable at 6 months after surgery; or
    2. PSA is detectable and increases on two or more lab determinations; or
    3. The individual has post-operative stage T3b to T4; or
    4. Post-operative pathology reveals positive surgical margins.

IMRT is considered medically necessary in the treatment of individuals with head and neck cancer (see definitions), with the exception of individuals with early stage larynx cancer (stage I and II).

IMRT is considered medically necessary for esophageal cancer.

IMRT is considered medically necessary in the treatment of mediastinal tumors for which radiation is indicated.

IMRT is considered medically necessary in the treatment of individuals with thyroid cancer.

IMRT is considered medically necessary in individuals with Central Nervous System (CNS) lesions (that are either primary or metastatic lesions) with close proximity to the optic nerve, lens, retina, optic chiasm, cochlea, or brain stem.

IMRT is considered medically necessary in pediatric individuals less than age 21 with a radiosensitive tumor.

IMRT is considered medically necessary in individuals with cancer of the anus or anal canal, primary malignant gynecologic tumors (uterus, cervix, ovary, fallopian tube), primary pelvic sarcomas, bladder carcinoma, and rectal adenocarcinoma.

IMRT is considered medically necessary in individuals who require repeat irradiation of a field that has received prior irradiation.

IMRT is considered medically necessary for the treatment of breast cancer when criteria A, B, or C below are met:

  1. In individuals with left-sided breast lesions when:
    1. The target volume coverage results in cardiac radiation exposure that is expected to be greater than or equal to 25 Gy to 10 cc or more of the heart (V25 greater than or equal to 10 cc) with 3D conformal radiation therapy (3D-CRT) despite the use of a complex positioning device (such as Vac-Lok),  and
    2. With the use of IMRT, there is a reduction in the absolute heart volume receiving 25 Gy or higher by at least 20% (for example, volume predicted to receive 25 Gy by 3D-CRT is 20 cc and the volume predicted by IMRT is 16 cc or less);
      or 
  2. In individuals with large breasts when the treatment planning with 3D-CRT results in hot spots (focal regions with dose variation greater than 10% of target) and the hot spots are able to be avoided with IMRT;
    or
  3. In individuals who are to receive internal mammary node irradiation based on any of the following:
    1. Pathologically enlarged (as reported based on imaging technique utilized) internal mammary lymph node(s) by CT, MRI, PET/CT, or CXR; or
    2. Pathologically involved internal mammary lymph node(s) (based on aspiration cytology or tissue biopsy pathology); or
    3. The individual is at high risk of internal mammary lymph node involvement based on:
      1. Greater than or equal to 4 positive axillary lymph nodes; or
      2. Medial quadrant tumor with 1 or more positive axillary lymph nodes; or
      3. Medial quadrant T3 tumor.

IMRT is considered medically necessary for the treatment of lung cancer when ALL of the following criteria are met:

  1. For individuals with primary lung cancer where concurrent chemotherapy and radiation is to be used;  and
  2. The percent of normal lung receiving more than 20 Gy (V20) accounts for more than 30% of the normal lung, defined as the total lung volume minus the planning target volume (PTV);  and
  3. An IMRT plan will reduce the V20 to at least 10% below the V20 that is achieved with the 3D-CRT plan (for example, from 40% down to 30% or lower);  and
  4. There is documentation that the treatment plan addresses tumor motion that is both accounted for and managed such that:
    1. A 4D planning CT scan was performed and the primary tumor and included lymph nodes were observed to move less than 1 cm and this degree of motion was included in the planning tumor volume; or
    2. A 4D planning CT scan was performed and respiratory gating will be employed to minimize the risk of inadequate coverage; or
    3. A 3D planning CT scan was performed with free-breathing, end-inspiration and end-expiration breath-hold to minimize the risk of inadequate coverage.

IMRT is considered medically necessary for the treatment of the following abdominal cancers:  gastric, gastroesophageal junction, pancreas, and hepatobiliary cancer when ALL of the following criteria are met:

  1. The disease is primary and non-metastatic, that is, confined regionally to the primary organ (including regional lymph nodes) ;  and
  2. Dosimetric treatment planning comparisons between 3D-CRT and IMRT have been made;  and
  3. Dosimetric treatment planning with IMRT predicts the radiation dose to adjacent organs would be within normal tissue tolerance; AND at least ONE of the following criteria are met:
    1. 3D-CRT planning predicts the mean liver dose will be greater than 30 Gy and IMRT planning predicts the mean liver dose would be less than or equal to 25 Gy; or
    2. 3D-CRT planning predicts a mean dose to the bilateral kidneys of greater than 18 Gy and IMRT planning  predicts that no more than 90% of the volume of one kidney receives greater than 18 Gy.  If only one kidney is present, the IMRT planning predicts that no more than 15% of the kidney receives greater than 18 Gy; or
    3. 3D-CRT planning predicts the maximum spinal cord dose would exceed 50 Gy and IMRT planning predicts the maximum spinal cord dose would be less than or equal to 45 Gy; or
    4. 3D-CRT planning predicts the maximum dose to the small bowel will be greater than 54 Gy and IMRT planning predicts the maximum dose to the small bowel would be less than 50 Gy.

Note:   The maximum dose of radiation is defined as the highest dose to a volume of 0.03 cc.

Investigational and Not Medically Necessary:

IMRT is considered investigational and not medically necessary for all other indications including, but not limited to:

  1. Lung cancer, except when the above criteria are met; or
  2. Breast cancer, except when the above criteria are met; or
  3. Abdominal cancers, except when the above criteria are met; or
  4. Cancers of unknown primary; or
  5. Treatment of large arteriovenous malformations (AVM).
Rationale

IMRT radiation planning and delivery offers the potential to deliver radiation more precisely to a target (usually a malignant tumor) than current two- or three-dimensional conformal radiation techniques (2D-CRT, 3D-CRT) with the goal of improving precision to allow increased doses of radiation to the target with decreased exposure to surrounding normal tissues.  This improved precision has the potential to improve local tumor control and reduce acute and late radiation toxicity.  IMRT achieves this enhanced precision by using computer software and CT images to perform "inverse treatment planning," a technique which iteratively adjusts beam parameters to identify a combination that meets pre-specified dose-volume criteria. 

IMRT differs from conformal radiation techniques (2D-CRT, 3D-CRT) in that the software used with IMRT has the ability to modulate the intensity of the overlapping radiation beams projected onto the target.  The IMRT software produces a predicted dose distribution of radiation which allows an estimate of the dose to the target and surrounding tissues, including adjacent normal structures.  When these IMRT software-derived treatment plans are applied to an individual, the actual target and surrounding tissue exposure may vary from the estimated exposure, especially in tissues that move, such as the lung (respiration) or heart (cardiac cycle).  More recent refinements in IMRT address target motion using gating techniques.

IMRT may be delivered using a variety of techniques.  The beam can be shaped as it exits a linear accelerator (linac) using a multi-leaf collimator (MLC) that blocks or "collimates" the beam to create curved edges.  A computer can vary the aperture size continuously and independently for each MLC leaf pair, dividing the beam into "beamlets."  The MLC can move around the individual, referred to as dynamic MLC, or may be turned off during movement and then turned on once the linac reaches prespecified positions (i.e., "step and shoot" technique).  Tomotherapy is a distinct type of IMRT delivery system, consisting of a radiation portal that moves spirally around the subject with varying intensity.  Finally, compensator-based IMRT is a technically simpler but more resource-intense delivery system that can be adapted to existing linear accelerators.  Each of these various techniques alter the planned radiation exposure, but have, in many circumstances, not been adequately studied to verify whether these differences in IMRT software planned exposure are associated with meaningful differences in actual tissue exposure and improved clinical outcomes, when compared to IMRT without these techniques or 2D-CRT or 3D-CRT.

IMRT has been promoted over non-modulated external beam radiation (EBRT), two-dimensional (2D) and three-dimensional (3D) conformal techniques (2D-CRT, 3D-CRT) on the basis of computer planning studies that have shown better planning target volume coverage and better sparing of organs and tissues at risk.  Much of the literature comparing 3D conformal radiation therapy techniques with IMRT is limited to a comparison of predicted dose distribution to the tumor target and adjacent normal tissues.  These comparative studies have demonstrated that for a number of tumors, depending on location, IMRT delivers more conformal and uniform radiation to the tumor target.  It is hypothesized that more conformal and uniform (fewer "hot and cold spots") radiation delivery might improve clinical outcomes (local tumor control) by permitting higher tumor doses with less toxicity.  However, some of the published treatment plan comparisons show that IMRT may increase normal tissue exposure to low doses of radiation compared to 2D-CRT or 3D-CRT (Brenner, 2003; Hall, 2006).  This has raised a theoretical concern that IMRT may actually increase the late effects, such as secondary malignancy, of radiation therapy to adjacent structures.  In addition, a treatment plan with improved precision, when directed towards a moving target (for example, lung lesion with respiration), may result in inadequate radiation delivery as the moving target moves in and out of the treatment zone. 

The predicted dose distribution differences between IMRT and conformal therapy are often minor and are always derived from predicted exposures using software-based treatment planning comparisons.  The predicted differences are a surrogate for the outcomes of interest: radiation side effects, tumor control and cure.  IMRT capable devices have rapidly disseminated into the community.  Given the inherent complexity of treatment planning and delivery with IMRT, it is necessary to evaluate whether results achieved in the research setting and specialized centers can be reliably obtained in the general practice community.

Despite the concerns mentioned above, IMRT has been demonstrated to have clinical advantages in several situations.  IMRT has been shown to reduce radiation side effects when used in the treatment of prostate and other pelvic tumors, by avoiding exposure of the rectum, small bowel and bladder.  IMRT has also been shown to reduce side effects when used for treatment of tumors of the head and neck, to avoid exposure to the spinal cord, brainstem, parotid and lacrimal glands, eyes and optic tracts, as well as additional tumor types and locations, such as all segments of the esophagus and mediastinal tumors usually associated with lymphomas.  

Prostate Cancer

Dose escalation as a means to reduce the incidence of local recurrence of prostate cancer is an active area of study.  With standard 2D radiation planning techniques used until the early 1990s, doses were limited to 67-70 Gy, due to acute and chronic toxicities.  In the 1990s, the development of 3D-CRT permitted further dose escalation, and the results of several randomized controlled trials suggested that this dose escalation was associated with improved biochemical outcomes (Pollack, 2002).  More recently, IMRT has been studied as a further evolution of 3D-CRT with intent to allow even more precise treatment planning and dose escalation.

Multiple dosimetric and treatment planning comparative studies have favored IMRT over 3D-CRT in the treatment of localized prostate cancer.  IMRT has demonstrated improved conformality to, and homogeneity within, the target tissue.  It has been hypothesized that IMRT may improve treatment outcomes by permitting escalated tumor doses without increasing normal tissue toxicity (bowel/bladder).  There is evidence from randomized controlled trials showing a dose-response relation above 68 Gy for local and biochemical control of prostate cancer.  In addition, dose-volume-toxicity relations have been established for rectal bleeding (proctitis) and other gastrointestinal and genitourinary toxicity (Hanlon, 2001).  For these reasons, radiation oncologists have hypothesized that IMRT may provide improved clinical outcomes over 3D-CRT.  However, since IMRT aims radiation at the tumor from more directions and subjects more normal tissue to low-dose radiation than conventional EBRT or 3D-CRT, concern has been raised that IMRT might actually increase the risk of late effects of radiation therapy. 

In a systematic review of the literature (Veldeman, 2008), 16 comparative case series of IMRT in prostate cancer were reviewed.  A difficulty with most comparative studies, published to date, is the use of historic controls, since over the past decade, diagnostic improvements have led to stage migration and Gleason-score drift adding bias to historical comparisons.  This type of bias would be a source of increased biochemical control for more recently treated groups.  The results of the limited number of case series comparing biochemical control outcomes using IMRT with 3D-CRT are mixed.  Vora (2007) showed improvement in 5-year biochemical control with IMRT (75.6 Gy) versus 3D-CRT (68.4 Gy), while Kupelian (2002) demonstrated no difference in biochemical relapse-free survival at 30 months between 3D-CRT (78 Gy in 39 fractions) and a short-course IMRT regimen delivering 70 Gy in 28 fractions.  Despite the limitations of the studies identified, Veldeman concluded that:

The consistency in the findings of clinical comparative studies and predictions from planning studies (external validity) allow the conclusion to be made that IMRT, on its own or as a component of improved radiotherapy techniques, creates a window for dose escalation with unchanged or lower gastrointestinal and genitourinary toxic effects and unchanged or better sexual function.

In a retrospective, comparison study, Sheets (2012) examined the comparative morbidity and disease control outcomes for a cohort of men with prostate cancer treated with proton beam radiation therapy (PBRT), IMRT and conformal radiation techniques. The authors compared outcomes of 684 men with nonmetastatic prostate cancer treated with PBRT (from 2002 to 2007) to 9437 men treated with IMRT using the Surveillance, Epidemiology, and End Results (SEER) - Medicare-linked database (2000 through 2009). To balance analysis of the two treatment groups, propensity score matched rates were calculated for each outcome due to a lack of overlap in baseline characteristics between men treated with either PBRT or IMRT. Because of the unequal distribution of men treated with PBRT across institutional-level variables, the authors performed sensitivity analysis with the Radiation Therapy Oncology Group affiliation, "As an instrumental variable to assess potential unmeasured confounding." Median follow-up for the comparison was 50 months for PBRT (range, 0.3-90.2 months) and 46 months for IMRT (range, 0.4-88.3 months). Morbidity outcomes included conditions associated with RT for prostate cancer, including gastrointestinal morbidity, urinary incontinence, non-incontinence urinary morbidity, sexual dysfunction, and hip fractures. When comparing men treated with PBRT to those treated with IMRT, the IMRT group had a lower rate of gastrointestinal morbidity (absolute risk, 12.2 versus 17.8 per 100 person-years; relative risk [RR], 0.66; 95% confidence interval [CI], 0.55-0.79). There were no significant differences in rates of the other morbidities or additional cancer-related therapies between PBRT and IMRT. Despite some limitations cited with the use of SEER-Medicare data for the assessment of clinical outcomes, the authors suggested "...that IMRT may be associated with improved disease control without compromising morbidity compared with conformal RT, although proton therapy does not appear to provide additional benefit."

The conclusions drawn by Sheets (2012) in the retrospective, propensity score matched cohort study comparing PBRT to IMRT identified that there were no significant differences found among men treated with PBRT, compared to IMRT in morbidity or receipt of additional cancer therapy, except an association with increased gastrointestinal morbidity in men who were treated with PBRT for localized prostate cancer.  Due to the retrospective nature of the study, conclusions cannot be drawn at this time that IMRT is superior to PBRT in improving therapeutic outcomes for the treatment of localized prostate cancer; however, these results may suggest that PBRT and IMRT are at least as likely to produce equivalent therapeutic results when used as initial monotherapy radiation treatment for localized prostate cancer.

In the updated National Comprehensive Cancer Network® (NCCN® ) Clinical Practice Guidelines in Oncology for prostate cancer (2017), PBRT is not recommended for routine use at this time, although it can be used as an alternative radiation source for localized prostate cancer. The NCCN practice guideline cites a lack of clinical trial data demonstrating "superiority or equivalence" of PBRT compared to conventional external beam for the treatment of prostate cancer. Active surveillance, radical prostatectomy (RP), or radiotherapy are included as primary management options as initial therapy for localized prostate cancer. "IMRT causes less acute and late genitourinary toxicity and similar freedom from biochemical failure, compared with iodine-125 or palladium-103 permanent seed implants" (NCCN, 2017).  

To summarize, while much of the evidence suggests that PBRT is safe and may provide effective tumor control in men with prostate cancer; this evidence is derived from retrospective analyses conducted at a limited number of research centers or from studies with other methodological limitations. There is insufficient evidence from the available clinical trials to determine whether PBRT is equal or superior to conventional RT, 3D-CRT or IMRT, and who would benefit most from each type or combination of radiotherapy for the treatment of prostate cancer.

Zelefsky (2008b) compared the long-term toxicity of 3D-CRT and IMRT for 1571 individuals with T1-T3 localized prostate cancer treated between 1988 and 2000.  Doses ranged from 66 Gy to 81 Gy with median follow-up of 10 years.  The overall likelihood at 10 years for the development of Grade 2 or greater gastrointestinal (GI) toxicities was 9%, and the use of IMRT reduced the risk for Grade 2 or greater GI toxicities compared with those treated with 3D-CRT from 13% to 5% (p<0.001).  While higher doses, regardless of type of delivery, were associated with increased GI and genitourinary (GU) Grade 2 toxicities, the risk of proctitis was significantly reduced with IMRT.  In this study, the development of acute symptoms was a strong predictor of late toxicities.

In a review by the Institute for Clinical and Economic Review, the authors concluded that the literature on comparative rates of toxicity between IMRT and 3D-CRT in the treatment of localized prostate cancer has serious methodological weaknesses.  There are no prospective randomized trials, and the case series that do exist lack concurrent cohorts and/or fail to describe the selection process by which individuals were assigned to IMRT vs. 3D-CRT.  In spite of these limitations, the authors concluded that the series published to date, demonstrate a reduced rate of rectal toxicity for IMRT at radiation doses above 75 Gy (Grade 2 toxicity 4% for IMRT vs. 14% for 3D-CRT).  However, data on GU toxicity have not shown superiority of IMRT over 3D-CRT, nor is there data to suggest that IMRT provides a lower risk of erectile dysfunction (Pearson, 2007).

Studies of post-prostatectomy IMRT have demonstrated superior dose distribution to the target volume with the use of IMRT, as compared with 3D conformal radiation delivery, with better sparing of nearby critical healthy tissue structures and less severe toxicity-related morbidity (Alongi, 2009).  Additional studies have suggested disease-specific survival benefit from salvage radiotherapy following prostatectomy using the PSA level as a prognostic indicator of recurrence (Stephenson, 2007; Trock, 2008). 

A multi-institutional, retrospective, comparative data analysis was conducted to determine if salvage RT upon early PSA relapse is equivalent to immediate adjuvant RT following radical prostatectomy.  This study included 130 subjects who received immediate adjuvant radiotherapy (ART) and 89 subjects who received salvage radiotherapy (SRT).  All study subjects had an undetectable PSA following radical prostatectomy (RP).  Homogenous subgroups were built, based on the status of lymphatic invasion (LVI) and surgical margins (SM) to allow a comparison of ART and SRT.  Biochemical disease-free survival (bDFS) was calculated from the date of surgery and from the end of RT.  In the SRT group, results were analyzed at a median follow-up of 121 months from the date of RP (60-94 range) and at median follow-up of 78 months from the end of RT (48-161 range).  In the ART group, results were analyzed at median follow-up of 103.5 months (55-190 range) from the date of RP and at median follow-up of 99 months (48-196 range) from the end of RT.  In both the SM negative (-)\LVI group and the SM positive (+)\LVI group, data analysis showed that SRT was a significant predictor of decreased bDFS from the date of surgery; in the SM +\LVI + group, there was a trend toward significance.  From the end of RT, SRT was also a significant predictor of bDFS in three groups: (1) SM-\LVI-; (2) SM+\LVI-; and (3) SM+\LVI+.  The authors concluded that preoperative PSA was a significant predictor of bDFS in the SM-\LVI- group from the date of RP only and that immediate ART post RP for individuals with high risk features in the prostatectomy specimen significantly reduces the bDFS after RP compared with early SRT upon PSA relapse (Budiharto, 2010).  These findings align with the updated NCCN Guidelines which gave a Category 2A recommendation for ART when surgical margins are positive (NCCN, 2015).  A 2013 guideline from the American Urological Association (AUA) and the American Society for Therapeutic Radiation and Oncology (ASTRO) and also endorsed by the American Society of Clinical Oncology (ASCO; Freedland, 2014), which is titled:  Adjuvant and Salvage Radiotherapy after Prostatectomy, supports the use of ART as follows:

Physicians should offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy (i.e., seminal vesicle invasion, positive surgical margins, extraprostatic extension) and should offer salvage radiotherapy to patients with prostatic specific antigen or local recurrence after prostatectomy in whom there is no evidence of distant metastatic disease (Thompson, 2013).  

Bladder Cancer

The ability of IMRT to deliver the RT dose preferentially to target structures in close proximity to organs at risk and other non-target tissues makes it a valuable tool enabling the radiation oncologist to deliver dose to target volumes while minimizing dose to adjacent normal tissues (ACR, 2011).  At present, there is support in the available published evidence for the use of IMRT when nearby normal tissues would receive unacceptable doses of radiation from conventional 3D-CRT, particularly the small intestine.  According to the updated NCCN Clinical Practice Guidelines in Oncology for Bladder Cancer (2016), an estimated 69,250 new cases of urinary bladder cancer were diagnosed in the U.S. in 2011, and approximately 14,990 deaths resulted from bladder cancer during 2011.  The NCCN also informed that the approximate probability of recurrence within 5 years for the various stages of bladder disease range between 50% and 90%.  Although the NCCN guideline does not specifically address IMRT, its Principles of Radiation Management of Invasive Disease recommends:

Treating the whole bladder with or without pelvic lymph nodes with 40-45 Gy followed by a boost to the bladder tumor to a total dose up to 66 Gy excluding, if possible, normal areas of the bladder from the high dose volume.

Such high dose RT treatment plans would potentially benefit from the use of IMRT, as compared to conventional 3D-CRT.

Cancer of the Oropharynx, Hypopharynx, Larynx, Oral Cavity and Thyroid

Intensification of radiotherapy by dose escalation in combination with chemotherapy is associated with an increase in severe acute and late radiation toxicity (Veldeman, 2008).  For cancers of the head and neck, dose escalation is limited by acute mucositis, xerostomia, dysphagia, and fibrosis of neck tissues.  A number of case series have looked at the potential of IMRT to achieve higher efficacy and/or lower toxicity with better quality of life.  For example, Grade 2 and 3 xerostomia was less frequent in some, but not all, case series comparing IMRT with other forms of radiotherapy.  Other studies have reported significantly better recovery of salivary gland function after IMRT compared with historical controls (Munter, 2007).  In a matched pair comparison with conventional radiotherapy, Graf (2007) reported that xerostomia related quality of life (QoL) variables were significantly better in the IMRT group than conventional radiotherapy group. 

In a review of the literature, Van den Steen (2007) identified a total of nine comparative trials including one randomized controlled clinical trial comparing IMRT with other radiotherapies.  The authors noted that organ motion is practically absent in head and neck cancer, and they concluded that IMRT provides better sparing of both the salivary glands and the optic nerve when compared to 3D-CRT.  However, they were unable to identify high quality evidence comparing IMRT with 3D-CRT with regard to relapse or survival. 

Fang (2008) published a single institution, nonrandomized, longitudinal study of 203 individuals with newly diagnosed nasopharyngeal carcinoma (NPC).  They reported quality of life measures and survival outcomes in those treated with either 3D-CRT (n=93) vs. IMRT (n=110).  The distributions of clinical stage according to the American Joint Committee on Cancer (1997) were I: 15 (7.4%); II: 78 (38.4%); III: 74 (36.5%); and IV: 36 (17.7%).  Quality of life (QoL) was longitudinally assessed by the European Organization for Research and Treatment of Cancer (EORTC) with use of EORTC questionnaires at five time points as follows: before initiation of radiation therapy (RT), during RT (36 Gy), and at 3, 12, and 24 months after RT.  The study results showed 3-year locoregional control, metastasis-free survival, and overall survival rates of 84.8%; 76.7%; and 81.7% for the 3D-CRT group which did not significantly differ from the IMRT group (p>0.05).  A general trend of maximal deterioration in most QoL scales was observed during RT in both groups, followed by a gradual recovery thereafter.  There was no significant difference in most scales between the two groups at each time point.  The exception was that individuals treated by IMRT had a both statistically and clinically significant improvement in global QoL, fatigue, taste/smell, dry mouth, and feeling ill at the time point of 3 months after RT.  The authors concluded that:

The potential advantage of IMRT over 3D-CRT in treating NPC might occur in QoL outcome during the recovery phase of acute toxicity. The benefit of IMRT over 3D-CRT was not found to last up to one to two years after RT. 

A limitation of this study is its lack of a randomized controlled design.

According to the NCCN Guidelines on Head and Neck Cancers, surgery is the preferred initial treatment for Stage T1-2, N0 disease with curative intent, if feasible (T1-2 refers to early stage disease; N0 refers to no regional lymph node metastasis). The following is excerpted from the NCCN:

For tumors of the larynx, the decision to perform either total laryngectomy or conservation laryngeal surgery (i.e., laser resection, hemilaryngectomy, supraglottic laryngectomy, etc.) will be decided by the surgeon but should adhere to the principle of complete tumor extirpation with curative intent…IMRT is a preferred technique for cancers of the oropharynx, nasopharynx, maxillary sinus or paranasal/ethmoid sinus, in order to minimize dose to critical structures.  When targeting the oropharynx, IMRT is a preferred technique to minimize dose especially to the parotid glands.  IMRT has been shown to be particularly useful in reducing long-term toxicity in oropharyngeal, paranasal  sinus, and nasopharyngeal cancers by reducing the dose to salivary glands, temporal lobes, mandible, auditory structures (including cochlea), and optic structures. The application of IMRT to other sites (for example, the oral cavity, salivary glands, hypopharynx and larynx), where either 3D-CRT or IMRT is recommended, is evolving and may be used at the discretion of treating physicians (NCCN, 2017). 

To date, there is a lack of published evidence that focuses on early Stage 1-2 laryngeal disease to compare surgical treatment with IMRT outcomes (Nutting, 2011). Accordingly, IMRT is not appropriate for these early stage tumors.

Central Nervous System Tumors

Radiation to the central nervous system and spine must be carefully delivered to avoid exposure of the highly radio-sensitive tissues, such as the optic nerve and brain stem.  IMRT has been investigated as a way of increasing the dose of radiation therapy to the target while avoiding these radiation sensitive sites.  Three comparative case series on glioblastoma multiforme, malignant astrocytoma, and pediatric medulloblastoma have compared IMRT with EBRT using historic controls.  Fuller (2007) compared IMRT alone (n=30) or as boost therapy (n=12) with 3D-CRT in 42 individuals with glioblastoma multiforme and found no survival outcome advantage for those treated with IMRT alone, over those treated with 3D-CRT and IMRT as boost therapy.  Median survival was 8.7 months.  Non-survival endpoints, such as quality of life and functional status, were not compared.  Toxic effects were similar in both groups, although type of disease (primary vs. recurrent), type of surgical resection, and combination with chemotherapy may have affected treatment outcome.

Luchi (2006) compared the clinical outcomes of 25 individuals with malignant astrocytoma treated with IMRT to 60 historic controls treated with conventional EBRT.  Overall survival (p=0.043) and progression-free survival (p<0.0001) at 1 year and 2 years were significantly better with IMRT.

Ototoxicity is common after combined cisplatin-based chemotherapy and radiotherapy for medulloblastoma in children.  Huang (2002) retrospectively studied 26 children treated for medulloblastoma using either conventional radiotherapy or IMRT.  When compared with conventional radiotherapy, IMRT delivered 68% of the radiation dose to the auditory structures (mean dose: 36.7 Gy vs. 54.2 Gy), and the overall incidence of ototoxicity was lower in the IMRT treated group (13% vs. 64%; p<0.014). 

For CNS tumors, the dosimetric advantages which have been demonstrated have been associated with some relevant clinical outcome improvements, but not a clear overall survival advantage.  The enhanced precision is relevant when tumors encroach upon vital radiosensitive structures, such as the brain stem and optic nerve; however, additional prospective, randomized controlled studies comparing IMRT to 3D-CRT are needed before more widespread use of IMRT can be supported in CNS tumors away from these structures.

Cancer of the Anus and Anal Canal

A case series of 17 individuals with squamous cell carcinoma of the anal canal was reported by Milano (2005).  Seven individuals were also planned with 3D-CRT for dosimetric comparison to IMRT.  Dosimetric comparisons indicated that IMRT could reduce the mean and threshold doses to the small bowel, bladder, and genitals.  Thirteen of the 17 individuals received concurrent 5-FU and mitomycin C, and 1 received 5-FU alone.  Of those who received mitomycin C, 38% had Grade 4 hematologic toxicity.  Three of 17 did not achieve a complete response and required an abdominoperineal resection and colostomy.  At median follow-up of 20.3 months, there were no other local failures.  Two-year overall survival, disease-free survival, and colostomy-free survival were 91%, 65% and 82% respectively.  The authors concluded that compared with historical controls, local control was not compromised, in spite of planning to reduce exposure of normal tissue and increase conformality.  Similar results which compared favorably to historic controls were reported by Salama (2008) in a case series of 53 individuals treated with concurrent chemotherapy and IMRT.  Median follow-up in this study was 14.5 months with acute Grade 4 neutropenia occurring in 34% of treated individuals.  Forty-nine individuals (92.5%) had a complete response, 1 had a partial response, and 3 had stable disease.  Eighteen-month overall survival, colostomy-free survival, freedom from local failure, and freedom from distant failure were 93.4%, 83.7%, 83.9% and 92.9%.  The authors reported the results of this series compared favorably with historic controls treated with non-IMRT radiotherapy.

A retrospective chart review was conducted at Duke University to determine if individuals with anal cancers treated with IMRT had reduced incidence of toxicities associated with chemoradiotherapies.  Forty-seven subjects with anal malignancies (89% canal; 11% with perianal skin) were treated with IMRT between August 2006 and September 2008.  The types of anal cancer included in this study were as follows: anal canal, perianal skin, squamous cell carcinoma (SCC), and non-squamous histologies (adenocarcinoma, melanoma, neuroendocrine tumors, rhabdomyosarcoma, and epitheliod sarcoma).  The median follow-up was 14 months (19 months for SCC).  Toxicity rates were as follows: Grade 4 leukopenia - 7%; thrombocytopenia - 2%; Grade 3 leukopenia - 18%; diarrhea - 9 %; anemia - 4%; Grade 2 skin - 93%; diarrhea - 24%; and leukopenia - 24%.  The 2-year actuarial overall survival (OS), metastasis-free survival (MFS), loco-regional control (LRC), and colostomy-free survival (CFS) rates were 85%, 78%, 90%, and 82% respectively.  For SCC, the 2-year rates for OS, MFS, LRC, and CFS were 100%, 100%, 95%, and 91% respectively.  The authors concluded that IMRT-based chemoradiotherapy for anal cancer results in significant reductions in normal tissue dose and acute toxicities versus historical controls treated without IMRT, leading to reduced rates of toxicity-related treatment interruption (Pepek, 2010).

Pelvic Tumors

Since children are usually smaller in size than adults, there is increased concern for the proximity of critical structures, as well as growth and developmental issues, and the need to minimize radiation exposure is assisted through the use of IMRT.  Lee (2005) compared treatment planning dose-volume histograms with IMRT, 3D-CRT, and proton beam therapy in 3 pediatric subjects with pelvic sarcoma.  IMRT showed more bladder dose reduction than the other techniques in pelvic sarcoma irradiation.  Koshy (2003) compared IMRT with 3D-CRT in 10 adults with retroperitoneal carcinoma and 1 with inguinal sarcoma.  Three were treated with 3D-CRT and the remaining 8 received IMRT.  3D-CRT plans were generated and compared with IMRT with respect to tumor coverage and organs at risk.  Mean dose to the small bowel decreased from 36 Gy with 3D-CRT to 27 Gy using IMRT and tumor coverage (V95) increased from 95.3% with 3D-CRT to 98.6% with IMRT.  Volume of small bowel receiving greater than 30 Gy was decreased from 63.5% to 43.1% with IMRT.  

Gallagher (1986) performed a prospective trial to evaluate the impact of several techniques to reduce the volume of small bowel receiving radiation in a group undergoing adjuvant radiotherapy.  They found that the severity of acute effects could be closely correlated with the volume of small bowel irradiated.  Both acute and late effects have been correlated with the dose of small bowel receiving more than 45 Gy (Bourne, 1983; Roeske, 2001).

Primary or postoperative radiotherapies for pelvic tumors, including endometrial and cervical cancer, place the small bowel, rectum and bladder at risk.  Lower rates of acute and chronic gastrointestinal toxicity have been suggested by a case series (n=40) using historic controls (Mundt, 2002) and dosimetric planning studies (Heron, 2003; Portelance, 2001; Roeske, 2003), comparing IMRT and conventional pelvic radiation in the treatment of cervical and uterine cancer.  In a nonrandomized comparison of 36 individuals with gynecologic malignancy (24 cervix, 12 uterus) treated with IMRT with or without chemotherapy and 88 individuals (44 cervix, 44 uterus) treated with conventional whole pelvic radiation therapy (WPRT) with or without chemotherapy, IMRT was felt to have a lower risk of acute hematologic toxicity than WPRT only in those receiving both radiotherapy and chemotherapy (Brixey, 2002). 

Chen (2007a) compared the outcomes of 33 individuals with high-risk cervical cancer after hysterectomy treated with concurrent chemotherapy and adjuvant IMRT pelvic radiotherapy; 35 historic controls were treated with chemotherapy and four-field (Box-RT) radiotherapy.  The results of this case series with non-contemporaneous controls suggested that locoregional control at 1 year was comparable, while IMRT had lower rates of both acute and chronic gastrointestinal toxicity (36 vs. 80%, p=0.00012; 6% vs. 34% p=0.02).  Acute, but not chronic, genitourinary toxicity (30% vs. 60%, p=0.022; 9% vs. 23%, p=0.231) was significantly less in the IMRT treated group. 

Adenocarcinoma of the Rectum

In a dosimetric planning comparison of IMRT and 3D-CRT in the treatment of locally advanced rectal adenocarcinoma, Guerrero Urbano (2006) concluded that the bowel volume irradiated to 45 Gy and 50 Gy was significantly reduced with IMRT by 26% and 42% respectively, which could potentially lead to less bowel toxicity.

Re-irradiation of Previously Irradiated Fields

Individuals may require a repeat course of irradiation to previously irradiated fields in several situations.  For example, survivors of childhood Hodgkin disease may have received mantle irradiation with exposure of the heart as part of their treatment.  Later in life, these same individuals may develop lung or breast cancer which requires radiation treatment of this new tumor in the same anatomy that was previously exposed to irradiation.  Others with bone metastases adjacent to the spinal canal may require a repeat course of palliative radiation to control pain and are at risk of exceeding the tolerance of the spinal cord to cumulative doses of RT, which raises the risk of paralysis.  In these rare situations, there is currently a lack of good quality, published, peer reviewed literature to guide clinical care.  However, based in part on clinical input received, the enhanced precision of IMRT may be beneficial in this circumstance, since the extent to which prior tissue is exposed to RT can be considered as one of the parameters in treatment planning for that individual.  Accordingly, in those circumstances where repeat irradiation is required and IMRT can deliver that radiation more safely by avoiding or minimizing radiation to critical structures which have been previously irradiated, the use of IMRT may be appropriate for that individual (NCCN Rectal cancer, 2016).

Breast Cancer

Radiotherapy given after breast-conserving surgery or mastectomy reduces the risk of local and regional recurrences and improves overall survival when appropriate radiotherapy techniques are used (Poortmans, 2007).  In the past, most centers used wedged tangential fields to minimize the volume of lung and heart exposed to radiation.  In the treatment of breast cancer, the radiation must traverse more tissue along the chest wall than it traverses in the subareolar region.  Because of this difference in tissue volume (more at chest wall, less at areola), conventional external beam radiation therapy may result in higher doses or "hot spots" in the breast tissue beneath the nipple.  To compensate for the changing shape of the breast, wedge-shaped beam attenuators are placed in the radiation beam that gradually attenuate the beam from minimum attenuation, along the chest wall, to maximum attenuation in the subareolar region.  Since the breast contour also changes significantly along its superior to inferior axis, "hot spots" can develop in areas of the breast away from its central axis.  To address this, 3D wedge-shaped beam attenuators (3D-CRT) and IMRT techniques are being used to more evenly deliver radiation to the targeted breast tissue.  However, there are no evidence-based guidelines from national medical organizations or public health agencies which currently recommend IMRT as routine therapy for breast cancer.  The current NCCN guidelines for breast cancer indicate that uniform dose distribution is the objective and list various approaches to achieve this including IMRT.  The following is excerpted from the 2017 NCCN document:

The Panel recommends whole breast irradiation to include the majority of the breast tissue; breast irradiation should be performed following CT-based treatment planning so as to limit irradiation exposure of the heart and lungs, and to assure adequate coverage of the primary tumor and surgical site. Tissue wedging, forward planning with segments (step and shoot), or intensity-modulated radiation therapy (IMRT) is recommended…Preliminary studies of accelerated partial breast irradiation suggest rates of local control in select patients with early stage breast cancer may be comparable to those treated with whole breast RT.  Follow-up is limited and studies are ongoing.  Patients are encouraged to participate in clinical trials (NCCN, 2017).

Although studies are ongoing, to date, there are few published randomized trials comparing clinical outcomes of IMRT to 3D-CRT in the treatment of breast cancer.  However, in its 2007 Model Policy on IMRT, the American Society for Therapeutic Radiation and Oncology (ASTRO) considers IMRT a treatment option for "Selected cases, (i.e., not routine) of breast cancers with close proximity to critical structures" (ASTRO, 2007).

Selvaraj (2007) compared dosimetric planning data in 20 breast cancer cases randomly selected for comparison of IMRT with 3D-CRT.  Dosimetric data suggested that IMRT could provide improved homogeneity in the breast dosage and reduction in the dose to lung and heart.  The authors concluded that IMRT may potentially provide improved cosmetic results and reduced late treatment toxicity to heart and lung.

A randomized comparative trial of IMRT and 2D (not 3D-CRT) studied 306 women with early stage breast cancer requiring whole breast radiotherapy after breast conservation surgery (Donovan, 2007).  The primary endpoint in this study was the change in breast appearance scored from serial photographs taken prior to radiotherapy and at 1, 2, and 5 years following treatment.  Only 240 (79%) individuals with 5-year photographs were available for analysis.  Change in breast appearance was identified in 58% of breasts allocated to standard 2D radiotherapy versus 40% of breasts treated with IMRT.  Individuals treated with 2D radiotherapy were more likely to have a change in breast appearance at 1 year (p=0.008).  Significantly fewer subjects in the IMRT group developed palpable induration in the treated breast when assessed qualitatively at 2 and 5 years post-therapy.  However, no significant differences between treatment groups were found in self-reported breast discomfort, breast hardness or quality of life.  This study did not compare the results of IMRT with present day 3D-CRT breast radiation techniques.

Another study described the results of a double-blind, multicenter, randomized controlled trial of 331 individuals with breast cancer who were randomly assigned to either 3D-CRT techniques with wedge compensation or IMRT.  Although the test results suggest clinically significant improvement in dose distribution and short-term complication rates (results extended up to 6 weeks post-radiotherapy with development of moist skin desquamation at 31.2% in the IMRT treated group and 47.8% in the standard treatment group [p=0.002]), there was no statistically significant difference in pain or quality of life measures between the two treatment arms.  However, the presence of moist skin desquamation did significantly correlate with pain and reduced quality of life.  Multivariate analysis found the use of IMRT (p=0.003) and smaller breast size (p≤0.001) were associated with a decreased risk of moist desquamation at 6 weeks (Pignol, 2008).  

McDonald (2008) reported outcomes of a retrospective chart review comparison with a contemporaneous cohort for a total of 240 women with Stages 0-III breast cancer at a single institution who underwent either 3D-CRT radiation therapy or IMRT after conservative surgery from 1999-2003.  Computed tomography simulation was used to design standard tangential breast fields with enhanced dynamic wedges for the 3D-CRT group and both enhanced dynamic wedges and dynamic multi-leaf collimators for the IMRT treated group.  Trial participants received a dose of 44-50.4 Gy to the whole breast in 1.8-2 Gy fractions, followed by a boost of 10-20 Gy.  Median breast dose was 50 Gy, and median total dose was 60 Gy in both groups.  The median follow-up was 6.3 years for the subjects who received IMRT and 7.5 years for those treated with 3D-CRT.  A modest difference in Grade 2 (erythema, patchy moist desquamation, moderate edema) and Grade 3 (confluent, moist desquamation, pitting edema) skin toxicity was found (39% vs. 52%; p=0.047) between the IMRT and 3D-CRT treatment groups.  There were no significant differences in the incidence of radiation pneumonitis, ipsilateral extremity lymphedema or secondary malignancies between the two treatment groups.  In addition, there were no statistically significant differences in overall survival, disease-specific survival, freedom from ipsilateral and contralateral breast tumor recurrence, or distant metastasis. 

Only recently has postoperative radiotherapy after lumpectomy been shown to provide a clear survival benefit (Vallis, 2004).  It is argued that improved tumor control and reduced risk of metastasis were offset by increased radiation induced cardiac mortality in earlier studies (prior to 3D-CRT treatment planning) using older technology and larger target volumes.  These target volumes frequently included the parasternal lymph nodes which resulted in larger heart volume radiation in those with left-sided breast cancer (Lohr, 2009).  The cardiac dose of breast radiation therapy has decreased over recent years as a result of improvements in technique (3D-CRT planning) and a shift toward breast conserving therapy.  However, there has been more widespread use of potentially cardiotoxic adjuvant therapies: anthracyclines, taxanes and trastuzumab in the treatment of early stage breast cancer.  Late effects of cardiac radiation injury occur years after completion of therapy and include chronic pericarditis, coronary artery disease, cardiomyopathy, valvular disease and conduction abnormalities. 

Additional evidence includes an article by Gagliardi (2010) which summarized the results of several decades, including prior radiation planning and delivery techniques that predate 3D-CRT, of data suggesting a correlation between dose volume measures and risk of pericarditis.  Studies of long-term cardiac mortality include data from retrospective studies of subjects treated with older techniques no longer in use and outdated target definitions.  A few studies based on 3D dose/volumes suggest that dose and, to a lesser degree, the irradiated volume are predictors of long term cardiac mortality.  Gagliardi (1996) derived a dose-response curve for cardiac mortality based on data from two breast cancer randomized trials of surgery with or without radiation therapy which showed an increased cardiac mortality in the radiation therapy group.  The data were used to develop an NTCP (normal tissue complication probability) biologic-mathematical model. 

Lohr (2009) compared treatment plans using 3D-CRT with aperture-based IMRT in 14 individuals with left-sided breast cancer with an "unfavorable thoracic geometry" defined as the "heart anatomically close to the thoracic wall, concave thoracic wall/pectus excavatum, such that the glandular breast tissue was located circumferentially around the anterior heart."  IMRT reduced the maximal dose to the left ventricle by a mean of 30.9% (49.14 vs. 33.97 Gy) and the average heart volume exposed to greater than 30 Gy was reduced from 45 cc to 5.84 cc.  Excess risk of cardiac mortality was calculated for both treatment plans using a "relative seriality model" developed by Kaellman (1992) and later modified by Gagliardi (1996).  The model-based probability for radiotherapy-associated cardiac death was 6.03% for the 3D plans and 0.25% for the IMRT plans. 

Wang (2010) evaluated a rapid automated treatment planning process to select subjects with left-sided breast cancer for what is described as a "Moderate deep inspiration breath-hold (mDIBH) using active breathing control (ABC)" technique to displace the heart out of the breast radiation field and reduce the radiation dose to the left anterior descending (LAD) coronary artery and heart.  The modeling study compared doses to the LAD for individuals with unfavorable cardiac anatomy, defined as having greater than 10 cc of the heart receiving 50% of the prescribed dose (V50) using standard techniques (free-breathing) versus the mDIBH technique.  The automated planning software rapidly generated (9 minutes/plan) the heart contour from the level of the aortic root to the apex of the heart.  Significant differences were found between the standard free-breathing and mDIBH plans for the heart V50 (29.9 vs. 3.7 cc).  In 20 individuals with unfavorable cardiac anatomy selected for mDIBH with ABC, treatment planning comparisons showed that the mean LAD dose could be reduced from 20.47 Gy to 5.94 Gy and the maximal dose to 0.2 cc of the LAD could be reduced from 41.55 Gy to 15.07 Gy (p values for both comparisons <0.001).

The full clinical significance (cardiovascular morbidity and mortality) of radiation-associated cardiac toxicity models, such as those described above, is difficult to confirm with measured clinical outcomes, due to the latency of symptoms (10 years or more) and lack of accurate dosimetric data from historical studies using what are now outdated techniques.  However, a growing body of evidence from treatment planning comparisons suggests an association between left-sided breast RT and late effect cardiac disease (Darby, 2013; McGale, 2011; Nilsson, 2011).

The incidence of internal mammary node (IMN) metastasis in subsets of individuals with breast cancer was investigated in a large Chinese study of subjects with breast cancer treated with either radical or modified radical mastectomy and IMN dissection.  In this study, 1679 subjects underwent extended radical or modified mastectomy with IMN dissection, but no preoperative treatment, between 1956 and 2003.  Four individual variables were selected for investigation: (1) tumor location; (2) tumor size; (3) age; and (4) number of axillary lymph nodes (ALNs) involved.  These variables were further categorized into the following subcategories: for tumor location (lateral, central, medial); tumor size (T1 ≤ 2 cm; T2 2 to ≤ 5 cm; T3 > 5 cm); age (≤ 35; 36-50; > 50); ALN involvement (0; 1-3; 4-6; ≥ 7).  Significant association was found for these four variables in terms of risk for IMN metastasis (e.g., incidence of IMN metastasis for subjects with 4-6 and ≥ 7 positive ALNs was 28.1% and 41.5%).  In subjects with a medial tumor and positive ALNs, the incidence of IMN metastasis was 23.6% for subjects with 1-3 positive ALNs, 47.5% for subjects with 4-6 positive ALNs, and 38.7% for those with ≥ 7 positive ALNs.  The incidence of IMN metastasis was 25.4% for subjects with T3 (> 5cm) tumor and younger than 35 years of age.  The authors concluded that individuals with the following conditions were at high-risk for IMN metastasis (> 20%): (1) 4 or more positive ALNs; (2) medial tumor and positive ALNs; (3) T3 tumor and younger than 35 years; (4) T2 tumor and positive ALNs, 5) T2 medial tumor (Huang, 2008).    

A large, randomized, controlled, Phase III multi-center trial (RCT) is currently being conducted by the Radiation Oncology Group and Breast Cancer Group of the European Organization for Research and Treatment of Cancer (EORTC) which is designed to determine the impact of adding elective internal mammary and medial supraclavicular (IM-MS) regional lymph node irradiation to standard radiotherapy on overall survival, toxicity and World Health Organization (WHO) performance status in 4004 subjects with localized Stage I-III breast cancer with medially or centrally located tumors and/or ALN invasion (EORTC, 2010; Matzinger, 2010).  Although results of this ongoing RCT were originally expected in 2012, information has not been updated since 2010 on the National Cancer Institute website or in publications. 

The findings above regarding IMN irradiation are augmented by updated NCCN 2017 Clinical Practice Guidelines on Invasive Breast Cancer which assign an upgraded Category 1 recommendation for IMN irradiation when the IMNs clinically appear to be pathologically involved, based on CT treatment planning which, "Should be used in all cases where radiation therapy is delivered to the IMN field…If IMN are clinically or pathologically positive, radiation therapy should be given to the IMN."  A uniform consensus (Category 3) was not reached with regard to elective IMN irradiation for other high risk groups and are "Left to the discretion of the treating radiation oncologist" (Category 3).  (See Definitions section of this document for a description of the NCCN Categories of Evidence and Consensus).  

Tumors within the Chest and Chest Wall

Approximately half of the individuals with locally advanced lung cancer receive radiotherapy (Jemal, 2007).  Treatment with concomitant chemotherapy is limited by the sensitivity of normal lung to the effects of radiation.  Additional challenges in the treatment of lung cancers with radiotherapies include respiratory motion and closely adjacent organs with low radiation tolerance.  In recent years, a number of advancements in imaging and radiation delivery have taken place. 

Appropriately designed and randomized trials comparing clinical outcomes of IMRT to 3D-CRT have not been reported in subjects with primary or metastatic lung cancer.  In theory, IMRT may have a comparative advantage due to its ability to better conform the radiation to the tumor, however, concern has been raised about using IMRT in lung and upper abdominal cancer treatment due to respiratory motion.  Unlike 3D-CRT, IMRT irradiates only a portion of the target volume at a time creating the potential to miss or under-treat the target volume, resulting in a negative impact on tumor control (Gierga, 2004; Liao, 2010).  Despite the limitations of the published evidence currently available, IMRT therapies for lung cancer have rapidly increased in the United States.  A number of dosimetric treatment planning comparisons suggest that IMRT has the potential to allow for dose escalation without added risk to normal surrounding tissues and organs.  Lavrenkov (2007) investigated the effects of IMRT versus 3D-CRT on functional lung tissue in the treatment of non-small cell lung cancer (NSCLC) in a group of 17 subjects with Stage I-IIIb disease.  Functional lung tissue was defined by integrating single photon emission computed tomography (SPECT) images into the treatment planning.  IMRT and 3D-CRT treatment plans were compared for each subject.  In 11 of the 16 subjects with Stage IIIa-b disease, the planning target volume was equally well targeted with IMRT and 3D-CRT plans, but IMRT produced a better ratio (PTV 90/fV20; 7.2 vs. 5.3, p=0.001) of planning target volume receiving 90% of the prescribed dose (PTV90) to volume of functional lung irradiated to 20 Gy (f V20).  For the remaining 6 subjects who had stage I-II disease, there was no difference in dosimetric planning outcomes using IMRT versus 3D-CRT. 

Schwarz (2005) conducted a dosimetric study which examined the effects of dose escalation on nearby structures in a group (10 subjects) with NSCLC.  Results indicated that the size and shape of the target volume significantly impacted the ability to escalate the dose for both CRT and IMRT groups.  Tumor location within the lung was also discussed, and it was noted that all targets in this study were located in the superior half of the lung where organ motion, due to respiration, is more limited.  In this small dosimetric treatment planning comparison, achievable dose using CRT was limited by the lung dose threshold while, for more than half of the IMRT plans, the esophagus was the dose-limiting organ.  The investigators noted that allowing dose heterogeneity in the target enabled further dose escalation with IMRT for large and concave tumors. 

A comparative case series (Yom, 2007) reported on 68 individuals with NSCLC treated with IMRT and concurrent chemotherapy.  Pulmonary toxic effects were compared between the IMRT group and a historical control group of 222 subjects who received 3D-CRT.  A significantly lower incidence of Grade 3 or higher radiation pneumonitis was detected in the IMRT group (8%) than in the 3D-CRT group (32%; p=0.002) at 12 months.  Non-pulmonary toxic effects were not reported.

Liao (2010) reported a retrospective nonrandomized comparative study of 4-dimensional CT simulation (CT imaging combined with respiratory gating) IMRT (4D-CT/IMRT) and 3D-CRT for disease outcomes and toxicities in 409 subjects with locally advanced and unresectable NSCLC treated at a single institution with concomitant chemotherapy.  Both groups received a median dose of 63 Gy.  The study included 318 subjects who received 3D-CRT and chemotherapy between 1999-2004 and 91 subjects who received 4D-CT/IMRT and chemotherapy from 2004-2006.  Mean follow-up times in the 3D-CRT group were 2.1 years (range 0.1-7.9) and 1.3 years (range 0.1-3.2) for the 4D-CT/IMRT group.  Locoregional progression (LRP), distant metastases (DM), and overall survival (OS) were compared.  While the rates of LRP (p=0.37) and DM (p=0.81) were not different between the two treatment groups, OS was significantly better (p=0.039) in the 4D-CT/IMRT group.  Although the lung mean dose in this comparison was similar in the two treatment groups, the V20 (volume of lung receiving 20 Gy) was higher in the 3D-CRT group (p=0.0013) and the incidence (79/371 for both groups combined) of Grade 3 or greater radiation pneumonitis was significantly less (p=0.017) for the 4D-CT/IMRT group. 

There are several limitations to the conclusions that can be drawn from this nonrandomized, nonconcurrent retrospective comparison of 3D-CRT and 4D-CT/IMRT.  Although this study suggests better OS with 4D-CT/IMRT, it should be noted that since the comparisons were not concurrent, the observed survival benefit may have been impacted by other factors.  For instance, stage migration may have been a confounding factor, since pretreatment evaluation for NSCLC with PET imaging increased in use from 7% in 2000 to 37% in 2004.  In this study, 49% of the study subjects in the 3D-CRT and 82% in the 4D-CT/IMRT groups had pretreatment PET imaging.  The authors also note that changes in radiation treatment designs for NSCLC, better management of radiation toxicity, and more effective systemic therapies during the later years of the study might also be responsible for improved survival outcome in the IMRT group.  In addition, the limited follow-up time in this comparison was significantly shorter in the IMRT group (1.3 vs. 2.1 years), and although acute radiation lung injury may become clinically apparent in 1 to 3 months following completion of RT, chronic pulmonary lung damage following radiotherapy (radiation fibrosis) typically takes 6 to 24 months to evolve.

Pleural mesothelioma often creates a concave target volume as it encompasses the lung and has been targeted for IMRT therapy.  However, no comparative studies have been found.  Small non-comparative studies have reported fatal radiation pneumonitis with the use of IMRT for pleural mesothelioma.  One study (Allen, 2006) reported fatal (Grade greater than or equal to 4) radiation pneumonitis in 6 of 13 individuals treated with extrapleural pneumonectomy, chemotherapy, and postoperative IMRT.  However, in another small case series with no concurrent chemotherapy, there were no Grade 3 or higher acute toxic effects, except for 7% of cases of acute Grade 3 radiation induced esophagitis (Ahamad, 2003).

A dosimetric analysis of radiotherapies for the treatment of esophageal carcinoma was performed by Chen (2007b) which compared two forms of IMRT technique: helical tomotherapy (IMRT in which the radiation source rotates around the subject) and "step-and-shoot" IMRT (the multi-leaf collimator reshapes the treatment field as the radiation beam turns on and off) with 3D-CRT in individuals with mid-distal esophageal carcinoma.  Six individuals with locally advanced, mid-distal esophageal carcinoma were treated with neoadjuvant chemoradiation followed by surgery.  Radiotherapy included 50 Gy to gross planning target volume (PTV) and 45 Gy to elective PTV in 25 fractions.  Dose-volume histograms (DVHs), homogeneity index (HI), volumes of lung receiving more than 10, 15, or 20 Gy (V[10], V[15], V[20]), and volumes of heart receiving more than 30 or 45 Gy (V[30], V[45]) were determined.  Treatment plans for helical tomotherapy IMRT showed sharper dose gradients, more conformal coverage, and better HI, compared with "step and shoot" IMRT and 3D-CRT plans.  Mean V(20) of lung was significantly reduced in tomotherapy IMRT plans.  However, both IMRT plans resulted in larger V(10) of lung, compared to 3D-CRT plans.  The heart was significantly spared in both IMRT treatment plans compared to 3D-CRT plans, in terms of V(30) and V(45).  The authors concluded that tomotherapy IMRT plans are superior in terms of target conformity, dose homogeneity, and V(20) of lung (Chen, 2007b). 

Regarding irradiation to treat mediastinal tumors (thymomas, thymic carcinoma, lymphomas of the mediastinum), evolving evidence is gathering from the limited number of trial results currently available.  Koeck conducted a comparative treatment planning analysis according to the guidelines of the German Hodgkin Study Group. This study analyzed the impact of target volume reduction with involved node (IN) RT vs. involved field (IF) RT and 3D-CRT vs. IMRT in 20 subjects with early unfavorable mediastinal Hodgkin's lymphoma (HL) for achievable plan quality, treatment efficiency and degree of sparing of organs at risk for radiation exposure.  Dose-volume histograms (DVH) were evaluated for planning target volumes (PTV) and organs at risk (OAR).  Treatment plans were created for 3D-CRT and IMRT for both the IF and IN, based on CT datasets for the 20 trial participants.  Results showed almost identical mean dose to the PTV for all radiation plans.  For the IF and IN PTVs, target conformity was better with IMRT but homogeneity was better with 3D-CRT.  Mean doses to the heart and spinal cord were reduced with IMRT, whereas mean doses to the lungs and breasts were increased with IMRT.  The volume of OAR exposed to high doses of RT was smaller with IMRT and volume of OAR exposed to low doses was smaller with 3D-CRT.  The authors concluded that the findings demonstrated a pronounced benefit with IMRT for irradiation of lymph nodes anterior to the heart.  However, since only 5 subjects in this study had lymph node involvement requiring RT in the anterior mediastinum, all differences between 3D-CRT and IMRT were considered statistically insignificant.  Reduction of target volumes to IN-PTV most effectively improved OAR sparing regardless of the RT technique (Koeck, 2011).

The NCCN Guidelines on Hodgkin lymphoma and the Guidelines on Non-Hodgkin lymphomas Principles of Radiation Therapy both state:

Advanced radiation therapy technologies, such as 4D-CT simulation, IMRT, breath-hold or respiratory gating, image-guided therapy or proton therapy may offer significant and clinically relevant advantages in specific instances to spare important organs at risk (OARs), such as the heart, lungs, kidneys, spinal cord….and decrease the risk for late normal tissue damage while still achieving the primary goal of local tumor control…The demonstration of significant dose-sparing for these OARs reflects best clinical practice (NCCN, 2017).

The 2017 NCCN Guidelines on Thymomas and Thymic Carcinomas only provides the following guidance regarding RT techniques: "RT should be given by 3D conformal techniques to reduce surrounding normal tissue damage (heart, lungs, esophagus, spinal cord).  IMRT may further improve the dose distribution and decrease dose to the normal tissue" (NCCN, 2017).  In 2010, Gomez authored a review of the current RT techniques available for thymic malignancies noting that, due to the rarity of invasive thymomas, the majority of published studies are retrospective, and there have been no dedicated studies examining toxicity in the setting of thymoma with 3D-CRT or IMRT, compared with older conventional techniques.  However, this author thinks that, until such results mature and are available, outcomes data regarding reduced toxicity can be extrapolated from data on 3D-CRT and IMRT treatment of other thoracic tumors, such as lymphoma and NSCLC (Gomez, 2010).  

Based on the studies described above and clinical input received, in individuals where long term side effects of increased radiation are a significant concern, the use of IMRT may be appropriate in the treatment of primary lung cancers when the IMRT treatment plan demonstrates reductions in the dose to normal lung tissue, as compared to 3D-CRT, and lung motion is adequately accounted for and addressed.

Upper Abdominal Malignancies

Local control and survival of individuals with most upper abdominal malignancies is poor.  Challenges associated with the safe delivery of tumoricidal doses of radiation therapies to these malignancies include organ motion due to respiration, gastrointestinal filling and peristalsis, and the presence of many normal tissues with low tolerance to radiation.  Although treatment planning studies have demonstrated the potential for dose escalation with IMRT, degradation of these IMRT plans due to organ motion has also been demonstrated.  For these reasons, organ motion reduction and image guidance strategies will be needed in conjunction with IMRT (Taremi, 2007). 

The pancreas is located in close proximity to several organs at risk with low radiation-dose tolerance, that is, the liver, kidneys, spinal cord and small bowel.  Pancreatic cancer is radio-resistant and shows high rates of local, nodal, and distant spread.  Although IMRT would appear to be a suitable technique to decrease toxic effects and enable dose escalation, no comparative studies have been identified using IMRT in the treatment of cancer of the pancreas.  Three non-comparative case series showed evidence for feasibility of IMRT dose escalation to 55-60 Gy in combination with chemotherapy for pancreatic cancer (Bai, 2003; Ben-Josef, 2004; Milano, 2004).  In a small case series (Crane, 2001), 5 individuals were treated with IMRT and gemcitabine.  Four of these individuals needed hospital admission for supportive care; the fifth died of an unrelated cause shortly after completion of treatment.  This Phase I study was closed due to excessive toxic effects.

Few studies of IMRT in the treatment of gastric cancer have been published, to date.  Van der Geld (2008) evaluated treatment planning and dosimetric comparisons of 3D-CRT and IMRT, with and without techniques for respiratory gating, in a small case series of 5 individuals.  IMRT significantly reduced mean renal dose exposure compared with 3D-CRT (15 Gy vs. 20 Gy left kidney; 16.6 Gy vs. 32 Gy right kidney).  No significant increase in renal sparing was seen with the addition of respiratory gating to either 3D-CRT or IMRT.  Milano (2006) reported a small series of 7 individuals with gastric cancer treated with IMRT.  IMRT planning was compared with 3D-CRT, and IMRT significantly reduced the volume exceeding threshold dose to the liver and at least one kidney.  Compared with 3D-CRT, IMRT plans had a greater percentage of target receiving the prescribed dose (50.4 Gy).  In this series, IMRT was said to be well tolerated; no individuals developed acute gastrointestinal toxicity greater than Grade 2. 

Boda-Heggemann (2009) reported a comparison of 3D-CRT (n=27) and IMRT (n=33) treatment of two consecutive cohorts following resection for advanced gastric cancer.  The majority of 3D-CRT treated subjects received 5-fluorouracil (5FU) while those treated with IMRT received XELOX (70%) or 5FU (30%) as adjuvant therapy.  Median overall survival was 18 months in the 3D-CRT group and more than 70 months in the IMRT group (p=0.049).  Actuarial predicted survivals were 67% in the IMRT group and 37% in the 3D-CRT group (p value not reported).  Acute renal toxicity, as measured by a rise in serum creatinine, was lower in the IMRT cohort with a difference at 6 weeks ( p=0.021).  Grade 2 (LENT-SOMA scale) renal toxicity was seen in 2 subjects in the 3D-CRT group and none in the IMRT group.  Investigators concluded that adjuvant IMRT with XELOX is more effective and associated with less renal toxicity than 3D-CRT with 5FU in subjects with advanced gastric cancer, but the strength of this conclusion is limited by its nonconcurrent cohort study design.

Minn (2010) reported a nonconcurrent retrospective comparative study of clinical outcomes and toxicity in 57 subjects with gastric or gastroesophageal junction cancer treated with postoperative chemoradiation for gastric cancer (December 1998 to June 2008) using IMRT (26) or 3D-CRT (31).  All but 1 subject was treated with either concurrent chemotherapy with capecitabine (31) or 5FU (25), and the median radiation dose was 45 Gy.  Median follow-up for the 3D-CRT treated group was 1.3 years (range 0.1-9.4 years) and 1.3 years (range 0.4-4.1 years) for the IMRT treated group.  The 2-year overall survival rates did not differ significantly (51% vs. 65% p=0.5), and the rates of locoregional failure were similar (13% IMRT; 15% 3D-CRT).  Grade 2 or greater acute GI toxicity was similar between the two groups (IMRT 61.2% and 3D-CRT 61.5%).  Mean serum creatinine before radiotherapy to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but showed a modest increase in the 3D-CRT group from 0.80 to 1.0 mg/dL (p=0.02).  Although the median kidney mean dose was higher in the IMRT versus the 3D-CRT group (13.9 Gy vs. 11.1 Gy, p=0.05), the mean kidney V20 did not significantly differ between the two groups (IMRT 17.5% vs. 3D-CRT 22%; p=0.17).  While the median liver mean dose for IMRT and 3D-CRT were 13.6 Gy and 18.6 Gy respectively, there was no statistically significant difference.  However, there was a significant difference between the mean liver V30 which was 16.1% for IMRT and 28% for 3D-CRT (p<0.001).  Limitations of the study include its nonconcurrent retrospective design, relatively small number of study subjects, short follow-up and non-standardized chemotherapy regimens.

Only recently has IMRT been explored as an option in the treatment of tumors of the liver and biliary tract.  Until recently, studies had been limited to treatment planning and dosimetric comparisons of IMRT with 3D-CRT.  Cheng (2003) compared the difference in dose-volume data between 3D-CRT and IMRT for 12 individuals with hepatocellular carcinoma (HCC) and previously documented radiation-induced liver disease after 3D-CRT treatment between 1993 and 1999 at a single institution.  Planning comparisons suggested that IMRT is capable of preserving acceptable target coverage and improving non-hepatic organ sparing (spinal cord dose reduction 5.7% vs. 33.2%) for individuals with HCC.  Eccles (2008) compared IMRT with 3D-CRT in 26 individuals with unresectable hepatic malignancies.  IMRT improved planning target volume in 19 of 26 treatment plans, but dose escalation was feasible in only 9 cases by an average of 3.8 Gy.

Two single arm case series reporting outcomes with IMRT in subjects with hepatobiliary cancers have been published.  The first (Jang, 2009) described 42 subjects with advanced HCC with multiple extrahepatic metastases.  Helical tomotherapy was performed for all lesions in each subject.  All received capecitabine during the course of IMRT as a radiosensitizer.  IMRT was followed by transarterial or systemic chemotherapy for those eligible (n=23).  Median overall survival was 12.3 months with an overall survival of 15% at 24 months.  McIntosh (2009) reported a small retrospective case series of 20 subjects with unresectable HCC treated with IMRT and concurrent capecitabine.  Eleven subjects also had transarterial chemoembolization before radiation therapy.  Mean survival of 18 individuals, who were able to complete the IMRT, was 9.6 months.  No acute or latent radiation toxicity greater than Grade 2 was reported. 

In 2010, several organ-specific papers were written which detailed the findings of the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) initiative.  The QUANTEC data provided focused summaries of  dose/volume/outcome limits for many of the organs potentially impacted by radiation treatment.  Several abdominal organs were included in the QUANTEC data including gastric, pancreatic, hepatobiliary and the gastroesophageal (GE) junction where 3D-CRT was noted to jeopardize or exceed maximal tissue tolerances and increase the potential for adverse events related to severe tissue toxicity.  The QUANTEC data indicated that IMRT was superior to 3D-CRT in reducing the toxic effects to nearby organs at risk and, thereby, preventing or significantly reducing radiation-induced disease of the liver, kidneys, spinal cord and small bowel.  Dose/volume constraints were developed as a result of the QUANTEC data which demonstrated that IMRT is a safer method of RT delivery in certain abdominal tumors where sparing of nearby organs at risk is desirable (Benson, 2015; Bentzen, 2010; Dawson, 2010).

Arteriovenous Malformations

Arteriovenous malformations (AVM) are one of several cerebral vascular malformations that affect the brain and spinal cord and consist of a compact collection of abnormal arteries that drain directly into large veins with no intervening capillary bed.  AVMs enlarge with time and may eventually become symptomatic.  The absence of a capillary bed enables rapid, low resistance arterial to venous shunts to develop, as well as aneurysms and venous stasis.  AVMs are thin-walled vessels with a resultant tendency to hemorrhage repeatedly, if unidentified and untreated, which explains why AVMs account for approximately 20% of all cerebrovacular events in children less than 15 years of age.  Due to the potentially lethal nature of these anomalous vessels, emergent treatment is imperative which includes embolization, surgical resection and radiation.  There has been recent interest in the use of IMRT to obliterate large and complex AVM malformations, some of which are inoperable and located in delicate areas of the pediatric brain. However, the published evidence, to date, is limited to a case series of seven childhood AVMs (Fuss, 2005) and a dosimetric planning study (Qi, 2007).  At present, the safety and efficacy of IMRT in the treatment of AVMs is unproven.

Background/Overview

For decades, dose escalation as a means to reduce the incidence of local recurrence of malignant tumors has been studied.  Standard 2D planning techniques, which were used until the early 1990s, were limited by acute and late radiation toxicity.  In the 1990s, 3 Dimensional Conformal Radiotherapy (3D-CRT) techniques were developed that reduced the risk of acute toxicities.  3D-CRT uses computer software to integrate CT images of the internal anatomy in the treatment position and allows the volume receiving the highest radiation dose to conform more exactly to the shape of the target.  These 3D-CRT techniques have permitted further dose escalation.  Intensity modulated radiation therapy (IMRT) is a further evolution of 3D-CRT designed to allow even more precise treatment planning to better target the lesion, while sparing surrounding normal tissue.

The principle behind IMRT is the use of intensity-modulated beams, which are defined as beams that deliver more than two intensity levels for a single beam direction.  The delivery of treatment with radiation beams with varying intensity across the beam surface makes IMRT useful for obtaining highly conformal dose distributions needed to irradiate complex targets positioned near, or immediately adjacent to, sensitive normal tissues (ASTRO, 2007).  One distinguishing feature of IMRT is that the radiation fluence varies across the beam, in contrast to conventional radiation therapy in which a homogeneous radiation dose is delivered to the tumor target, minimally modulated by the use of traditional wedges, blocks and compensators.  In IMRT, non-uniform intensities are assigned to tiny subdivisions of beams, called "beamlets," enabling custom design of optimum dose distributions.

The terminology associated with conformal RT and IMRT varies in the published literature, and several different terms are used for similar concepts (examples of language used in scientific evidence are provided as follows):

The volume of tissue, as a percentage of the organ being radiated that receives 20 Gy (or more), can be expressed as either V20 or V20%.  The volume of tissue in absolute terms, (for example, a unit of volume, usually cc or cubic centimeter, as opposed to a percentage) that receives 20 Gy (or more) can be expressed as V20Gy.

Definitions

Anal canal cancer: The superior border of the functional anal canal, separating it from the rectum, has been defined as the palpable upper border of the anal sphincter and puborectalis muscles of the anorectal ring.  It is approximately 3 to 5 cm in length, and its inferior border starts at the anal verge, the lowermost edge of the sphincter muscles, corresponding to the introitus of the anal orifice (NCCN, 2017).

Gy (Gray): The international system unit of absorbed dose of radiation.

Head and neck cancers: Cancers arising from the oral cavity and lips, larynx, hypopharynx, oropharynx, nasopharynx, paranasal sinuses and nasal cavity, salivary glands, mucosal melanoma and occult primaries in the head and neck region are considered "head and neck cancers."

Image guided radiation therapy (IGRT): This technique utilizes imaging technology to modify treatment delivery to account for changes in the position of the intended target. IGRT is used in conjunction with IMRT for tumors that are located near or within critical structures and/or in tissue with inherent setup variation.

Localized prostate cancer: Prostate cancer which is T-status T1-3a (the tumor has spread through the capsule on one or both sides but has not invaded the seminal vesicles or other structures) and any N disease (either no spread to lymph nodes or there has been spread to the regional lymph nodes). Note that spread beyond the local lymph nodes is considered metastatic disease.

Medial quadrant tumor: A tumor which is located in either the upper or lower medial (inner) quadrants or both of the breast. 

NCCN Clinical Practice Guidelines in Oncology. © 2017. National Comprehensive Cancer Network, Inc.
Categories of Evidence and Consensus:

Category 1:  The recommendation is based on high-level evidence, (e.g., randomized controlled trials) and there is uniform NCCN consensus;
Category 2A:  The recommendation is based on lower-level evidence and there is uniform NCCN consensus;
Category 2B:  The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement);
Category 3:  The recommendation is based on any level of evidence but reflects major disagreement.

All recommendations are category 2A unless otherwise noted (NCCN, 2017).

NCCN Tumor Classification System (taken from the American Joint Committee on Cancer (AJCC):  "The T classification of the primary tumor is the same regardless of whether it is based on clinical or pathologic criteria or both." 

T0:  No evidence of primary tumor;
T1:  Tumor less than or equal to 20 mm or less in greatest dimension;
T2:  Tumor greater than 20 mm but less than or equal to 50 mm in greatest dimension;
T3:  Tumor greater than 50 mm in greatest dimension;
T4:  Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules).

Radiation therapy: Treatment with high energy radiation from X-rays or other sources of radiation.

Xerostomia: The medical term for extreme dryness of the mouth.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Medically Necessary:

CPT  
77301 Intensity modulated radiotherapy plan, including dose-volume histograms for target and critical structure partial tolerance specifications [when specified as IMRT treatment plan]
77338 Multi-leaf collimator (MLC) device(s) for intensity modulated radiation therapy (IMRT), design and construction per IMRT plan
77385 Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple
77386 Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; complex
   
HCPCS  
G6015 Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session
G6016 Compensator-based beam modulation treatment delivery of inverse planned treatment using 3 or more high resolution (milled or cast) compensator, convergent beam modulated fields, per treatment session
   
ICD-10 Diagnosis  
C00.0-C14.8 Malignant neoplasm of lip, oral cavity and pharynx
C15.3-C15.9 Malignant neoplasm of esophagus
C20 Malignant neoplasm of rectum
C21.0-C21.8 Malignant neoplasm of anus and anal canal
C30.0-C31.9 Malignant neoplasm of nasal cavity, middle ear, accessory sinuses
C53.0-C53.9 Malignant neoplasm of cervix uteri
C54.0-C55 Malignant neoplasm of corpus uteri, uterus
C56.1-C56.9 Malignant neoplasm of ovary
C57.00-C57.02 Malignant neoplasm of fallopian tube
C67.0-C67.9 Malignant neoplasm of bladder
C73 Malignant neoplasm of thyroid gland

When services may be Medically Necessary when criteria are met:
For the procedure codes listed above for all other diagnoses not listed.

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

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Government Agency, Medical Society, and Other Authoritative Publications:

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  3. American Society for Therapeutic Radiation and Oncology (ASTRO). Model Policy on Intensity Modulated Radiation Therapy (IMRT). Revised December 9, 2015.
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  5. Blue Cross Blue Shield Association. Special Report: Intensity Modulation Radiation Therapy for Cancer of the Breast or Lung. TEC Assessment, 2005; 20(13).
  6. Blue Cross Blue Shield Association. Technology Evaluation Center (TEC). Accelerated Partial Breast Irradiation as Sole Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer Assessment Program. TEC Assessment 2007; 22(4).
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  8. Dawson LA, Kavanagh BD, Paulino AC, et al. Radiation-associated kidney injury. QUANTEC: organ-specific paper.  Int J Radiat Oncol Biol Phys. 2010; 76(3):S108-S115.
  9. European Organization for Research and Treatment of Cancer – EORTC. Lymph node radiation therapy in patients with stage I, stage II, or stage III breast cancer that has been surgically removed. NLM Identifier NCT00002851. Last updated on January 28, 2010. Available at: http://clinicaltrials.gov/ct2/show/NCT00002851?term=NCT00002851.&rank=1. Accessed on April 21, 2017.
  10. European Organization for Research and Treatment of Cancer – EORTC. Radiation Therapy, Surgery, and Chemotherapy in Treating Patients With Rectal Cancer That Can Be Surgically Removed. NCT00002523. Last updated September 1, 2016. Available at: http://clinicaltrials.gov/show/NCT00002523. Accessed on April 21, 2017.
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  12. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. QUANTEC:organ-specific paper. Int J Radiat Oncol Biol Phys. 2010; 76(3):S77-S85.
  13. Galvin JM, Ezzell G, Eisbrauch A, et al.; American Society for Therapeutic Radiology and Oncology; American Association of Physicists in Medicine. Implementing IMRT in clinical practice: a joint document of the American Society for Therapeutic Radiology and Oncology and the American Association of Physicists in Medicine. Int J Radiat Oncol Biol Phys. 2004; 58(5):1616-1634.
  14. Hartford AC, Galvin JM, Beyer JC, et al.; American College of Radiology (ACR) and American Society for Therapeutic Radiology and Oncology (ASTRO) Practice Guideline for Intensity-Modulated Radiation Therapy (IMRT). Am J Clin Oncol. 2012; 35:612–617.
  15. Hartford AC, Palisca MG, Eichler TJ, et al.; American Society for Therapeutic Radiology and Oncology, American College of Radiology. American Society for Therapeutic Radiology and Oncology (ASTRO) and American College of Radiology (ACR) Practice Guidelines for Intensity-Modulated Radiation Therapy (IMRT). Int J Radiat Oncol Biol Phys. 2009; 73(1):9-14.
  16. Hong TS, Pretz JL, et al. American College of Radiology (ACR) Appropriateness Criteria® Anal Cancer. Expert Panel on Radiation Oncology-Rectal/Anal Cancer. Gastrointest Cancer Res. 2014; 7(1):4-14.
  17. Hummel S, Simpson EL, Hemingway P, Stevenson MD, Rees A. Intensity-modulated radiotherapy for the treatment of prostate cancer: A systematic review and economic evaluation. Health Technol Assess. 2010; 14(47):1-108, iii-iv.
  18. Institute of Cancer Research, United Kingdom. Intensity-Modulated Radiation Therapy in Treating Patients with Localized Prostate Cancer.  NCT00392535. Last updated May 19, 2011. Available at: http://clinicaltrials.gov/ct2/show/NCT00392535?term=imrt&recr=Open&type=Intr&phase=12&rank=28.  Accessed on April 21, 2017.
  19. Jackson A, Marks LB, Bentzen SM, et al. The lessons of QUANTEC:  Recommendations for reporting and gathering data on dose-volume dependencies of treatment outcome.  Int J Radiat Oncol Biol Phys. 2010; 76(3):S155-S160.
  20. Kavanagh BD, Pan CC, Dawson LA, et al.  Radiation dose-volume effects in the stomach and small bowel. QUANTEC: organ-specific paper.  Int J Radiat Oncol Biol Phys. 2010; 76(3 Suppl):S101-S107.
  21. Kirkpatrick JP, van der Kogel AJ, Schultheiss TE. Radiation dose-volume effects in the spinal cord. QUANTEC organ-specific paper.  Int J Radiat Oncol Biol Phys. 2010; 76(3):S42-S49.
  22. Michalski JM, Gay H, Jackson A, et al. Radiation dose-volume effects in radiation-induced rectal injury.  QUANTEC organ-specific paper. Int J Radiat Oncol Biol Phys. 2010; 76(3):S123-S129.
  23. Michalski JM, Lawton C, El Naqa I, et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010; 76(2):361-368.
  24. Michalski JM, Yan Y, Watkins-Bruner D, et al. Preliminary toxicity analysis of 3-dimensional conformal radiation therapy versus intensity modulated radiation therapy on the high-dose arm of the Radiation Therapy Oncology Group 0126 prostate cancer trial. Int J Radiat Oncol Biol Phys. 2013; 87(5):932-938.
  25. National Cancer Institute (NCI). Intensity-modulated radiotherapy: current status and issues of interest. Intensity Modulated Radiation Therapy Collaborative Working Group. Advanced Technologies for Breast Cancer. ASTRO Presentation. 2006. Available at: http://rrp.cancer.gov/content/docs/workshop_2006/McCormick.ppt. Accessed on April 21, 2017.
  26. NCCN Clinical Practice Guidelines in Oncology. © 2017. National Comprehensive Cancer Network, Inc. For additional information: http://www.nccn.org/index.asp. Accessed on April 24, 2017.
    • Anal Carcinoma (V2.2017). Revised April 20, 2017.
    • Breast Cancer (V2.2017). Revised April 6, 2017.
    • Bladder Cancer (V2.2017). Revised February 15, 2017.
    • Head and Neck Cancers (V1.2017). Revised February 6, 2017.
    • Thymomas and Thymic Carcinomas (V1.2017). Revised March 2, 2017.
    • Melanoma (V1.2017). Revised November 10, 2016.
    • B-cell Lymphomas (V3.2017).  Revised March 27, 2017.
    • T-cell Lymphomas (V2.2017).  Revised February 21, 2017.
    • Hodgkin Lymphoma (V1.2017). Revised March 1, 2017.
    • Esophageal and Esophagogastric Junction Cancers (V1.2017). Revised March 21, 2017.
    • Non-small cell Lung Cancer (V5.2017).  Revised March 16, 2017.
    • Pancreatic Adenocarcinoma (V1.2017).  Revised February 24, 2017.
    • Hepatobiliary Cancers (V1.2017).  Revised March 15, 2017.
    • Gastric Cancer (V1.2017). Revised March 21, 2017.
    • Colon Cancer (V2.2017). Revised March 13, 2017.
    • Rectal Cancer (V3.2017). Revised March 13, 2017.
    • Prostate Cancer (V2.2017). Revised February 21, 2017.
    • Thyroid Carcinoma (V1.2017). Revised March 31, 2017.
  27. Nguyen PL, Aizer A, Assimos DG, et al. American College of Radiology (ACR) Appropriateness Criteria® Definitive External-Beam Irradiation in stage T1 and T2 prostate cancer. Am J Clin Oncol. 2014; 37(3):278-288.
  28. Oliver RJ, Clarkson JE, Conway D, et al.  The CSROC Expert Panel, Worthington HV. Interventions for the treatment of oral cancer: radiotherapy. (Protocol) Cochrane Database Syst Rev. 2007;(1):CD006387.
  29. Pan CC, Kavanagh BD, Dawson LA, et al. Radiation-associated liver injury. QUANTEC: organ-specific paper. Int J Radiat Oncol Biol Phys. 2010; 76(3):S94-S100.
  30. Ratko TA, Douglas GW, de Souza JA, et al. Radiotherapy Treatments for Head and Neck Cancer Update. Comparative Effectiveness Review No. 144. (Prepared by Blue Cross and Blue Shield Association Evidence-based Practice Center under Contract No. 290-2007-10058.) AHRQ Publication No. 15-EHC001-EF. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); December 2014. Available at: https://www.effectivehealthcare.ahrq.gov/ehc/products/569/2018/head-neck-cancer-update-report-141208.pdf . Accessed on April 21, 2017.
  31. Roach M, 3rd , Hanks G, Thames H, Jr., et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference.  Int J Radiat Oncol Biol Phys. 2006; 65(4):965-974.
  32. Roeske JC, Lujan AE, Krishnamachari U, et al. Dose volume histogram analysis of acute gastrointestinal toxicity for gynecologic patients receiving intensity modulated whole pelvis radiotherapy. ASTRO Abstract 1086. 43rd Annual Meeting. 2001.  
  33. Samson DM, Ratko TA, Rothenberg BM et al. Comparative effectiveness and safety of radiotherapy treatments for head and neck cancer. Comparative Effectiveness Review No. 20. (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract from the Agency for Healthcare Research and Quality. May 2010. Available online at: http://www.effectivehealthcare.ahrq.gov/ehc/products/19/448/Head-Neck%20Cancer_exec%20summary.pdf.  Accessed on April 21, 2017.
  34. Sun F, Yesanmi O, Fontanarosa J, et al. Therapies for Clinically Localized Prostate Cancer: Update of a 2008 Systematic Review. Comparative Effectiveness Review No. 146. (Prepared by the ECRI Institute–Penn Medicine Evidence-based Practice Center under Contract No. 290-2007-10063.) AHRQ Publication No. 15-EHC004-EF. Rockville, MD: Agency for Healthcare Research and Quality; December 2014. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/521/2023/prostate-cancer-therapies-update-report-141216.pdf. Accessed on April 21, 2017.
  35. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013; 190(2):441-449.
  36. Vanderbilt University. Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) for Localized Prostate Cancer. NCT01326286. Last updated February 27, 2017. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01326286?term=proton+prostate+cancer&rank=19. Accessed on April 21, 2017.
  37. Werner-Wasik M, Yorke E, Deasy J, et al. Radiation dose-volume effects in the esophagus. QUANTEC organ- specific paper.  Int J Radiat Oncol Biol Phys. 2010; 76(3):S86-S93.
  38. Whelan TJ, Olivotto I, Ackerman I, et al: NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer. 2011 ASCO Annual Meeting. Abstract LBA1003. Presented June 6, 2011.  (N.B. Includes link to Buchholz T.  Expert Point of View: Patients with Early Breast Cancer Benefit from Regional Nodal Irradiation.  The ASCO® Post. November 15, 2011).
Websites for Additional Information
  1. Radiological Society of North America, Inc. (RSNA). Intensity-modulated radiotherapy IMRT. Available at:  http://search.rsna.org/search?q=IMRT&site=All&client=RSNA&output=xml_no_dtd&proxystylesheet
    =RSNA&excludeapps=1&filter=0&getfields=imageUrl&proxyreload=1&sort=date%3AD%3AL%3Ad1&entsp=a__RSNA_policy&wc=200&wc_mc=1&oe=UTF-8&ie=UTF-8&ud=1&exclude_apps=1. Accessed on April 21, 2017.
Index

Intensity Modulated Radiation Therapy (IMRT)
Tomotherapy

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. 
Reviewed 05/03/2017 Hematology/Oncology Subcommittee review. Updated the formatting in the Position Statement section. The Definitions and References sections were updated.
Revised 05/05/2016 MPTAC review. The revisions recommended by the Hematology/Oncology Subcommittee were approved.
Revised 05/04/2016 Hematology/Oncology Subcommittee review. The medically necessary indications for IMRT were expanded to include the entire esophagus and also mediastinal tumors for which radiation therapy is indicated. In the lung cancer medically necessary criteria, the percentage of normal lung receiving more than 20 Gy was changed from more than 35% to 30%. The Rationale, Coding and References sections were updated.
Revised 12/09/2015 MPTAC review. The revisions recommended by the Hematology/Oncology Subcommittee were approved.
Revised 12/05/2015 Hematology/Oncology Subcommittee review. The medically necessary criteria for IMRT of GI tract tumors were revised for clarification to indicate that the tumor must be primary and non-metastatic, that is confined regionally to the primary organ including regional lymph nodes.
Revised 11/05/2015 MPTAC review.
Revised 11/04/2015 Hematology/Oncology Subcommittee review.  Changed the document number from RAD.00041 to THER-RAD.00007.  The position statement regarding thyroid cancer was expanded to remove the word, anaplastic, and consider IMRT as medically necessary in thyroid cancer.  A new position statement was added for tumors of the gastrointestinal tract when criteria are met. The Rationale, Coding and References sections were updated.  Removed ICD-9 codes from Coding section.
Revised 05/07/2015 MPTAC review.
Revised 05/06/2015 Hematology/Oncology Subcommittee review. The medically necessary criteria for IMRT in primary lung cancer was revised to remove "curative intent" and say when concurrent chemotherapy and radiation is to be used. The Note regarding IMRT and proton beam RT (PBRT) relevant to RT for prostate cancer has been removed for alignment with RAD.00015 Proton Beam Radiation Therapy. The Rationale and References sections were updated.
  01/01/2015 Updated Coding section with 01/01/2015 CPT and HCPCS changes; removed codes 77418, 0073T deleted 12/31/2014.
Reviewed 05/15/2014 MPTAC review.
Reviewed 05/14/2014 Hematology/Oncology Subcommittee review. The Rationale and References were updated.
Reviewed 11/14/2013 MPTAC review.
Reviewed 11/13/2013 Hematology/Oncology Subcommittee review. The Rationale and References were updated.
Revised 11/08/2012 MPTAC review.
Revised 11/07/2012 Hematology/Oncology Subcommittee review. The medically necessary statements for primary malignant gynecologic tumors (uterus, cervix, ovary, fallopian tube), primary pelvic sarcomas, and rectal adenocarcinoma were clarified to remove dose volume limitations.  Bladder cancer was added to the medically necessary indications. The Rationale and References were updated.
Revised 05/10/2012 MPTAC review. The revisions recommended by the Hematology/Oncology Subcommittee were approved.
Revised 05/09/2012 Hematology/Oncology Subcommittee review. The medically necessary criteria for localized prostate were revised to remove the Gy dosage.  A Note regarding the comparison of PBRT and IMRT was added to the localized prostate section.  The criteria for CNS tumors were expanded to additional radiosensitive structures: lens, retina, optic chiasm, and cochlea. The pediatric indications were clarified to state in individuals less than age 21. The Rationale and References were updated.
Revised 12/23/2011 MPTAC review. The revisions proposed by the Hematology/Oncology Subcommittee interim vote were approved.  Rationale, Definitions, and References were updated.
Revised 12/06/2011 Hematology/Oncology Subcommittee review. An interim vote proposed expanded medically necessary criteria for internal mammary node irradiation in breast cancer when criteria are met.  
Revised 11/17/2011 MPTAC review. Suggested revisions below were approved. References were updated.
Revised 11/16/2011 Hematology/Oncology Subcommittee review. The language in the medically necessary criteria for use in breast cancer were revised to clarify use of positioning devices and to add individuals with internal mammary node involvement meeting criteria for radiation therapy.  The medically necessary criteria for prostate post-prostatectomy were revised to reduce the Gy dose to greater than or equal to 64 Gy and to add positive surgical margins.  Statements on anal and rectal cancer were clarified.  Criteria for lung cancer were revised to add 3D CT planning.
Revised 05/19/2011 MPTAC review. The revisions suggested below by the Hematology/Oncology Subcommittee were approved.  The Rationale, Background and References were also updated.
Revised 05/18/2011 Hematology/Oncology Subcommittee review. Clarified the position statement about CNS tumors to add "…that are either primary or metastatic lesions."  Revised the language of the medical necessity criteria for breast and lung cancer for consistency with the other position statements (regarding the volume of radiation dose [V20 vs. V20 %, for example]).  Added arteriovenous malformations (AVM) to the list of indications for IMRT considered investigational and not medically necessary.
Revised 11/18/2010 MPTAC review meeting 11/18/2010 and approved the changes as recommended by the  Hematology/Oncology Subcommittee.  On 12/13/2010, MPTAC approved the additional recommendations by the Hematology/Oncology Subcommittee.  The Rationale, Definitions, Coding and Reference sections were also updated.
Revised 11/17/2010 Hematology/Oncology Subcommittee review. The position statement was revised for re-irradiation of a previously radiated field and prostate cancer.   The sub-committee voted to add Medical Necessity criteria for breast and lung cancer, with a subsequent vote to take place on the language of the criteria once finalized.  Criteria were drafted and a follow-up vote occurred on 12/07/2010.  The result of this additional vote was that the sub-committee added breast and lung cancer as medically necessary with criteria and not medically necessary when criteria are not met.
Revised 05/13/2010 MPTAC review. The medical necessity criteria for IMRT of the prostate were broadened to include post-prostatectomy when criteria are met. The language was clarified regarding excessive radiation exposure with standard 3D conformal radiation treatment in primary GYN tumors, primary pelvic sarcoma and locally advanced rectal adenocarcinoma.  The Rationale and References were updated.
Revised 05/12/2010 Hematology/Oncology Subcommittee review. Recent evidence for use of IMRT in post-surgical prostate cancer with rising PSA was reviewed.
  01/01/2010 Updated Coding section with 01/01/2010 CPT changes.
Revised 08/27/2009 MPTAC review.  A position statement has been added regarding re-irradiation of a field involving the spinal cord when criteria are met.  The Rationale, Coding and References were updated.
Revised 06/17/2009 Hematology/Oncology ad hoc Subcommittee review. Consideration for an additional position statement to address re-irradiation was raised and discussed with a recommendation to present this revision to MPTAC.
Revised 01/13/2009 Hematology/Oncology ad hoc Subcommittee review.  The position statement regarding prostate cancer has been revised to remove the word "non-metastatic" and replace it with localized prostate cancer.
Revised 11/20/2008 MPTAC review.
Revised 11/19/2008 Hematology/Oncology Subcommittee review. The medical necessity criteria have been expanded to add anaplastic thyroid cancer and primary pelvic sarcoma. The Rationale, Background, Coding and Reference sections have been updated.
Revised 08/28/2008 MPTAC review. The expanded medical necessity criteria from the Hematology/Oncology Subcommittee ad hoc review to add pelvic tumors and locally advanced rectal adenocarcinoma when criteria are met were approved. The Rationale section has also been expanded to add information related to IMRT for breast cancer with updated studies. References and Coding sections were also updated.
Revised 07/07/2008 Hematology/Oncology Subcommittee ad hoc review. The medical necessity criteria were expanded to add pelvic tumors and locally advanced rectal adenocarcinoma when criteria are met.
Revised 11/29/2007 MPTAC review.
Revised 11/28/2007 Hematology/Oncology Subcommittee review. The medical necessity criteria for IMRT were expanded to add squamous cell carcinoma of the anus as now considered medically necessary. References were updated with recently published studies of IMRT for breast cancer and additional indications.  The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary."  Coding was also updated.
Reviewed 12/18/2006 Hematology/Oncology Subcommittee review.
Reviewed 06/08/2006 MPTAC review. References were updated to include recently published literature and the 2005 TEC Assessment. 
  04/12/2006 Updated CPT coding.
Reviewed 12/01/2005 MPTAC review. 
Reviewed 11/30/2005 Hematology/Oncology Subcommittee review.
Revised 09/22/2005 MPTAC review.  Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.
Pre-Merger Organizations Last Review Date Document Number Title
Anthem, Inc.

 

No prior document  
WellPoint Health Networks, Inc.

12/02/2004

4.11.09 Intensity Modulated Radiation Therapy (IMRT)