Intensity Modulated Radiation Therapy

Number: 0590

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses intensity modulated radiation therapy.

1. Medical Necessity

   Aetna considers the following interventions medically necessary:
   
   
   1. Intensity modulated radiation therapy (IMRT) for certain indications where critical structures cannot be adequately protected with standard 3-dimensional (3D) conformal radiotherapy;
      
      For medical necessity criteria, see eviCore Healthcare Radiation Therapy Clinical Guidelines. Note: eviCore guidelines undergo a formal review annually; however, eviCore reserves the right to change and update the guidelines without prior notice. Draft guidelines are posted 90 days prior to implementation. Additional clinical guidelines may be developed as needed or may be withdrawn from use.
      
      
   2. Placement of fiducial markers if the above criteria are met, and the radiation target is not clearly visible, and bony anatomy is not sufficient for adequate target alignment;
      
      
   3. Interfraction image guidance (i.e., image guidance between fractions) or intrafraction image guidance systems (i.e., real-time within fraction image guidance) (e.g., Calypso 4D Localization System, the RayPilot System) for delivering IMRT and other conformal radiotherapy.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
32553	Placement of interstitial device(s) for radiation therapy guidance (eg, fiducial markers, dosimeter), percutaneous, intra-thoracic, single or multiple
49327	Laparoscopy, surgical; with placement of interstitial device(s) for radiation therapy guidance (eg, fiducial markers, dosimeter), intra-abdominal, intrapelvic, and/or retroperitoneum, including imaging guidance, if performed, single or multiple (List separately in addition to code for primary procedure)
49411	Placement of interstitial device(s) for radiation therapy guidance (eg, fiducial markers, dosimeter), percutaneous, intra-abdominal, intra-pelvic (except prostate), and/or retroperitoneum, single or multiple
49412	Placement of interstitial device(s) for radiation therapy guidance (eg, fiducial markers, dosimeter), open, intra-abdominal, intrapelvic, and/or retroperitoneum, including image guidance, if performed, single or multiple (List separately in addition to code for primary procedure)
77301	Intensity modulated radiotherapy planning, including dose-volume histograms for target and critical structure partial tolerance specifications
77338	Multi-leaf collimator (MLC) device(s) for intensity modulated radiation therapy (MRT), design and construction per IMRT plan
77385 - 77386	Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed
77387	Guidance for localization of target volume for delivery of radiation treatment delivery, includes intrafraction tracking, when performed
HCPCS codes covered if selection criteria are met:
A4648	Tissue marker, implantable, any type, each
C9728	Placement of interstitial device(s) for radiation therapy/surgery guidance (eg, fiducial markers, dosimeter), for other than the following sites (any approach): abdomen, pelvis, prostate, retroperitoneum, thorax, single or multiple
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
G6017	Intra-fraction localization and tracking of target or patient motion during delivery of radiation therapy (e.g., 3D positional tracking, gating, 3D surface tracking), each fraction of treatment
ICD-10 codes covered if selection criteria are met:
C00.0 - D49.9	Neoplasms
Z51.0	Encounter for antineoplastic radiation therapy

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Background

Note on Definition of Intensity Modulated Radiation Therapy (IMRT): For purposes of this policy, to qualify as IMRT, radiation therapy requires highly sophisticated treatment planning utilizing numerous beamlets to generate dosimtery in accordance with assigned dose requirements to the tumor and organs at risk.

Note: For purposes of this policy, critical structures can not be adequately protected with standard three-dimensional (3D) conformal radiotherapy if IMRT would decrease the probability of grade 2 or grade 3 radiation toxicity, as compared to conventional 3D conformal radiation therapy, in greater than 15 % of irradiated similar cases.

Intensity-modulated radiation therapy, also known as tomotherapy, is a type of stereotactic radiosurgery that delivers a highly conformal, 3D distribution of radiation doses. IMRT uses computer‐controlled linear accelerators to deliver precise radiation doses to specific areas within a tumor. This therapy allows for increased precision by the conforming of the radiation to the planned target site while significantly reducing the amount of radiation to surrounding healthy tissues. Image-guided radiation therapy (IGRT) may be performed in conjunction with IMRT and includes, but may not be limited to, computed tomography (CT), magnetic resonance imaging (MRI), ultrasound or X-ray. IGRT is utilized to direct and guide the delivery of radiation to maximize accuracy and precision throughout treatment.

Different techniques are utilized to control the radiation amount given during IMRT. The most common approach is the use of multileaf collimators (MLCs). These devices are attached to the linear accelerator. The MLCs are composed of computer controlled tungsten "leaves" or panels that move while the radiation beam is directed toward the target. The leaves act as filters that block out certain areas. This modifies the beam’s intensity so that the radiation is distributed according to the treatment plan.

Another delivery approach is compensator‐based IMRT. This approach utilizes custom made (based on the 3D images and the treatment plan) high density blocks to control the administration of the radiation. The blocks are put into place, the patient is positioned and the radiation is delivered.

Fiducial markers are gold seeds or stainless steel screws that are implanted in and/or around a soft tissue tumor or within the bony spine, to act as a radiologic landmark, to more precisely define the target lesion's position. Fiducial markers may be placed using CT, endoscopic or surgical guidance.

Collimator-based IMRT uses computers to modify the intensity of the beam across each individual field with the use of moving collimators.  Conventional treatment with multi-leaf collimation (MLC) uses static positions of the collimator leaves whereas IMRT allows the dynamic motion of the various collimator leaves during each session of therapy. 

With compensator-based IMRT, a pre-shaped piece of material (the compensator or modulator) is used to modulate the beam.  The amount of modulation of the beam is based on the thickness of material through which the beam is attenuated.  This modulation requires the fabrication and the manual insertion of the modulator into the tray mount of a linear accelerator.

Intensity-modulated radiation therapy typically involves inverse treatment planning, although forward treatment planning has been used.  Forward treatment planning involves estimating the radiation delivery profile based on the number, directions and shape of the beams.  In inverse treatment planning, the radiation oncologist and physicist determine the treatment target, the normal structures that should be protected, the required radiation dose for the tumor and the tolerated doses for the surrounding normal tissues; the computer then computes the beam profiles needed to yield those results.

The outlined objectives for radiation dose distribution are in prescribed dose volume histograms.  The histograms are translated into beam configurations that will deliver tumor and normal tissue doses prescribed.  Intensity-modulated radiation therapy optimizes the treatment plan based on the physician’s dose instructions, the specific dose constraints for planned treatment volume (PTV) and information about tumor size, shape and location in the body.  A medical linear accelerator equipped with a dynamic MLC shapes the radiation beams wrapping around the tumor, conforming to its shape and delivers the radiation.

Intensity-modulated radiation therapy involves at least 5 separate ports.  The beam angle or gantry position is what determines a port or entry point of the beam.  Segments are part of the individual beam profile and there may be many per port or beam angle.  If the segment is truly an independent port within a port (often called "en field") and can be demonstrated to provide sufficient beam profiling, then it may be considered a separate port within the same beam angle and be considered a port for purposed of defining IMRT.

An evidence review by ANAES (2003) noted that, although the clinical indications for IMRT remain to be established, clinical interest in IMRT is greatest for cancers of the head and neck and for prostate cancer.  In addition, ANAES found that there is some emerging interest in use of IMRT for cancers of the lung and central nervous system (CNS).  

An assessment by the Belgian Health Care Knowledge Centre (KCE) (Van den Steen et al, 2007) concluded that weak-to-moderate quality evidence is available demonstrating a reduction in toxicity after IMRT compared with 2D RT or 3D CRT for head and neck cancer, prostate cancer and breast cancer.  The assessment found that current reports do no allow for a good comparison of relapse or survival data between IMRT and conventional techniques.

On the topic of patient safety, the assessment observed that total body irradiation is higher using IMRT and, in theory, may overall double the incidence of fatal secondary malignancies compared with standard external radiotherapy techniques.  The assessment noted that younger patients are especially at risk.  The report also noted that large variations exist in total body irradiation between various IMRT techniques.  Also use of daily radiation-based imaging for treatment set-up verification adds to the overall radiation exposure.

CNS and Head and Neck Tumors

Intensity-modulated radiation therapy may be indicated in CNS and head and neck tumors, due to the close proximity of critical structures in these anatomic regions.

A study by Claus and associates (2001) examined the use of IMRT for the treatment of patients with ethmoid sinus tumors.  The authors suggested that IMRT has the potential to save binocular vision because the dose to the optic pathway structures can be reduced selectively by this procedure.  Nutting and colleagues (2001) compared conventional, 3D conformal, and IMRT for the treatment of parotid gland tumors.  The researchers found that compared to conventional radiotherapy, IMRT not only reduced radiation dose to critical normal tissues, but also produced a further reduction in the dose to the cochlea and oral cavity.  These encouraging findings are corroborated by more recent studies.

Nutting et al (2001) reported that IMRT improved the planning target volume coverage and reduced the spinal cord dose, and concluded that IMRT should reduce the risk of myelopathy or may allow dose escalation in patients with thyroid cancer.  Adams and co-workers (2001) stated that IMRT offers significant advantages over conventional radiotherapy and 3D-conformal RT techniques for treatment of maxillary sinus tumors.

Chao et al (2001) reported that the dosimetric advantage of IMRT, when compared with conventional techniques, did translate into a significant reduction of late salivary toxicity in patients with oropharyngeal carcinoma (n = 430).  There was no adverse impact on tumor control and disease-free survival in patients treated with IMRT.  Huang and colleagues (2002) observed that for pediatric patients with medulloblastoma (n = 26), the conformal technique of IMRT delivered much lower doses of radiation to the auditory apparatus, while still delivering full doses to the desired target volume.  These findings suggest that, despite higher doses of cisplatin, and despite RT before cisplatin therapy, treatment with IMRT can achieve a lower rate of hearing loss.

Dogan and associates (2002) noted their improvement of IMRT treatment plans for patients with concave-shaped head and neck tumors.  They stated that IMRT showed better target coverage and sparing of critical structures than that of 3D conformal RT and 2D RT.

Lee et al (2002) reported their experience with IMRT in the treatment of patients with nasopharyngeal carcinoma (n = 67).  These investigators found excellent local-regional control for nasopharyngeal carcinoma with IMRT.  This technique provided excellent tumor target coverage and allowed the delivery of a high dose to the target with significant sparing of the salivary glands and other nearby critical normal tissues.

An assessment by the Belgian Health Care Knowledge Center (KCE) (Van den Steen et al, 2007) concluded that, as IMRT for head and neck cancer is more difficult to plan and deliver, and still an area of investigation, for the time being its use in these patients should be restricted to centers with the necessary expertise and preferentially those that are performing research in this area.  The assessment (Van den Steen et al, 2007) identified a total of 9 comparative trial reports, including 1 randomized controlled clinical trial (RCT), concerning head and neck cancer (9 reports, including 1 RCT).  The reported stated that head and neck cancer constitutes an appropriate candidate indication for the highly accurate irradiation achievable using IMRT as organ motion is practically absent.  The report found that the benefit of IMRT has been documented compared with 3D CRT for the sparing of organs at risk, mainly the salivary glands, and in 1 study also the optic nerve.  From the trials published it can be concluded that well-performed IMRT can improve quality of life (e.g., less xerostomy) in head and neck cancer patients.  There are, however, no robust data comparing IMRT with 3D CRT with regard to relapse or survival.  As head and neck cancer radiation treatment is reportedly not being performed optimally by many radiation oncologists and as IMRT remains difficult to plan and deliver, it has been suggested to restrict such IMRT treatments to centers with the necessary expertise (e.g., IMRT research activities, patient outcome follow-up).

The assessment identified 1 non-randomized trial concerning medulloblastoma (Van den Steen et al, 2007), a small retrospective comparison in cisplatin treated children with medulloblastoma, which suggests IMRT can reduce ototoxicity compared with 3D conformal RT.

Beadle and colleagues (2017) compared the placement and duration of feeding tube use among patients with head and neck cancer (HNC) from 1999 through 2011.  The cohort, demographics, and cancer-related variables were determined using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, and claims data were used to analyze treatment details.  A total of 2,993 patients were identified.  At a median follow-up of 47 months, 54.4 % of patients had ever had a feeding tube placed.  The median duration from feeding tube placement to removal was 277 days.  On zero-inflated negative binomial regression, patients who received IMRT and 3-dimensional RT (3DRT) (non-IMRT) had similar rates of feeding tube placement (odds ratio [OR], 1.10; p = 0.35); however, patients who received 3DRT had a feeding tube in place 1.18 times longer than those who received IMRT (p = 0.03).  The difference was only observed among patients who received definitive RT; patients who underwent surgery and also received adjuvant RT had no statistically significant difference in feeding tube placement or duration.  The authors concluded that patients with HNC who received definitive IMRT had a significantly shorter duration of feeding tube placement than those who received 3DRT.  These data suggested that there may be significant quality-of-life (QOL) benefits to IMRT with respect to long-term swallowing function in patients with HNC.

De Sanctis and colleagues (2019) stated that oral mucositis is a common dose-limiting toxicity (DLT) during radiotherapy with or without chemotherapy in HNC patients. This potentially severe complication globally worsens QOL and negatively impacts local control and survival's outcomes.  Several studies have been published on feasibility and/or clinical benefit of IMRT mucosa-sparing technique.  In 2017, the Italian Association of Radiation Oncology Head and Neck Cancer Working Group organized a study group to perform a systematic review.  The aim was to verify if practical indications, including dose-constraints and demonstrated clinical benefit, could be proposed for oral mucosa (OM)-sparing IMRT in order to reduce the incidence of severe acute mucositis.  The authors concluded that although dose to OM should be reduced as much as possible without compromising target volumes coverage, it is still tricky to firmly state that OM-sparing procedure should be considered the standard of care, especially due to high subjective variability in OM contour.

Prostate Cancer

Guidelines on prostate cancer from the National Comprehensive Cancer Network (NCCN, 2003) indicate that IMRT is an alternative to 3D conformal RT for ultra-high dose (dosage of 75 Gy or more) radiation treatment of prostate cancer.  NCCN guidelines state that "3D conformal or IMRT (intensity modulated radiation therapy) techniques should be employed in preference to conventional techniques" in the treatment of prostate cancer.  "The standard dose has been 70 Gy in 35-38 fractions to the prostate ± seminal vesicles, which appears to be appropriate for patients with low risk cancers.  For patients with intermediate or high risk cancers, doses between 75-80 Gy are better …. If target (PTV) margins are reduced, such as for doses above 75 Gy, extra attention to daily prostate localization with ultrasound or implanted fiducials is indicated."

A coding guide from the American Society for Therapeutic Radiation and Oncology (ASTRO, 2007) explains that IMRT has several advantages for use in prostate cancer, where dose escalation is planned to delivery radiation doses in excess of those commonly utilized with conventional treatments.  In prostate cancer, the target volume is in close proximity to critical structures (rectum, bladder, femoral head, and penile bulb) and must be covered with narrow margins to adequately protect immediately adjacent structures to reduce the probability of radiation toxicity.  The coding guide explains that IMRT is the only treatment modality that can achieve this, rather than conventional 3D treatment planning.

Zelefsky and colleagues (2001) presented the long-term outcome and tolerance of 3D CRT and IMRT for localized prostate cancer.  Patients (n = 1,100) were categorized into prognostic risk groups based on pre-treatment prostate specific antigen (PSA), Gleason score and clinical stage.  At 5 years the PSA relapse-free (RF) survival rates in patients at favorable, intermediate and unfavorable risk were 85 %, 58 %, and 3 %, respectively.  Radiation dose was the most powerful variable impacting PSA RF survival in each prognostic risk group.  The 5-year actuarial PSA RF survival rate for patients at favorable risk who received 64.8 to 70.2 Gy was 77 % compared to 90 % for those treated with 75.6 to 86.4 Gy.  The corresponding rates were 50 % versus 70 % in intermediate risk cases, and 21 % versus 47 % in unfavorable risk cases.  Only 4 of 41 patients (10 %) who received 81 Gy had a positive biopsy 2.5 years or greater after treatment compared with 27 of 119 (23 %) after 75.6 Gy, 23 of 68 (34 %) after 70.2 Gy and 13 of 24 (54 %) after 64.8 Gy.  The incidence of toxicity after 3D conformal CRT was dose-dependent.  The 5-year actuarial rate of grade 2 rectal toxicity in patients who received 75.6 Gy or greater was 14 % compared with 5 % in those treated at lower dose levels.  Treatment with IMRT significantly decreased the incidence of late grade 2 rectal toxicity since the 3-year actuarial incidence in 189 cases managed by 81 Gy was 2 % compared with 14 % in 61 cases managed by the same dose of 3D CRT.  The 5-year actuarial rate of grade 2 urinary toxicity in patients who received 75.6 Gy or greater 3D CRT was 13 % compared with 4 % in those treated up to lower doses.  Intensity modulated radiation therapy did not affect the incidence of urinary toxicity.  Sophisticated CRT techniques with high dose 3D CRT and IMRT improve the biochemical outcome in patients with favorable, intermediate and unfavorable risk prostate cancer.  Intensity modulated radiation therapy is associated with minimal rectal and bladder toxicity, and, hence, represents the treatment delivery approach with the most favorable risk-to-benefit ratio.

An assessment by the Belgian Health Care Knowledge Center (KCE) (Van den Steen, 2007) concluded that IMRT or 3D CRT is recommended for high dose external radiotherapy in prostate cancer.  The report identified a total of 6 comparative trial reports (no RCTs) of IMRT for prostate cancer.  The report noted that the standard curative treatments for prostate cancer are radical prostatectomy and radiotherapy (external beam or brachytherapy).  The report found fairly strong evidence that patients with localized, intermediate risk, and high risk disease, i.e., patients normally not suited for surgery, benefit from a higher than conventional total radiation dose as can be achieved using 3D CRT or IMRT.  No additional overall survival benefit has been shown.  The report explained that IMRT plans can provide a steep high to low-dose gradient at the edge of the target volume for improved avoidance of adjacent normal structures, such as the rectum, bowel and bladder.  For this reason IMRT was used first for prostate cancer treatment in many centers.  Most comparative studies report less rectal toxicity after IMRT compared with 3D CRT, also at high doses.  The challenge is to precisely target the prostate (and sometimes the lymph nodes) each session.  Frequent image-based adjustments can help to achieve this.

Canter and colleagues (2011) stated that surgical treatment for men with localized prostate cancer – open, laparoscopic, or robotically-assisted – remains one of the therapeutic mainstays for this group of patients.  Despite the stage migration witnessed in patients with prostate cancer since the introduction of PSA screening, detection of extra-prostatic disease at the time of surgery and biochemical recurrence following prostatectomy pose significant therapeutic challenges.  Radiation therapy after radical prostatectomy (RP) has been associated with a survival benefit in both the adjuvant and salvage setting.  Nevertheless, optimal targeting of the prostate bed following surgery remains challenging.  The Calypso 4D Localization System (Calypso Medical Technologies, Seattle, WA) is a target positioning device that continuously monitors the location of 3 implantable electromagnetic transponders.  These transponders can be placed into the empty prostatic bed after prostatectomy to facilitate the delivery of RT in the post-surgical setting.  The authors detailed their technique for transrectal placement of electromagnetic transponders into the post-prostatectomy bed for the delivery of adjuvant or salvage IMRT.  They prefer this technique of post-surgical RT because it allows for improved localization of the target area allowing for the maximal delivery of the radiation dose while minimizing exposure of surrounding normal tissues.  The authors noted that although emerging, their initial oncologic and functional outcomes have been promising.

Sheets et al (2012) examined the comparative morbidity and disease control of IMRT, proton therapy, and conformal RT for primary prostate cancer treatment.  Main outcome emasures were rates of gastro-intestinal (GI) and urinary morbidity, erectile dysfunction, hip fractures, and additional cancer therapy.  Use of IMRT versus conformal RT increased from 0.15 % in 2000 to 95.9 % in 2008.  In propensity score-adjusted analyses (n = 12,976), men who received IMRT versus conformal RT were less likely to receive a diagnosis of GI morbidities (absolute risk, 13.4 versus 14.7 per 100 person-years; relative risk [RR], 0.91; 95 % confidence interval (CI): 0.86 to 0.96) and hip fractures (absolute risk, 0.8 versus 1.0 per 100 person-years; RR, 0.78; 95 % CI: 0.65 to 0.93) but more likely to receive a diagnosis of erectile dysfunction (absolute risk, 5.9 versus 5.3 per 100 person-years; RR, 1.12; 95 % CI: 1.03 to 1.20).  Intensity-modulated radiation therapy patients were less likely to receive additional cancer therapy (absolute risk, 2.5 versus 3.1 per 100 person-years; RR, 0.81; 95 % CI: 0.73 to 0.89).  In a propensity score-matched comparison between IMRT and proton therapy (n = 1,368), IMRT patients had a lower rate of GI morbidity (absolute risk, 12.2 versus 17.8 per 100 person-years; RR, 0.66; 95 % CI: 0.55 to 0.79).  There were no significant differences in rates of other morbidities or additional therapies between IMRT and proton therapy.  The authors concluded that among patients with non-metastatic prostate cancer, the use of IMRT compared with conformal RT was associated with less GI morbidity and fewer hip fractures but more erectile dysfunction; IMRT compared with proton therapy was associated with less GI morbidity.

Breast Cancer

According to an ASTRO coding guide, IMRT is not routinely indicated in breast cancer, but may be indicated in selected cases of breast cancers with close proximity to critical structures (ASTRO, 2007).

There are no evidence-based guidelines from leading national medical organizations or Federal public health agencies that conclude that IMRT is routinely indicated for breast cancer.   An assessment from the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2006) concluded that available data are insufficient to determine whether IMRT is superior to 3D CRT for improving health outcomes of patients with breast cancer.  The assessment identified no studies (randomized or non-randomized; prospective or retrospective) that directly compared health outcomes of IMRT with health outcomes of 3D CRT (using concurrent or historical controls).  The TEC assessment noted that follow-up was short (less than 1 year) in the 2 available single-arm (non-comparative) studies on IMRT for breast cancer, and that acute skin toxicity and cosmesis were the only outcomes reported in these studies.

Since publication of the TEC assessment, Pignol et al  (2008) reported on a RCT that found that breast IMRT (BIMRT) reduced acute skin toxity compared to standard adjuvant breast irradiation using wedge compensation (WC).  The investigators explained that standard adjuvant breast irradiation using wedge compensation is associated with a high rate of acute skin reactions including moist desquamation.  These side effects are more likely to occur in the breast crease and for women with large breasts.  In this study, 358 patients receiving breast irradiation were randomized to receive either BIMRT or WC up to 50 Gy, with or without a boost of 16 Gy.  Study subjects were assessed for skin toxicity weekly during the treatment and until 6 weeks post-treatment by a masked clinical research assistant.  The investigators found that BIMRT compared to WC reduced moist desquamation in all breast quadrants (31 % versus 48 %), p = 0.0019) and in the infra-mammary fold (26 % versus 43 %, p = 0.0012).  The investigators reported that BIMRT did not significantly reduce the maximum toxicity grade 3 to 4 in all breast quadrants compared to WC (p = 0.20).  The use of IMRT significantly reduced infra-mammary fold skin toxicity grade 3 to 4 (odds ratio [OR] = 2.62, 95 % CI: 0.136 to 0.603).  The investigators reported that breast volume was the most significant patient related factor associated with increased acute skin toxicity.  The authors concluded that, compared to the standard WC radiation treatments, BIMRT significantly reduced the development of severe moist desquamation.

Donovan et al (2007) reported on the results of a RCT that found that BIMRT was associated with fewer late adverse effects compared to WC.  In this study, 306 women were prescribed whole breast radiation therapy after tumour excision for early stage cancer were randomized to BIMRT or 2D RT delivered using standard WC.  All patients were treated to a dose of 50 Gy in 25 fractions over 5 weeks followed by an electron boost to the tumor bed of 11.1 Gy in 5 fractions.  The primary endpoint was change in breast appearance scored from serial photographs taken before radiotherapy and at 1, 2 and 5 years follow-up.  Secondary endpoints included patient self-assessments of breast discomfort, breast hardness, quality of life and physician assessments of breast induration.  Two hundred forty (79 %) patients with 5-year photographs were available for analysis.  Change in breast appearance was identified in 71 of 122 (58 %) subjects assigned to WC compared to 47 of 118 (40 %) subjects assigned to BIMRT.  The investigators reported that the subjects assigned to WC were 1.7 times more likely to have a change in breast appearance than subjects assigned to IMRT after adjustment for year of photographic assessment (95 % CI: 1.2 to 2.5, p = 0.008).  Significantly fewer subjects assigned to BIMRT developed palpable induration assessed clinically in the center of the breast, pectoral fold, infra-mammary fold and at the boost site.  The investigators stated that no significant differences between treatment groups were found in patient reported breast discomfort, breast hardness or quality of life.  The authors concluded that this analysis suggests that minimization of unwanted radiation dose inhomogeneity in the breast reduces late adverse effects.  Incidence of change in breast appearance was statistically significantly higher in subjects in the WC group compared with the BIMRT group.  The investigators noted that a beneficial effect on quality of life remains to be demonstrated.

In an editorial that accompanied the paper by Pignol et al (2008), Haffy and colleagues (2008) stated that it is clear from the phase III clinical trials by Pignol et al (2008) as well as Donovan et al (2007) that there are both dosimetric and clinical advantages to improved homogeneity achieved with IMRT to the whole breast.

An assessment by the Belgian Health Care Knowledge Center (KCE) (Van den Steen et al, 2007) concluded that use of IMRT may reduce skin complications in breast cancer radiotherapy, primarily in heavy breasted women.  The assessment identified a total of 3 comparative trial reports, including 2 RCTs, of IMRT in breast cancer.  The assessment found that, in large breasted patients treatment to the whole breast with standard tangential fields may produce rather inhomogeneous dose distributions.  This may lead to increased late skin toxicity (poor cosmesis, fibrosis, pain).  Two RCTs (1 reported as abstract only) and 1 retrospective comparison of IMRT with conventional external radiotherapy confirm that IMRT reduces the frequency of skin complications.  No improvement in overall quality of life could be demonstrated using standard techniques.  The assessment stated that long term studies are required to assess the risk of induction of a secondary tumor in the contralateral breast after IMRT before introduction into common practice.

Lung Cancer

An assessment from the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2006) concluded that available data are insufficient to determine whether IMRT is superior to 3D CRT for improving health outcomes of patients with lung cancer.  The assessment identified no studies that directly compared health outcomes of IMRT with health outcomes of 3D CRT for lung cancer, using concurrent or historical controls.  The report noted that the only available single-arm study of IMRT for lung cancer, a dose-escalation trial, closed for excessive toxicity after 5 patients received 84 Gray.

Other Indications

Many of the technical advances associated with the delivery of external-beam radiotherapy, including IMRT, have been accepted without formal evaluation of their impact on patient-related outcomes, largely because the evolution of radiotherapy has been on empirical grounds wherein an improvement in the distribution of radiation dose is seen as necessarily beneficial.  It is not as clear, however, that increased prescribed doses of radiation are necessarily beneficial.  A key question of debate is whether indications for IMRT are established based solely upon results of dosimetric planning studies, or whether well-designed clinical outcome studies are necessary to prove the benefits of IMRT over standard 3D CRT for each of IMRT's potential applications. 

The benefit of IMRT in rests in its potential to increase the therapeutic ratio by allowing, in theory, the delivery of higher doses of radiation with little or no increase in normal tissue complications.  These goals are achieved by more accurately targeting the radiation, and by reducing the irradiated volume to vital structures.  The potential risks of IMRT lie in these reduced margins (given the uncertainties associated with tumor delineation, organ movement, patient set-up variation) and in the tolerance of small volumes of normal tissue to high-dose treatment.  Briefly stated, should the treatment volumes be conformed too tightly to the contour, uncertainties in treatment reproducibility may lead to geographic "misses" of the target.  In addition, dose escalation beyond the tolerance of normal tissues may increase late complications and reduce the therapeutic ratio, and exposure of more normal tissue to modest doses peripheral to the target volume may increase treatment-induced oncogenesis.

Guerro-Urbano et al (2004) systematically reviewed the evidence of the effectiveness of IMRT in cancer.  The investigators found that dosimetric planning studies have demonstrated which tumor types have the largest potential gains, and small clinical studies are beginning to report short-term outcome data from patients.  "Most of these reports are small Phase I or Phase II trials where there has been no true comparison of IMRT with conventional radiotherapy technique."  The investigators note that, because "a better dose distribution does not necessarily correlate with better clinical outcome or improved sparing associated with improved side effect profile and/or improvements in quality of life", IMRT "should be tested head to head with conventional radiotherapy techniques where possible."

A structured review of current evidence for IMRT (Maceiras-Rozas et al, 2005) prepared for the Galician Agency for Health Technology Assessment concluded that the scientific evidence on the effectiveness and security of IMRT in comparison with CRT is scarce and of low quality, which limits establishment of rigorous conclusions.  The evidence review identified studies comparing IMRT to CRT that met their predetermined quality criteria.  The evidence review summarized the results of studies of IMRT for prostate cancer and head and neck cancer that met these predetermine criteria.  There were no studies of IMRT for other indications that met their previously established criteria.  The evidence review concluded that prospective comparative studies are necessary to evaluate the effectiveness and cost-effectiveness of IMRT in comparison with CRT.

Guidelines from the National Cancer Institute (2005) on the use of IMRT in clinical trials summarize the current state of the evidence supporting IMRT.  The guidelines state that "IMRT is still a nascent technology."  The guidelines state: "Currently, most published reports on the clinical use of IMRT are single institution studies, and are either treatment planning studies for a limited number of cases showing the improvement in dose distributions generated by IMRT, or dosimetric studies confirming IMRT treatment.  There are no published reports at present of prospective randomized clinical studies involving IMRT, and this lack of information clearly limits our knowledge of the effect of the use of IMRT on clinical outcomes."  The guidelines state that, although IMRT has potential advantages in physical dose distribution with IMRT, and therefore the potential for improvement in patient outcomes, there exists concern for actual IMRT treatment execution.  The guidelines discussed a number of specific concerns, including the potential to miss a tumor (or at least underdose a portion of the tumor) and/or to have significant high dose volumes in the normal tissues.  Another specific concern is that the widespread use of IMRT could lead to an increased incidence of RT associated carcinomas due to the larger volume of normal tissue exposed to low doses and the increase in whole body doses as a result of the increased doses of radiation required for delivery of IMRT (NCI, 2005).  

An assessment of IMRT by the Belgian Health Care Knowledge Center (KCE) (Van den Steen et al, 2007) found that, in general, more long-term data are needed for IMRT treated patients, to confirm any survival advantage and to assess the increased risk of secondary malignancies in comparison with standard external radiotherapy techniques.  Manufacturers and users of IMRT hardware and software should be made more aware of this risk of induction of secondary malignancies, and product improvement is to be stimulated.

Over the next decade, prospective, RCTs will clarify the role of IMRT in radiation oncology (ACCC, 2003).  The issues explored will include which tumor sites are appropriate for IMRT treatment and the total maximum body dose to the patient for specific beam plans.

A number of groups have been created to help foster successful IMRT clinical trials.  In 1999, the National Cancer Institute funded the Advanced Technology Radiation Therapy Quality Assurance Review Consortium.  This group will develop guidelines for using IMRT techniques in national clinical trials.  Protocol requirements for IMRT treatment delivery were agreed upon by the committee chairs of the NCI-funded clinical trial groups at a meeting held in Bethesda, MD, on June 20, 2002, and the required nomenclature has been published in the NCI IMRT Working Group Report (2001).

In a phase II clinical study, Rochet and colleagues (2011) will evaluate the toxicity of whole abdominal IMRT in patients with advanced ovarian cancer.  The OVAR-IMRT-02 study is a single-center one-arm trial.  A total of 37 patients with optimally debulked ovarian cancer stage FIGO III (International Federation of Gynecology and Obstetrics) having a complete remission after chemotherapy will be treated with intensity-modulated whole abdominal radiotherapy (WAR) as a consolidation therapy.  A total dose of 30 Gy in 20 fractions of 1.5 Gy will be applied to the entire peritoneal cavity including the liver surface and the pelvic and para-aortic node regions.  Organ at risk are kidneys, liver (except the 1 cm-outer border), heart, vertebral bodies and pelvic bones.  Primary endpoint is tolerability; secondary objectives are toxicity, quality of life, progression-free and overall survival.  Intensity-modulated WAR provides a new promising option in the consolidation treatment of ovarian carcinoma in patients with a complete pathologic remission after adjuvant chemotherapy.  Further consequent studies will be needed to enable firm conclusions regarding the value of consolidation radiotherapy within the multi-modal treatment of advanced ovarian cancer.

Diffuse Intrinsic Brainstem/Pontine Glioma

Hu and associates (2016) stated that diffuse brainstem glioma is a devastating disease with very poor prognosis.  The most commonly used radiological treatment is conventional fractionated radiation.  So far, there is no meta-analysis or systematic review available that evaluated the benefits or harms of radiation in people with diffuse brainstem glioma.  In a Cochrane review, these investigators evaluated the effects of conventional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy techniques) for newly diagnosed diffuse brainstem gliomas in children and young adults aged 0 to 21 years.  These investigators searched the Cochrane Central Register of Controlled Trials (Central), Medline/PubMed, and Embase to August 19, 2015.  They scanned conference proceedings from the International Society for Pediatric Oncology (SIOP), International Symposium on Pediatric Neuro-Oncology (ISPNO), Society of Neuro-Oncology (SNO), and European Association of Neuro-Oncology (EANO) from January 1, 2010 to August 19, 2015.  They searched trial registers including the International Standard Randomized Controlled Trial Number (ISRCTN) Register, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and the register of the National Institutes of Health to August 19, 2015.  They imposed no language restrictions.  All RCTs, quasi-randomized trials (QRCTs), or controlled clinical trials (CCTs) that compared conventional fractionated radiotherapy (with or without chemotherapy) versus other therapies (including different radiotherapy techniques) for newly diagnosed diffuse brainstem glioma in children and young adults aged 0 to 21 years were selected for analysis.  Two review authors independently screened studies for inclusion, extracted data, assessed the risk of bias in each eligible trial, and conducted GRADE assessment of included studies.  They resolved disagreements through discussion; and performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions.  These researchers identified 2 RCTs that fulfilled their inclusion criteria.  The 2 trials tested different comparisons.  One multi-institutional RCT included 130 participants and compared hyper-fractionated radiotherapy (6-week course with twice-daily treatment of 117 cGy per fraction to a total dose of 7,020 cGy) with conventional radiotherapy (6-week course with once-daily treatment of 180 cGy per fraction to a total dose of 5,400 cGy).  The median time overall survival (OS) was 8.5 months in the conventional group and 8.0 months in the hyper-fractionated group.  These researchers detected no clear evidence of effect on OS or event-free survival (EFS) in participants receiving hyper-fractionated radiotherapy compared with conventional radiotherapy (OS: hazard ratio (HR) 1.07, 95 % CI: 0.75 to 1.53; EFS: HR 1.26, 95 % CI 0.83 to 1.90).  Radiological response (risk ratio (RR) 0.94, 95 % CI: 0.54 to 1.63) and various types of toxicities were similar in the 2 groups.  There was no information on other outcomes. According to the GRADE approach, the authors judged the quality of evidence to be low (i.e., further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate) for OS and EFS, and very low (i.e., the authors were very uncertain about the estimate) for radiological response and toxicities.  The second RCT included 71 participants and compared hypo-fractionated radiotherapy (39 Gy in 13 fractions over 2.6 weeks, 3 Gy per fraction) with conventional radiotherapy (54 Gy in 30 fractions over 6 weeks, 1.8 Gy per fraction).  This trial reported a median OS of 7.8 months for the hypo-fractionated group and 9.5 months for the conventional group.  It reported a progression-free survival (PFS) of 6.3 months for the hypo-fractionated group and 7.3 months for the conventional group.  They found no clear evidence of effect on OS (HR 1.03, 95 % CI: 0.53 to 2.01) or PFS (HR 1.19, 95 % CI: 0.63 to 2.22) in participants receiving hypo-fractionated radiotherapy when compared with participants receiving conventional radiotherapy.  The mainly observed adverse effect was local erythema and dry desquamation especially behind the auricles.  There were some other toxicities, but there was no statistically significant difference between treatment groups.  There was no information on other outcomes.  These investigators judged the quality of evidence to be moderate (i.e., further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate) for OS, and low for PFS and toxicities.  It should be mentioned that the sample size in this RCT was small, which could lead to insufficient statistical power for a clinically relevant outcome.  The authors concluded that they could make no definitive conclusions from this review based on the currently available evidence.  Further research is needed to establish the role of radiotherapy in the management of newly diagnosed diffuse brainstem glioma in children and young adults.  Future RCTs should be conducted with adequate power and all relevant outcomes should be taken into consideration.  Moreover, international multi-center collaboration is encouraged.  Considering the potential advantage of hypo-fractionated radiotherapy to decrease the treatment burden and increase the quality of remaining life, the authors suggested that more attention should be paid to hypo-fractionated radiotherapy.

Freese and colleagues (2017) noted that diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric disease, with a median survival of  less than 1 year.  These investigators  reviewed their institution's DIPG experience over an 8-year interval and performed a systematic review of the literature, specifically evaluating reports of re-irradiation (reRT) for DIPG.  These researchers retrospectively reviewed the medical records of 26 patients who underwent definitive IMRT for DIPG at a single institution between 2007 and 2015; 3 of these patients underwent reRT for progressive disease.  Clinical endpoints, including PFS and OS, were assessed.  The authors then performed a thorough PubMed search of the literature discussing reRT for patients with DIPG; 24 of the 26 patients (92 %) completed the initial course of radiation (54 Gy in 1.8-Gy fractions using IMRT).  Median age at diagnosis was 6.0 years (range of 2.0 to 26.5).  With respect to systemic therapy, 1 (4.2 %) received no systemic therapy, 1 (4.2 %) received concurrent systemic therapy alone, 4 (16.7 %) received adjuvant therapy alone, and 18 (75 %) received a combination of concurrent and adjuvant therapy.  Median follow-up time was 11 months from the date of initial diagnosis.  Median OS for the cohort was 12 months, with a 1-year OS of 51 %.  The 3 patients who underwent reRT received 20 Gy in 10 daily fractions using IMRT alone with no treatment toxicity noted.  The authors concluded that radiation therapy is essential in the definitive management of DIPG.  With advances in treatment techniques, it is feasible to re-irradiate select patients with progressive disease; however, further research is needed to optimize dose, delivery, and patient selection in the recurrent/progressive setting.  In the future, it may be reasonable to propose more focal delivery of reRT (i.e., hypo-fractionated radiation) in select patients with the goal of reducing treatment time and providing effective palliation.

Image-Guided Radiotherapy

An assessment by the Belgian Health Care Knowledge Centre (KCE) (Van den Steen et al, 2007) concluded that more frequent imaging for guidance of IMRT is expected to further improve the efficacy and safety of IMRT, particularly in targets showing internal movement, e.g., in case of prostate cancer.  The assessment noted that the high degree of dose conformality achievable with IMRT creates a challenge for the radiotherapist to accurately delineate the target and the organs at risk (Van den Steen et al, 2007).  It is also a challenge to reduce the variation between clinicians.  Another challenge is the accuracy and precision with which the target volume and critical structures can be localized day to day, especially for indications other than head and neck.  The assessment noted that image guided corrections for day to day set up errors or for internal organ motion have become important issues.  The report also stated that intrafraction organ motion has become the limiting factor for margin reduction around the clinical target volume.  Image-guided radiotherapy (IGRT) is therefore a growth area.  The report noted that recent reviews on the subject have been published (citing Balter and Kessler, 2007; Dawson and Jaffray, 2007).

In some cases, a treatment preparation session may be necessary to mold a special device that will help the patient maintain an exact treatment position (Van den Steen et al, 2007).  Prior to treatment, the patient's skin may be marked or tattooed with colored ink to help align and target the equipment.  Radio-opaque markers may also be use (e.g., gold marker seeds in case of prostate treatment).

The report observed that, in IMRT, images are acquired for 3 reasons (Van den Steen et al, 2007):

1. Treatment planning, i.e., delineation of target and normal structures, typically created once prior to treatment.  The report stated that IMRT planning may include positron emission tomography (PET) and magnetic resonance imaging (MRI).  Typically, IMRT sessions begin about 1 week after simulation.  The report noted that it is expected this model will become outdated and be replaced by image-guided IMRT.
2. Image guidance and/or treatment verification, for setup verification and correction.  The report stated that some treatment machines already have an integrated scanner integrated.  The report stated that the frequency of imaging (CT or other) will vary based on characteristics of the tumor dose gradient and the patient, e.g., daily (often on-line) imaging can be required for a pelvic irradiation of an obese patient.
3. Follow-up of treatment response, CT, MRI and PET scans are often used for this purpose.

A report on image-guided intensity modulated radiation therapy Australian Safety and Efficacy Register of New Interventional Procedures - Surgical (ASERNIP-S) (Zamora, et al. (2010) concluded: "Further comparative evidence is required to establish the effectiveness of image-guided intensity-modulated radiation therapy. However, the current evidence available suggests that by reducing treatment related uncertainties, image-guided intensity-modulated radiation therapy may allow the reduction of treatment margins, thus reducing exposure to radiation of normal tissue surrounding the tumour and treatment-related toxicities. This may allow for safe additional dose escalation to the tumour, increasing the likelihood of tumour eradication." 

The Calypso 4D Localization System (Calypso Medical Technologies, Seattle, WA) is an example of a device for intrafraction image guidance.  The system is intended to improve the accuracy of radiotherapy by tracking the exact position and motion of target organs during daily treatments (CMS, 2008).  Beacon electromagnetic transponders are implanted passive resonant circuits, encapsulated in a hermetically sealed, medical grade biocompatible glass capsule.  These miniature electrical circuits are comprised of a copper coil, ferrite rod and capacitor.  Each electromagnetic transponder is approximately the size of a small grain of rice.  Beacon transponders are activated by the Calypso 4D Localization System when the transponders are positioned directly under the system’s electromagnetic array.  The Calypso System is an electromagnetic tumor target positioning technology used in radiation therapy delivery.  The electromagnetic transponders emit an electromagnetic signal which is detected, measured, and used by the Calypso System to determine the location of the tumor target relative to the linear accelerator beam.  Electromagnetic transponders are implanted into the tumor target tissue prior to the delivery of radiation therapy.  This technology is intended to provide clinicians with continuous position information of a tumor target during external beam radiation therapy with sub-millimeter accuracy. 

Kupelian and colleagues (2007) reported the technical ability of the Calypso system to track the movement of the prostate.  The system was used at 5 centers to position 41 patients over a full course of therapy.  Electromagnetic positioning was compared to set-up using skin marks and to stereoscopic X-ray localization of the transponders.  Continuous monitoring was performed in 35 patients.  The authors concluded that the Calypso System is a clinically efficient and objective localization method for positioning prostate patients undergoing radiotherapy.

Proponents of the Calypso 4D Localization System argue that use of this tumor target position information can improve radiation treatment accuracy, thereby reducing the likelihood of radiation induced complications and improving the effectiveness of radiation therapy.  The Calypso system was cleared for marketing by the FDA based on a 510(k) application for use in prostate cancer.  Thus, the manufacturer was not required to provide the evidence of efficacy necessary to support a premarket approval application.  There are no published clinical trials demonstrating that the use of the Calypso system improves clinical outcomes of radiation therapy.  This technology is relatively new, and clinical studies are currently ongoing (Aral et al, 2010).

Sandler et al (2010) examined if patient-reported quality of life after high-dose external beam IMRT for prostate cancer can be improved by decreasing PTV margins while using real-time tumor tracking.  Study patients underwent radiotherapy with nominal 3-mm margins and electromagnetic real-time tracking.  Morbidity was assessed before and at the end of radiotherapy using Expanded Prostate Cancer Index Composite (EPIC) questionnaires.  Changes in scores were compared between the Assessing Impact of Margin Reduction (AIM) study cohort and the comparator Prostate Cancer Outcomes and Satisfaction with Treatment Quality Assessment (PROST-QA) cohort, treated with conventional margins.  The 64 patients in the prospective AIM study had generally less favorable clinical characteristics than the 153 comparator patients.  Study patients had similar or slightly poorer pre-treatment EPIC scores than comparator patients in bowel, urinary, and sexual domains.  AIM patients receiving radiotherapy had less bowel morbidity than the comparator group as measured by changes in mean bowel and/or rectal domain EPIC scores from pre-treatment to 2 months after start of treatment (-1.5 versus -16.0, p = 0.001).  Using a change in EPIC score greater than 0.5 baseline standard deviation as the measure of clinical relevance, AIM study patients experienced meaningful decline in only 1 health-related quality of life domain (urinary) whereas decline in 3 health-related quality of life domains (urinary, sexual, and bowel/rectal) was observed in the PROST-QA comparator cohort.  The authors concluded that prostate cancer patients treated with reduced margins and tumor tracking had less radiotherapy-related morbidity than their counterparts treated with conventional margins.  They stated that highly contoured IMRT shows promise as a successful strategy for reducing morbidity in prostate cancer treatment.

Helical tomotherapy is a novel 360-degree radiation treatment modality that combines a helical computed tomography (CT) scanner for online imaging with a linear accelerator that delivers IMRT.  It is available by means of the TomoTherapy Hi-ART System.  The on-board CT scanner provides image guidance and dose verification, allowing adjustments for slight, but critical, changes in the shape and position of the tumor.  It is intended to be a substitute for the curative or palliative treatment of specific cancers using conventional methods.  The novel features of the Hi-ART system supposedly offer the following advantages over conventional radiotherapy:

• Faster operating times
• Lower doses to adjacent critical structures, and therefore fewer adverse effects
• More accurate pre-treatment localization of the target on a daily basis (the mega-voltage CT images provide greater anatomical detail)
• More precise conformal dose coverage of the tumor, and hence the possibility of higher doses per session and shorter courses of treatment.

Helical tomotherapy is one form of IMRT.  However, the function of IGRT, i.e., the capability for 3D cross-sectional imaging available on a linear accelerator, may also be combined with other IMRT systems; currently available products are the Elekta Synergy system and the Varian On-Board imager system.  The Hi-ART system offers a fully integrated IMRT/IGRT package with CT imaging.

Research on the physical and dosimetric aspects suggests that helical tomotherapy may be superior to conventional radiotherapy in terms of radiation-dose distribution (including avoidance of sensitive structures) and dose-rate.  However, no full RCTs have yet been published.  A United Kingdom assessment concluded that "[a]lthough the Hi-ART system is novel it may not represent a significant breakthrough and the case for the Hi-ART system versus other IMRT systems (e.g., Elekta and Varian) has not yet been made" (National Horizon Scanning Centre, 2006).

The RayPilot System (formerly known as the Micropos 4DRT System) is another 4D intra-fraction image guidance system that has not yet received FDA approval.  Similar to the Calypso 4D Localization System, the RayPilot System entails the implantation of markers into the tumor, i.e., the prostate gland.  Continuous monitoring of the markers is then used for intra-fraction guidance.

Kindblom et al (2009) noted that the Micropos 4DRT system is being developed to provide accurate, precise, objective, and continuous target localization during radiotherapy.  This study involved the first in-vivo use of the system, aiming to evaluate the localization accuracy of this electromagnetic positioning technique compared with radiographic localization and to assess its real-time tracking ability.  An active positioning marker was inserted in the prostatic urethra of 10 patients scheduled to receive radiotherapy for localized prostate cancer.  A receiving sensor plate (antennae system) was placed at a known position in the treatment table-top.  Initial in-vivo system calibrations were performed in 3 subjects.  Ten additional patients were then enrolled in a study arm that compared radiographic transponder location to radio-transponder location simultaneously acquired by the Micropos 4DRT system.  Frontal and side radiographs were taken with the radiopaque transponder located at 3 different positions within the prostatic urethra.  The transponder insertions were all successful and without complications.  Comparison of the transponder location as per the Micropos 4DRT system with the radiographic transponder localization showed an average (+/-SD) absolute and relative 3D difference of 2.7 +/- 1.2 and 1.7 +/- 1.0mm, respectively.  Continuous transponder tracking capability was also demonstrated.  The authors concluded that electromagnetic positioning using the Micropos transponder system is feasible in-vivo.  Evaluation of this novel non-ionizing localization system, in this study using a transponder positioned in the prostatic urethra, indicated transponder localization accuracy to isocenter comparable with X-ray localization of a radiopaque marker.  This was a feasibility study.  The clinical value of this novel electromagnetic positioning system needs to be validated by well-designed studies.

Shah et al (2011) stated that in the past decade, techniques to improve radiotherapy delivery, such as IMRT, IGRT for both inter- and intra-fraction tumor localization, and hypo-fractionated delivery techniques such as stereotactic body radiation therapy, have evolved tremendously.  This review article focused on electromagnetic tracking in radiation therapy.  Electromagnetic tracking is still a growing technology in radiation oncology and, as such, the clinical applications are limited, the expense is high, and the reimbursement is insufficient to cover these costs.  At the same time, current experience with electromagnetic tracking applied to various clinical tumor sites indicates that the potential benefits of electromagnetic tracking could be significant for patients receiving radiation therapy.  Daily use of these tracking systems is minimally invasive and delivers no additional ionizing radiation to the patient, and these systems can provide explicit tumor motion data.  Currently, work is being done to incorporate electromagnetic tracking in several sites (e.g., breast, central nervous system, cervix, liver, lung, and pancreas) outside of the prostate (The Calypso 4D Localization System is approved by the FDA for use in prostate and post-prostatectomy prostate bed radiation therapy).  Hopefully, while these preliminary investigations are not yet FDA-approved, viable options to treat these sites will become clinically available within the next several years based on this early work.  The authors concluded that although there are a number of technical and fiscal issues that need to be addressed, electromagnetic tracking systems are expected to play a continued role in improving the precision of radiation delivery.  There are a number of technical and fiscal issues that need to be addressed in the near term, however, to ensure the success of these technologies in improving patient care over the next 10 years and beyond.

According to a coding guide from the American Society for Therapeutic Radiation and Oncology (ASTRO, 2007), IMRT is clinically indicated when highly conformal dose planning is required.  IMRT planning may be clinically indicated when one or more of the following conditions are present:

• An immediately adjacent area has been previously irradiated and abutting portals must be established with high precision
• Dose escalation is planned to deliver radiation doses in excess of those commonly utilized for similar tumors with convetional treatment
• The target volume is concave or convex, and the critical normal tissues are within or around that convexity or concavity
• The target volume is in close proximity to critical structures that must be protected
• The volume of interest must be covered with narrow margins to adequately protect immediately adjacent structures.

According to the coding guide (ASTRO, 2007), the most common sites that currently support the use of IMRT include:

• Carcinoma of the prostate
• Primary, metastatic or benign tumors of the central nervous system, including the brain, brain stem, and spinal cord
• Primary, metastatic tumors of the spine where spinal cord tolerance may be exceeded by conventional treatment
• Primary, metastatic or benign lesions to the head and neck area, including:
  
  
  • Aerodigestive tract
  • Orbits
  • Salivary glands
  • Sinuses
  • Skull base
     
• Re-irradiation that meets the requirements for medical necessity (as noted above).
• Selected cases of thoracic and abdominal malignancies
• Selected cases (i.e., not routine) of breast cancers with close proximity to critical structures
• Other pelvic and retroperitoneal tumors that meet requirements for medical necessity (as noted above).

IMRT may be necessary in lung cancer cases involving bilateral mediastinal involvement, extension to the midline of the mediastinum, cardiac involvement, or tumor abutting or involving vertebrae or brachial plexus, or great vessels.

Although not routinely indicated in breast cancer, IMRT may be necessary when more than 2 gantry angles are required to meet dose constraints or when internal mammary nodes must be treated.

IMRT is also indicated in pancreatic cancer, anal cancer and for postoperative use in endometrial, cervical and advanced rectal cancer.

Concurrent Chemotherapy and Intensity-Modulated Radiotherapy for the Treatment of Stage II Nasopharyngeal Carcinoma

Su and associates (2016) examined the efficacy of concurrent chemoradiotherapy (CCRT) for stage II nasopharyngeal carcinoma (NPC) patients treated with IMRT.  A total of 249 patients were retrospectively reviewed.  All patients were treated with IMRT; 143 patients treated with CCRT and 106 patients treated with IMRT alone.  With a median follow-up of 59.4 months, adding CCRT did not statistically significantly improve the 5-year OS (89.7 % versus 99.0 %, p = 0.278), locoregional relapse-free survival (LRRFS) (94.8 % versus 89.3 %, p = 0.167), and distant metastases-free survival (DMFS) (93.4 % versus 97.5 %, p = 0.349).  Patients with CCRT significantly experienced more acute toxic effects.  The main grades 3 to 4 toxicity reactions were mucositis (26.6 % versus 15.1 %, p = 0.03) and leukopenia/neutropenia (9.1 % versus 0.9 %, p = 0.005).  In subgroup analysis of patients with concurrent platinum single-agent chemotherapy the 5-year OS (98.4 % versus 81.9 %, p = 0.013) and DMFS (96.9 % versus 84.4 %, p = 0.043) of patients with platinum every 3 weeks (Q3W) were significantly higher than those with platinum weekly (QW) and no significant difference for LRFS (96.8 % versus 90.4 %, p = 0.150).  The authors concluded that CCRT did not improve the survival of patients with stage II NPC but increased the acute toxicity reactions.  Patients with platinum Q3W improved the 5-year OS and DMFS, compared with those with platinum QW.

In a systematic review and meta-analysis, Liu and colleagues (2018) compared clinical outcomes of CCRT with those of radiotherapy alone for stage II NPC in the IMRT era.  These researchers comprehensively searched PubMed, Embase, and the Cochrane Library to identify eligible studies; OS, PFS, DMFS, LRRFS with HRs, and toxicities with ORs were analyzed.  A total of 7 studies met the criteria, with 1,302 patients who were treated with IMRT alone or IMRT plus concurrent chemotherapy.  No significant survival benefit was shown by CCRT regardless of OS (HR = 1.17, 95 % CI: 0.73 to 1.89, p = 0.508), PFS (HR = 0.76, 95 % CI: 0.38 to 1.50, p = 0.430), DMFS (HR = 0.89, 95 % CI: 0.33 to 2.41, p = 0.816), or LRRFS (HR = 1.03, 95 % CI: 0.95 to 1.12, p = 0.498).  Additionally, CCRT notably increased the risk of acute grade 3 to 4 leukopenia (OR = 4.432, 95 % CI: 2.195 to 8.952, p < 0.001), compared to IMRT alone.  The authors concluded that adding concurrent chemotherapy to IMRT led to no survival benefit and increased acute toxicity reactions for stage II NPC.

Intensity-Modulated Radiation Therapy and Doxorubicin for the Treatment of Thyroid Cancer

Romesser et al (2021) stated that the use of external-beam radiotherapy (EBRT) for locally advanced non-anaplastic thyroid cancer remains controversial.  In a prospective, non-randomized, phase-II clinical trial, these researchers examined the effectiveness and tolerability of IMRT with or without concurrent chemotherapy (CC) in patients with locally advanced thyroid cancer.  This study examined the use of IMRT with or without concurrent doxorubicin in patients with gross residual or unresectable non-anaplastic thyroid carcinoma.  The primary endpoint was 2-year locoregional PFS.  Secondary end points included OS, safety, patient-reported outcomes, and functional outcomes.  A total of 27 patients were enrolled: 12 (44.4 %) with unresectable disease and 15 (55.6 %) with gross residual disease.  The median follow-up was 45.6 months (inter-quartile range [IQR] of 42.0 to 51.6 months); the 2-year cumulative incidences of locoregional PFS and OS were 79.7 % and 77.3 %, respectively.  The rate of grade-3 or higher acute and late toxicities was 33.4 %.  There were no significant functional differences 12 months after treatment (assessed objectively by the modified barium swallow study).  Patient-reported QOL in the experimental group was initially lower but returned to the baseline after 6 months and improved thereafter.  In a post-hoc analysis, CC with IMRT (CC-IMRT) resulted in significantly less locoregional failure at 2 years (no failure versus 50 %; p = 0.001), with higher rates of grade-2 or higher acute dermatitis, mucositis, and dysphagia but no difference in long-term toxicity, functionality, or patient-reported QOL.  The authors concluded that in light of the excellent locoregional control rates achieved with CC-IMRT and its acceptable toxicity profile as confirmed by functional assessments and patient-reported outcomes, CC-IMRT may be preferred over IMRT alone.  Moreover, these investigators stated that although this study was non-randomized and the sample was small (n = 27), these findings provided prospective data that suggested the need for more robust randomized studies as society guidelines are re-evaluated.

Neoadjuvant Intensity-Modulated Radiotherapy in Centrally Located Hepatocellular Carcinoma

Wu et al (2022) noted that centrally located hepatocellular carcinoma (HCC) is a special type of HCC whose outcome is unsatisfactory when treated with surgery alone.  No standard adjuvant or neoadjuvant treatment for this disease has been established that improves clinical outcomes.  In a prospective, non-randomized, single-center, single-group, phase-II clinical trial, these researchers examined the safety and effectiveness of adding neoadjuvant IMRT before surgery in patients with centrally located HCC.  This study was carried out between December 16, 2014, and January 29, 2019, at the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences in Beijing, China.  The last follow-up was on July 30, 2021.  Patients with centrally located HCC who underwent neoadjuvant IMRT and surgery were included in the analysis.  The primary endpoint was 5-year OS.  The secondary endpoints were tumor response to IMRT, 5-year disease-free survival (DFS), and treatment-related adverse events (AEs).  A total of 38 patients (mean [SD] age of 55.6 [9.3] years; 35 men [92.1 %] individuals) completed the prescribed neoadjuvant IMRT without interruption.  Radiographic tumor response to IMRT before surgery included partial response (PR; 16 [42.1 %]) and stable disease (SD; 22 [57.9 %]); 13 patients (34.2 %) achieved major pathological response, of which 5 (13.2 %) achieved pathologic complete response (CR).  With a median follow-up of 45.8 months, the median OS was not reached, and the OS rates were 94.6 % at 1 year, 75.4 % at 3 years, and 69.1 % at 5 years.  The median DFS was 45.8 months, and DFS rates were 70.3 % at 1 year, 54.1 % at 3 years, and 41.0 % at 5 years.  Radiotherapy-related grade-3 AEs were observed in 3 patients (7.9 %); 19 operative complications developed in 13 patients (34.2 %), including grade-I to grade-II complications in 12 patients (31.6 %) and grade-IIIa complication in 1 patient (2.6 %).  No grade-IIIb or higher operative complications were observed.  The authors concluded that the findings of this study suggested that neoadjuvant IMRT plus surgery was effective and well-tolerated in patients with centrally located HCC.  These researchers stated that these data may inform a future randomized clinical trial of this new treatment strategy.

Squamous Cell Carcinoma of the Glottic Larynx

Razavian et al (2023) stated that early-stage squamous cell carcinoma (SCC) of the glottic larynx is commonly treated with conventional 2D or 3D radiation therapy (CRT).  Despite its use in other HNCs, IMRT remains controversial in this patient population.  These investigators carried out a systematic review by querying 3 databases (PubMed, Embase, Web of Science) for studies published between January 1, 2000 and September 2, 2022.  Included studies reported outcomes in at least 10 patients treated with IMRT for early-stage glottic cancer.  Data were extracted and reported following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.  Pooled outcomes were estimated using random-effects models.  Primary outcome was the rate of local failure (LF) following IMRT.  Secondary outcomes included rates of regional failure (RF) following IMRT, and rates of LF and RF following CRT.  A total of 15 studies (14 retrospective, 1 prospective) consisting of 2,083 patients were identified.  IMRT was used in 873 patients (64 % T1, 28 % T2).  Multiple treatment (partial larynx, single vocal cord carotid-sparing) and image-guided RT techniques were used.  The pooled crude rate of LF was 7.6 % (95 % CI: 3.6 % to 11.5 %) and actuarial LF rates at 3- and 5- years were 6.3 % (95 % CI: 2.2 % to 10.3 %) and 9.0 % (95 % CI: 4.4 % to 13.5 %), respectively.  The pooled crude rate of RF after IMRT was 1.5 % (95 % CI: 0.5 % to 2.5 %).  On meta-regression analysis, increased rate of LF was significantly associated with T2 disease (p < 0.001) and grade 2-3 histology (p < 0.001).  Treatment with CRT was reported in 738 patients (76 % T1, 22 % T2).  Among the studies reporting outcomes of both modalities, there was no significant difference in LF (log odds ratio [OR]; p = 0.12) or RF (log OR; p = 0.58) between IMRT or CRT.  The authors concluded that in patients with early-stage glottic cancer, retrospective data suggested local and regional control were similar for patients treated with IMRT and CRT.  Moreover, these researchers stated that additional prospective studies with uniform methods of volume delineation and image-guidance are needed to confirm the effectiveness of IMRT.

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Appendix

Aetna considers IMRT medically necessary for the following indications when there is a concern about damage to surrounding critical structures with the use of external beam or 3D conformal radiation therapy:

• Anal cancer; or
• Anaplastic thyroid cancer; or
• Brain tumors in close proximity to critical structures; or
• Esophageal cancer where dose exceeds 50 Gy; or
• Gallbladder cancer where dose exceeds 50 Gy; or
• Head and neck cancer excluding T1 and T2 glottic cancer; or
• Left breast cancer if the lesion is in close proximity to the heart or other cardiovascular structures, where 3D CRT would exceed acceptable constraints; or
• Lung cancer if the lesion is in close proximity to the heart or other critical structures; or
• Pancreatic cancer where dose exceeds 50 Gy; or
• Postoperative radiation to pelvis for endometrial cancer; or
• Prostate cancer; or
• T4 rectal cancer where the treating volume incorporating the external iliac and inguinal lymph node chains.

Aetna considers IMRT experimental and not medically necessary for right breast cancer. Aetna considers IMRT experimental and investigational for all other indications.

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References