Coverage Policy Manual
Policy #: 2009035
Category: Radiology
Initiated: September 2003
Last Review: April 2018
  Intensity Modulated Radiation Therapy (IMRT), Lung

Description:
Randomized clinical trials have shown that postoperative radiation therapy improves outcomes for operable patients with lung cancer. Adding radiation to chemotherapy also improves outcomes for those with inoperable lung tumors that have not metastasized beyond regional lymph nodes.  Intensity modulated radiation therapy (IMRT) refers to a technique of conformal radiation planning and delivery that is designed to better target the lesion, thus sparing surrounding normal tissue and ultimately limiting side effects. The reduced morbidity may also permit higher dosing to the target lesions, thus reducing the risk of local recurrence. 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. Specifically, in IMRT, non-uniform intensities are assigned to tiny subdivisions of beams, called "beamlets," enabling custom design of optimum dose distributions.
 
The decision process for using IMRT requires an understanding of accepted practices that take into account the risks and benefits for such therapy compared to conventional treatment techniques.  While IMRT technology may empirically offer advantages over conventional or 3-Dimensional conformal radiation, a comprehensive understanding of all consequences is required before applying this technology.  
 
There is considerable documentation required in the medical record to support the use of IMRT.
 
This policy was developed to address lung cancer specifically and was separated from general IMRT policy in place since 2003.
 

Policy/
Coverage:
Intensity modulated radiation therapy (IMRT) of the lung, including, but not limited to, its use as a technique of dose escalation in the treatment of lung cancer, does not meet primary coverage criteria for effectiveness.  This use of IMRT is the subject of several ongoing clinical trials to determine effectiveness.
 
For contracts without primary coverage criteria the use of intensity modulated radiation therapy (IMRT) of the lung, including, but not limited to, its use as a technique of dose escalation in the treatment of lung cancer, is considered to be investigational.  Investigational services are exclusion in the member benefit certificate.   
 

Rationale:
Over the past several decades, methods to plan and deliver radiation therapy have evolved in ways that permit more precise targeting of tumors with complex geometries. The relevant trials for lung cancers were done before contemporary radiation therapy methods evolved. They used two-dimensional treatment planning based on flat images, and radiation beams with cross-sections of uniform intensity that were sequentially aimed at the tumor along 2 or 3 intersecting axes. Collectively, these methods are termed conventional external beam radiation therapy (EBRT).
 
Treatment planning first evolved by using 3-dimensional images, usually from computed tomography (CT) scans, to delineate the tumor, its boundaries with adjacent normal tissue, and organs at risk for radiation damage. These images, displayed from a “beam’s-eye view,” were used to shape each of several beams (e.g., with compensators, blocks, or wedges) to conform to the patient’s tumor geometry perpendicular to the beam’s axis. Computer algorithms were developed to estimate cumulative radiation dose delivered to each volume of interest by summing the contribution from each shaped beam. Methods also were developed to position the patient and the radiation portal reproducibly for each fraction, and immobilize the patient, thus maintaining consistent beam axes across treatment sessions. However, “forward” planning used a trial and error process to select treatment parameters (the number of beams and the intensity, shape, and incident axis of each). The planner/therapist modified one or more parameters and re-calculated dose distributions, if analysis predicted underdosing for part of the tumor or overdosing of nearby normal tissue.
 
Furthermore, since beams had uniform cross-sectional intensity wherever they bypassed shaping devices, it was difficult to match certain geometries (e.g., concave surfaces). Collectively, these methods are termed 3-dimensional conformal radiation therapy (3D-CRT).
 
Over the past decade, other methods were developed to permit beam delivery with non-uniform cross-sectional intensity. This often relies on a device (a multi-leaf collimator, MLC) situated between the beam source and patient, that moves along an arc around the patient. As it moves, a computer varies aperture size independently and continuously for each leaf. Thus, MLCs divide beams into narrow “beamlets,” with intensities that range from zero to 100% of the incident beam. With an alternative, termed TomoTherapy, a small radiation portal emitting a single narrow beam moves spirally around the patient, with intensity varying as it moves. Each method (MLC-based or TomoTherapy) is coupled to a computer algorithm for “inverse” treatment planning. The planner/radiotherapist delineates the target on each slice of a CT scan, and specifies the target’s prescribed radiation dose, acceptable limits of dose heterogeneity within the target volume, adjacent normal tissue volumes to avoid, and acceptable dose limits within the normal tissues. Based on these parameters and a digitally-reconstructed radiographic image of the tumor and surrounding tissues and organs at risk, computer software optimizes the location and shape of beam ports, and beam and beamlet intensities, to achieve the treatment plan’s goals. Collectively, these methods are termed intensity-modulated radiation therapy (IMRT).
 
Multiple studies have generated 3D-CRT and IMRT treatment plans from the same scans, then compared predicted dose distributions within the target and in adjacent organs at risk. Results of such planning studies show that IMRT improves on 3D-CRT with respect to conformality to, and dose homogeneity within, the target. Dosimetry using stationary targets generally confirms these predictions. Thus, radiation oncologists hypothesized that IMRT may improve treatment outcomes compared with those of 3D-CRT by one or more of the following mechanisms.
 
Increased conformality may permit escalated tumor doses without increasing normal tissue toxicity, and may thus improve local tumor control. Better dose homogeneity within the target may also improve local tumor control by avoiding underdosing (cold spots) within the tumor and may decrease toxicity by avoiding overdosing (hot spots). Finally, enhanced conformality for standard doses may reduce dose outside the target volume and thus decrease toxicity.
 
However, IMRT aims radiation at the tumor from many more directions, and thus subjects more normal tissue to low-dose radiation than occurs with conventional EBRT or 3D-CRT. This may increase late effects of radiation therapy. In addition, since lung tumors move as patients breathe, dosimetry with stationary targets may not accurately reflect doses delivered within target volumes and adjacent tissues in patients. Furthermore, treatment planning and delivery are more complex, time consuming, and labor-intensive for IMRT than for 3D-CRT. Thus, clinical studies must test whether IMRT improves tumor control or reduces acute and late toxicities, when compared with 3D-CRT. Testing this hypothesis requires direct comparative data on outcomes for separate groups of similar patients treated with each method.
Current methods and ongoing investigations seek to reduce positional uncertainty for tumors and adjacent normal tissues by various techniques. Patient immobilization cradles and skin or bony markers are used to minimize day-to-day variability in patient positioning.  It appears likely that respiratory motion alters the dose distributions actually delivered while treating patients from those predicted by plans based on static CT scans, or measured by dosimetry using stationary (non-breathing) targets. In addition, non-small cell lung cancer has more irregular, spiculated edges than many other tumors, including breast cancer. This precludes drawing tight margins on CT scan slices when radiation oncologists contour the tumor volume. It is unknown whether omitting some tumor cells or including some normal cells in the resulting target affects outcomes of 3D-CRT or IMRT. Another, more recent concern for highly conformal radiation therapy is the possibility that tumor size may change over the course of treatment as tumors respond or progress. Whether outcomes might be improved by repeating scans and modifying treatment plans accordingly (termed adaptive radiation therapy) is unknown.
 
These considerations emphasize the need to compare clinical outcomes rather than treatment plan predictions to determine whether one radiotherapy method is superior to another.
 
The literature search found no reports directly comparing health outcomes of IMRT with those of 3D-CRT for lung cancer treatment. There were no prospective comparative trials (randomized on non-randomized), and no prospective or retrospective single-arm studies of IMRT with similar groups of historical controls treated with 3D-CRT.
 
The literature search identified only 1 report on clinical outcomes of IMRT for patients with lung cancer. Holloway et al (2004) reported on a phase I dose escalation study that was terminated after the first 5 patients received 84 Gy in 35 fractions (2.4 Gy per fraction).  Treatment planning used combined CT and positron emission tomography for volumetric imaging, and treatment beams were gated to patients’ respiration. Acute toxicities included 1 patient with RTOG grade 2 dysphasia, 1 with grade 1 odynophagia, and 1 with grade 1 skin desquamation. In addition, 1 patient died of lung toxicity and was shown on autopsy to have bilateral diffuse pulmonary fibrosis with emphysema and diffuse alveolar damage. Of those who survived, 1 remained disease-free at 34 months, 2 developed metastases, and 1 developed an in-field recurrence.
 
Available evidence is insufficient to determine whether IMRT is superior to 3D-CRT for improving health outcomes of patients with lung cancer.
 
2006 Update
A literature search through November 2006 did not identify additional studies that would change the policy statement. These conclusions are based on the lack of studies with sufficient follow-up that compare IMRT to other forms of radiation therapy.
 
2007 Update
The policy was updated with a literature search using MEDLINE in December 2007.
No published trials were identified comparing IMRT with conventional approach. Thus the policy statement related to lung cancer remains unchanged.
 
2008 – 2009 Update
The policy was updated with a literature search using MEDLINE through January 2009. No randomized trials were identified in the search that compared IMRT to 3D-CRT for lung cancer.
 
As noted above, no randomized trials were identified that compared IMRT to 3D-CRT. Noting that the use of IMRT for in-operable non-small cell lung cancer (NSCLC) had not been well studied, Sura and colleagues (2008) reviewed their experience with IMRT for patients with inoperable NSCLC.  They reported a retrospective review of 55 patients with stage I-IIIB inoperable NSCLC treated with IMRT between 2001 and 2005. The study endpoints were toxicity, local control, and overall survival. With a median follow-up of 26 months, the 2-year local control and overall survival rates for stage I/II patients were 50% and 55%, respectively. For the stage III patients, 2-year local control and overall survival rates were 58% and 58%, respectively, with a median survival time of 25 months. Six patients (11%) experienced grade 3 acute pulmonary toxicity; 2 patients (4%) had grade 3 or worse late treatment-related pulmonary toxicity. The authors concluded that these results were promising.
 
Given the limited data related to outcomes and comparative studies, there is no change in the coverage statement.
 
2010 Update
No trials comparing IMRT and 3DCRT for the treatment of lung cancer were identified in a literature search through Dec 2009.
NCT00520702 directly compares 3DCRT with IMRT.  The trial is no longer recruiting but is still ongoing.
 
There are other active trials that use IMRT as part of a treatment regimen that do no directly compare the technique with other forms of radiation therapy.
  
2009035
 
October 2012 Update
 
A PubMed search through September 2012 was conducted to identify results of any randomized clinical trials that might support the use of IMRT to treat lung cancer.  There were two new dosimetry studies but this type of study does not report improvement in health outcomes.
 
Jensen et al., 2011, reported results from the Near Trial, a prospective, single center, phase II trial to evaluate efficacy and toxicity of radioimmunotherapy with intensity-modulated  radiation (IMRT) and cetuximab in stage III nonsmall cell lung cancer (NSCLC),  Thirty patients, median age 71 years were treated with an overall response rate of 63% (partial remission in 19 of 30 patients).  Median locoregional, distant, over-all progression-free survival was 20.5, 10.9 and 8.5 months, respectively.  Stage (IIIA vs IIIB) and histologic subtype did not have a significant impact on survival rates in these patients.  
 
In a review article Chi et al., 2011, concluded adjuvant IMRT could improve local control but the treatment could be associated with severe pulmonary toxicity, especially with concomitant chemotherapy,
if the dose to the remaining lung was no kept to a very low level.  
 
There are a number of ongoing clinical trials that include IMRT, IMRT with different chemotherapy regimens, and several studies of hypofractionated therapy, but only a few comparing IMRT with 3D-CRT:
NCT00520702 To compare IMRT with 3D CRT in the ability to decrease risk of treatment-related pneumonitis.  This is a relatively small study with 168 enrollees.
 
NCT006328653 This study is looking at three different radiation therapy dosing regimens, delivered with 3DCRT or IMRT, in treating patients with small cell lung cancer who are receiving cisplatin and etoposide (712 enrollees).
 
No new information to support a change in the coverage statement has been identified.  
 
2013 Update
The 2 clinical trials noted in the 2012 update are still ongoing though NCT00520702 is no longer recruiting patients.
Liao et al., 2010, reported a retrospective study of  318 patients treated with CT/3DCRT and 91 treated with 4DCT/IMRT with NSCLC.  Both groups received chemotherapy and a median dose of 63 Gy with mean follow-up times of 1.3 years for IMRT and 2.1 years for 3DCRT.  The authors concluded treatment with IMRT was at least as good as that with 3DCRT in terms of freedom from locoregional progression and distant metastasis.  There was a sidnificant reduction in toxicity and significant improvement in in overall survival with IMRT.  
 
Rodriques et al., 2011, reported on palliative thoracic radiotherapy in lung cancer.  Multiple studies showed a beneficial effect of palliative radiotherapy without any specific schedule being favored.  Stuides suggested that higher doses were associated with modest improvement in survival and total symptom score but were associated with increased toxicity, specifically esophagitis.  The authors noted the impact of newer treatment techniques such as IMRT and IGRT had not yet been clearly defined for this group of patients.
 
A Cochrane review in 2006, edited with no change to conclusions in 2012 (Lester,2006) concluded the majority of patients receiving palliative care should be treated with 1 or 2 fractions of therapy.  The use of high dose palliative therapy could be considered for selected patients with good performance status.  
 
A retrospective study of combined data from 7 prospective RTOG studies of patients with locally advanced NSCLC who received cehmotadiotherapy was reported by Machtay et al., in 2012.  None of the studies used high-technology forms of modern radiotherapy such as IMRT, IGRT, adpative RT, or respiratory-gated RT.  A total of 1,356 patients were analyzed for Biologically effective dose (BED). The median BED wa 74.7 Gy usually delivered with twice daily fractions. The 2-year and 5-year overall survival rates were 38% and 15% respectively; local-regional failure rates were 46% and 52% respectively.  
 
A Comparative Effectiveness Review by the Agency for Healthcare Research and Quality (Ratko, 2013) found that evidence was insufficient to permit conclusions on the comparative effectiveness of local nonsurgical therapies for inoperable or operable patients with stage 1 NSCLC or inoperable NSCLC patients with endoluminal tumor causing pulmonary symptoms.  Local nonsurgical interventions included conformal radiotherapy methods (SBRT, 3DRT, IMRT), conventional 2DRT, PBRT, RFA, brachytherapy, cryoablation, laser therapy, electrocautery, endobronchial debridement and stents.
 
No evidence was identified that would support a change in the current coverage statement.
 
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Randomized and nonrandomized studies
Harris et al, in 2014, compared the effectiveness of IMRT, 3D-CRT, or 2D-RT in treating stage III NSCLC using a cohort of patients treated between 2002 and 2009 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (Harris, 2014). OS was better with IMRT and 3D-CRT than 2D-CRT. In univariate analysis, improvements in OS and cancer-specific survival were associated with IMRT (hazard ratio [HR] 0.90, p=.02 and HR 0.89, p=.02, respectively). However, IMRT was similar to 3D-CRT after controlling for confounders in OS and cancer-specific survival (HR=0.94, p=0.23 and HR=0.94, p=0.28, respectively). On multivariate analysis, toxicity risks with IMRT and
3D-CRT were also similar. Results were similar between the propensity score matched models and the adjusted models.
 
In 2013, Shirvani et al reported on an M.D. Anderson Cancer Center study on the use of definitive IMRT in limited-stage small cell lung cancer (Shirvani, 2013). In this study, 223 patients were treated from 2000 to 2009, 104 received IMRT and 119 received 3D-CRT. Median follow-up times were 22 months (range, 4-83 months) for IMRT and 3D-CRT and 27 months (range, 2-147 months) for IMRT. In either multivariable or propensity score-matched analyses, OS and disease-free survival did not differ between IMRT and 3D-CRT. However, rates of esophagitis-related percutaneous feeding tube placements were lower with IMRT than 3D-CRT (5% vs 17%, respectively, p=0.005).
 
No literature was identified that would support a change in the policy statement.
 
2015 Update
A literature search conducted through March 2015 did not reveal any new information that would prompt a change in the coverage statement.
 
November 2017
A literature search using the MEDLINE database through October 2017 did not reveal any new literature that would prompt a change in the coverage statement.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2017, Chun et al reported a secondary analysis of trial that assessed the addition of cetuximab to a
standard chemotherapy regimen and radiation dose escalation (Chun, 2017). Use of IMRT or 3D-CRT was a stratification factor in the 2x2 design. Of 482 patients in the trial, 53% were treated with 3D-CRT and 47% were treated with IMRT, though treatment allocation was not randomized. Compared with the 3D-CRT group, the IMRT group had larger planning treatment volumes (486 mL vs 427 mL, p=0.005), larger planning treatment volume/volume of lung ratio (median, 0.15 vs 0.13; p=0. 13), and more stage IIIB breast cancer patients (38.6% vs 30.3%, p=0.056). Even though there was an increase in treatment volume, IMRT was associated with less grade 3 or greater pneumonitis (3.5% vs 7.9%, p=0.039) and a reduced risk (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.171 to 0.986; p=0.046), with no significant differences between the groups in 2-year overall survival (OS), progression-free survival, local failure, or distant metastasis-free survival.
 

CPT/HCPCS:
77301Intensity modulated radiotherapy plan, including dose-volume histograms for target and critical structure partial tolerance specifications
77338Multi-leaf collimator (MLC) device(s) for intensity modulated radiation therapy (IMRT), design and construction per IMRT plan
77385Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple
77386Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; complex
77387Guidance for localization of target volume for delivery of radiation treatment delivery, includes intrafraction tracking, when performed
G6015Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session

References: Chun SG, Hu C, Choy H, et al.(2017) . Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: a secondary analysis of the NRG Oncology RTOG 0617 randomized clinical trial. J Clin Oncol. Jan 2017;35(1):56-62. PMID 28034064

Chi A, Liao Z, et al.(2011) Intensity-modulated radiotherapy after extrapleural pneumonectomy in the combined-modality treatment of malignant pleural mesothelioma. J Thorac Oncol, 2011; 6:1132-41.

Garrido P, Rosell R, et al.(2009) Predictors of long-term survival in patients with lung cancer included in the randomized Spanish Lung Cancer Group 0008 phase II trial using concomitant chemoradiation with docetaxel and carboplatin plus induction or consolidation chemotherapy. Clin Lung Cancer, 2009; 10(3):180-6.

Harris JP, Murphy JD, Hanlon AL et al.(2014) A Population-Based Comparative Effectiveness Study of Radiation Therapy Techniques in Stage III Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 2014; 88(4):872-84.

Holloway CL, Robinson D, et al.(2004) Results of phase I study to dose escalate using intensity modulated radiotherapy guided by combined PET/CT imaging with induction chemotherapy for patients with non-small cell lung cancer. Radiother Oncol, 2004; 73(3):285-7.

Jensen AD, Munter MW, et al.(2011) Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity-modulated RT radiotherapy and cetuximab: the NEAR trial. Cancer, 2011; 117:2986-94.

Lester JF, Macbeth F, et al.(2012) Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database of Systemic Reviews, 2006, Iss 4. Art. N0.: CD002143.

Liao Z, Komaki RR, et al.(2010) Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy. Int J Radiat Oncol Biol Physics, 2010; 76:775-81.

Machtay M, Bae K, et al.(2012) Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Physics, 2012; 82:425-34.

Ratko TA, Vats V, et al.(2013) Compariative Effectiveness Review No 112 - Local nonsurgical therapies for stage I and symptomatic obstructive non-small-cell lung cancer. Agency for Healthcare Research and Quality - www.effectivehealthcare.ahrq.gov/reports/final.cfm.

Rodriques G, Videtic GM, et al.(2011) Palliative thoracic radiotherapy in lung cancer: an American Society for Radiation Oncology evidence-based clinical practice guideline. Practical Radiat Oncol, 2011; 1:60-71.

Shirvani SM, Juloori A, Allen PK et al.(2013) Comparison of 2 common radiation therapy techniques for definitive treatment of small cell lung cancer. Int J Radiat Oncol Biol Phys 2013; 87(1):139-47.

Socinski MA, Blackstock AW, et al.(2008) Randomized phase II trial of induction chemotherapy followed by concurrent chemotherapy and dose-escalated thoracic conformal radiotherapy (74 Gy) in stage III non-small-cell lung cancer:CALGB 30105. J Clin Oncol, 2008; 26(15):2457-63.

Sura S, Gupta V, et al.(2008) Intensity-modulated radiation therapy (IMRT) for inoperable non-small cell lung cancer: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Radiother Oncol, 2008; 87(1):17-23.

www.clinicaltrials.gov. Last accessed 10/22/2012.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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