|MP 8.01.46||Intensity Modulated Radiotherapy of the Breast and Lung|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/4:2014
|Return to Medical Policy Index|
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Radiotherapy (RT) is an integral component in the treatment of breast and lung cancers. Intensity-modulated radiotherapy (IMRT) has been proposed as a method of radiation therapy that allows adequate radiation therapy to the tumor while minimizing the radiation dose to surrounding normal tissues and critical structures.
For certain stages of many cancers, including breast and lung, randomized controlled trials have shown that postoperative radiation therapy improves outcomes for operable patients. Adding radiation to chemotherapy also improves outcomes for those with inoperable lung tumors that have not metastasized beyond regional lymph nodes.
Conventional external beam radiotherapy. Over the past several decades, methods to plan and deliver RT have evolved in ways that permit more precise targeting of tumors with complex geometries. Most early trials used 2-dimensional radiation therapy (2D-RT) 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).
Three-dimensional conformal radiation. Treatment planning evolved by using 3-dimensional images, usually from computed tomography (CT) scans, to delineate the boundaries of the tumor and discriminate tumor tissue from adjacent normal tissue and nearby organs at risk for radiation damage. Computer algorithms were developed to estimate cumulative radiation dose delivered to each volume of interest by summing the contribution from each shaped beam. Methods also were developed to position the patient and the radiation portal reproducibly for each fraction and immobilize the patient, thus maintaining consistent beam axes across treatment sessions. Collectively, these methods are termed 3-dimensional conformal radiation therapy (3D-CRT).
Intensity-modulated radiotherapy. IMRT, which uses computer software, CT images, and magnetic resonance imaging (MRI), offers better conformality than 3D-CRT, as it is able to modulate the intensity of the overlapping radiation beams projected on the target and to use multiple-shaped treatment fields. It uses a device (a multileaf collimator [MLC]) which, coupled to a computer algorithm, allows for “inverse” treatment planning. The radiation oncologist delineates the target on each slice of a CT scan and specifies the target’s prescribed radiation dose, acceptable limits of dose heterogeneity within the target volume, adjacent normal tissue volumes to avoid, and acceptable dose limits within the normal tissues. Based on these parameters and a digitally reconstructed radiographic image of the tumor and surrounding tissues and organs at risk, computer software optimizes the location, shape, and intensities of the beams ports, to achieve the treatment plan’s goals.
Increased conformality may permit escalated tumor doses without increasing normal tissue toxicity and thus may improve local tumor control, with decreased exposure to surrounding normal tissues, potentially reducing acute and late radiation toxicities. Better dose homogeneity within the target may also improve local tumor control by avoiding underdosing within the tumor and may decrease toxicity by avoiding overdosing.
Because most 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.
Methodologic issues with IMRT studies
Multiple-dose planning 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. However, these types of studies offer indirect evidence on treatment benefit from IMRT, and it is difficult to relate results of dosing studies to actual effects on health outcomes.
Comparative studies of radiation-induced side effects from IMRT versus alternative radiation delivery are probably the most important type of evidence in establishing the benefit of IMRT. Such studies would answer the question of whether the theoretical benefit of IMRT in sparing normal tissue translates into real health outcomes. Single-arm series of IMRT can give some insights into the potential for benefit, particularly if an adverse effect that is expected to occur at high rates is shown to decrease by a large amount. Studies of treatment benefit are also important to establish that IMRT is at least as good as other types of delivery, but in the absence of such comparative trials, it is likely that benefit from IMRT is at least as good as with other types of delivery.
Intensity-modulated radiotherapy (IMRT) may be considered medically necessary as a technique to deliver whole-breast irradiation in patients receiving treatment for left-sided breast cancer after breast-conserving surgery when all the following conditions have been met:
- Significant cardiac radiation exposure cannot be avoided using alternative radiation techniques
- IMRT dosimetry demonstrates significantly reduced cardiac target volume radiation exposure. (See Policy Guidelines section.)
IMRT may be considered medically necessary in individuals with large breasts when treatment planning with 3-dimensional (3D) conformal results in hot spots (focal regions with dose variation greater than 10% of target) and the hot spots are able to be avoided with IMRT. (See Policy Guidelines section.)
IMRT of the breast is considered investigational as a technique of partial-breast irradiation after breast-conserving surgery.
IMRT of the chest wall is considered investigational as a technique of postmastectomy irradiation.
IMRT may be considered medically necessary as a technique to deliver radiation therapy in patients with lung cancer when all of the following conditions are met:
- Radiation therapy is being given with curative intent
- 3D conformal will expose >35% of normal lung tissue to more than 20 Gy dose-volume (V20)
- IMRT dosimetry demonstrates reduction in the V20 to at least 10% below the V20 that is achieved with the 3D plan (eg, from 40% down to 30% or lower)
IMRT is considered not medically necessary as a technique to deliver radiation therapy in patients receiving palliative treatment for lung cancer.
IMRT is not medically necessary for the treatment of breast or lung cancer for all indications not meeting the criteria above.
TD 5/5 (Gy)a
TD 50/5 (Gy)b
Complication End Point
Portion of organ involved
Portion of organ involved
The tolerance doses in the table are a compilation from the following 2 sources:
Morgan MA (2011). Radiation oncology. In DeVita, Lawrence, and Rosenberg, Cancer (p.308). Philadelphia: Lippincott Williams and Wilkins.
Kehwar TS, Sharma SC. Use of normal tissue tolerance doses into linear quadratic equation to estimate normal tissue complication probability. Available at: http://www.rooj.com/Radiation%20Tissue%20Tolerance.htm
NP: not provided.
a TD 5/5, the average dose that results in a 5% complication risk within 5 years.
b TD 50/5, the average dose that results in a 50% complication risk within 5 years.
The following is an example of clinical guidelines that may be used with IMRT in left-sided breast lesions:
- The target volume coverage results in cardiac radiation exposure that is expected to be greater than or equal to 25 Gy to 10 cm3 or more of the heart (V25 ≥10 cm3) with 3D-CRT, despite the use of a complex positioning device (such as Vac-Lok™), and
- with the use of IMRT, there is a reduction in the absolute heart volume receiving 25 Gy or higher by at least 20% (eg, volume predicted to receive 25 Gy by 3D RT is 20 cm3, and the volume predicted by IMRT is ≤16 cm3).
The following are examples of criteria to define large breast size when using IMRT to avoid hot spots, as derived from randomized studies:
- Donovan et al(1) enrolled patients with “higher than average risk of late radiotherapy-adverse effects,” which included patients having larger breasts. The authors state that while breast size is not particularly good at identifying women with dose inhomogeneity falling outside current International Commission on Radiation Units and Measurements guidelines, they excluded women with small breasts (≤500 cm3), who generally have fairly good dosimetry with standard 2D compensators.
- In the trial by Pignol et al,(2) which reported that the use of IMRT significantly reduced the proportion of patients experiencing moist desquamation,breast size was categorized as small, medium, or large by cup size. Multivariate analysis found that smaller breast size was significantly associated with a decreased risk of moist desquamation (p<0.001).
The following CPT codes specifically describe IMRT:
77301: Intensity-modulated radiotherapy plan, including dose-volume histograms for target and critical structure partial tolerance specifications.
77418: Intensity-modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary, dynamic MLC, per treatment session.(code deleted 12/31/14)
77385: Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple
77386: Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; complex
0073T: Compensator-based beam modulation treatment delivery of inverse planned treatment using three or more high resolution (milled or cast) compensator convergent beam modulated fields, per treatment session.
Effective in 2010, a new code was added:
77338: Multi-leaf collimator (MLC) device(s) for intensity-modulated radiation therapy (IMRT), design and construction per IMRT plan.
Code 77338 is to be reported only once per IMRT plan and should not be reported with 0073T.
BlueCard/National Account Issues
State or federal mandates (eg, FEP) may dictate that all devices approved by the U.S. Food and Drug Administration may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.
For contracts that do not use this definition of medical necessity, other contract provisions including contract language concerning use of out-of-network providers and services may be applied. That is, if the alternative therapies (eg, 3D-conformal treatments) are available in-network but IMRT therapy is not, IMRT would not be considered an in-network benefit. In addition, benefit or contract language describing the "least costly alternative" may also be applicable for this choice of treatment.
- Donovan E, Bleakley N, Denholm E et al. Randomised trial of standard 2D radiotherapy (RT) versus intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Radiother Oncol 2007; 82(3):254-64.
- Pignol JP, Olivotto I, Rakovitch E et al. A multicenter randomized trial of breast intensity-modulated radiation therapy to reduce acute radiation dermatitis. J Clin Oncol 2008; 26(13):2085-92.
- Violet JA, Harmer C. Breast cancer: improving outcome following adjuvant radiotherapy. Br J Radiol 2004; 77(922):811-20.
- Arthur DW, Morris MM, Vicini FA. Breast cancer: new radiation treatment options. Oncology 2004; 18(13):1621-9; discussion 29-30, 36-38.
- Coles CE, Moody AM, Wilson CB et al. Reduction of radiotherapy-induced late complications in early breast cancer: the role of intensity-modulated radiation therapy and partial breast irradiation. Part II--Radiotherapy strategies to reduce radiation-induced late effects. Clin Oncol 2005; 17(2):98-110.
- Formenti SC, Truong MT, Goldberg JD et al. Prone accelerated partial breast irradiation after breast-conserving surgery: preliminary clinical results and dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2004; 60(2):493-504.
- Alonso-Basanta M MS, Lymberis S et al. Dosimetric comparisons of supine versus prone radiation: implications on normal tissue toxicity. Int J Radiat Oncol Biol Phys 2005; 63(2 suppl1):S182-3.
- Remouchamps VM, Vicini FA, Sharpe MB et al. Significant reductions in heart and lung doses using deep inspiration breath hold with active breathing control and intensity-modulated radiation therapy for patients treated with locoregional breast irradiation. Int J Radiat Oncol Biol Phys 2003; 55(2):392-406.
- Frazier RC, Vicini FA, Sharpe MB et al. Impact of breathing motion on whole breast radiotherapy: a dosimetric analysis using active breathing control. Int J Radiat Oncol Biol Phys 2004; 58(4):1041-7.
- Chang JY, Liu HH, Komaki R. Intensity modulated radiation therapy and proton radiotherapy for non-small cell lung cancer. Curr Oncol Rep 2005; 7(4):255-9.
- Dayes I, Rumble RB, Bowen J et al. Intensity-modulated radiotherapy in the treatment of breast cancer. Clin Oncol 2012; 24(7):488-98.
- Staffurth J. A review of the clinical evidence for intensity-modulated radiotherapy. Clin Oncol 2010; 22(8):643-57.
- Donovan EM, Bleackley NJ, Evans PM et al. Dose-position and dose-volume histogram analysis of standard wedged and intensity modulated treatments in breast radiotherapy. Br J Radiol 2002; 75(900):967-73.
- Donovan EM, Yarnold JR, Adams EJ et al. An investigation into methods of IMRT planning applied to breast radiotherapy. Br J Radiol 2008; 81(964):311-22.
- Barnett GC, Wilkinson J, Moody AM et al. A randomised controlled trial of forward-planned radiotherapy (IMRT) for early breast cancer: baseline characteristics and dosimetry results. Radiother Oncol 2009; 92(1):34-41.
- Barnett GC, Wilkinson JS, Moody AM et al. Randomized controlled trial of forward-planned intensity modulated radiotherapy for early breast cancer: interim results at 2 years. Int J Radiat Oncol Biol Phys 2012; 82(2):715-23.
- McDonald MW, Godette KD, Butker EK et al. Long-term outcomes of IMRT for breast cancer: a single-institution cohort analysis. Int J Radiat Oncol Biol Phys 2008; 72(4):1031-40.
- Kestin LL SM, Frazier RC et al. Intensity modulation to improve dose uniformity with tangential breast radiotherapy: Initial clinical experience. Int J Radiat Oncol Biol Phys 2005; 48(5):1559-68.
- Vicini FA, Sharpe M, Kestin L et al. Optimizing breast cancer treatment efficacy with intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2002; 54(5):1336-44.
- Selvaraj RN, Beriwal S, Pourarian RJ et al. Clinical implementation of tangential field intensity modulated radiation therapy (IMRT) using sliding window technique and dosimetric comparison with 3D conformal therapy (3DCRT) in breast cancer. Med Dosim 2007; 32(4):299-304.
- Hardee ME, Raza S, Becker SJ et al. Prone hypofractionated whole-breast radiotherapy without a boost to the tumor bed: comparable toxicity of IMRT versus a 3D conformal technique. Int J Radiat Oncol Biol Phys 2012; 82(3):e415-23.
- Freedman GM, Li T, Nicolaou N et al. Breast intensity-modulated radiation therapy reduces time spent with acute dermatitis for women of all breast sizes during radiation. Int J Radiat Oncol Biol Phys 2009; 74(3):689-94.
- Keller LM, Sopka DM, Li T et al. Five-year results of whole breast intensity modulated radiation therapy for the treatment of early stage breast cancer: the Fox Chase Cancer Center experience. Int J Radiat Oncol Biol Phys 2012; 84(4):881-7.
- Coon AB, Dickler A, Kirk MC et al. Tomotherapy and multifield intensity-modulated radiotherapy planning reduce cardiac doses in left-sided breast cancer patients with unfavorable cardiac anatomy. Int J Radiat Oncol Biol Phys 2010; 78(1):104-10.
- Leonard C, Carter D, Kercher J et al. Prospective trial of accelerated partial breast intensity-modulated radiotherapy. Int J Radiat Oncol Biol Phys 2007; 67(5):1291-8.
- Livi L, Buonamici FB, Simontacchi G et al. Accelerated partial breast irradiation with IMRT: new technical approach and interim analysis of acute toxicity in a phase III randomized clinical trial. Int J Radiat Oncol Biol Phys 2010; 77(2):509-15.
- Rudat V, Alaradi AA, Mohamed A et al. Tangential beam IMRT versus tangential beam 3D-CRT of the chest wall in postmastectomy breast cancer patients: a dosimetric comparison. Radiat Oncol 2011; 6:26.
- Bezjak A, Rumble RB, Rodrigues G et al. Intensity-modulated radiotherapy in the treatment of lung cancer. Clin Oncol 2012; 24(7):508-20.
- Liao ZX, Komaki RR, Thames HD, Jr. et al. 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 Phys 2010; 76(3):775-81.
- Holloway CL, Robinson D, Murray B et al. Results of a 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.
- Sura S, Gupta V, Yorke E et al. 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.
- Jiang ZQ, Yang K, Komaki R et al. Long-term clinical outcome of intensity-modulated radiotherapy for inoperable non-small cell lung cancer: the MD Anderson experience. Int J Radiat Oncol Biol Phys 2012; 83(1):332-9.
- Kwint M, Uyterlinde W, Nijkamp J et al. Acute esophagus toxicity in lung cancer patients after intensity modulated radiation therapy and concurrent chemotherapy. Int J Radiat Oncol Biol Phys 2012; 84(2):e223-8.
- Govaert SL, Troost EG, Schuurbiers OC et al. Treatment outcome and toxicity of intensity-modulated (chemo) radiotherapy in stage III non-small cell lung cancer patients. Radiat Oncol 2012; 7:150.
- Harris JP, Murphy JD, Hanlon AL et al. 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.
- Shirvani SM, Juloori A, Allen PK et al. 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.
- National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Breast Cancer. V.2.2014. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Last accessed March 20, 2014.
- National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Non-small Cell Lung Cancer. V.3.2014. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Last accessed March 20, 2014.
- National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer. V.2.2014. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Last accessed March 20, 2014.
- Marks LB, Bentzen SM, Deasy JO et al. Radiation dose-volume effects in the lung. Int J Radiat Oncol Biol Phys 2010; 76(3 Suppl):S70-6.
|CPT||77301||Intensity modulated radiotherapy plan, including dose volume histograms for target and critical structure partial tolerance specification|
|77338||Design and construction of a multi-leaf collimator for use in intensity modulated radiation therapy (IMRT)|
|77418||Intensity modulated treatment delivery, single or multiple fields/arcs, via narrow spatially and temporally modulated beams, binary dynamic MLC, per treatment session (code deleted 12/31/14)|
|77385||Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; simple|
|77386||Intensity modulated radiation treatment delivery (IMRT), includes guidance and tracking, when performed; complex|
|0073T||Compensator-based beam modulation treatment delivery of inverse planned treatment using three or more high resolution compensator convergent beam modulated fields, per treatment session|
|ICD-9 Diagnosis||investigational or not medically necessary for all codes|
|ICD-10-CM (effective 10/1/15)||Investigational or not medically necessary for all diagnoses|
|C34.00 – C34.92||Malignant neoplasm of bronchus and lung code range|
|C50.011 – C50.929||Malignant neoplasm of breast code range|
|ICD-10-PCS (effective 10/1/15)||ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this therapy.|
|DM000ZZ, DM001ZZ, DM002ZZ, DM010ZZ, DM011ZZ, DM012ZZ||Radiation oncology, breast, beam radiation, codes by anatomical location (left or right breast) and modality (photons < 1 MeV, photons 1-10 MeV and photons > 10 MeV)|
|DB020ZZ, DB021ZZ, DB022ZZ||Radiation oncology, respiratory system, beam radiation lung, codes by modality (photons < 1 MeV, photons 1-10 MeV and photons > 10 MeV)|
Intensity modulated radiation therapy
|12/14/05||Add policy to Medicine section, Oncology subsection||New policy|
|12/12/06||Replace policy||Policy updated with literature search; policy statement unchanged.|
|12/13/07||Replace policy||Policy updated with literature search; no change in policy statement. Reference numbers 14 – 16 added.|
|04/24/09||Replace policy||Policy updated with literature search, references 17 – 19 added; policy statement unchanged. Policy renumbered and moved to Therapy section. Policy number changed from 2.03.08 to 8.01.46.|
|12/29/09||Coding update only||add 77338|
|05/13/10||Replace policy||Policy updated with literature search, references 20 – 26 added. Policy statements for use in whole breast irradiation and lung cancer to not medically necessary.|
|10/08/10||Replace policy||Clinical input reviewed, policy statements unchanged.|
|03/08/12||Replace policy||Policy updated with literature search. References 11, 13, 15, 23-24 and 30-31 added. Policy statement added indicating chest wall IMRT postmastectomy is investigational. Policy statement added indicating whole breast IMRT may be medically necessary in large-sized breasts. Policy statements on whole breast and lung IMRT changed from not medically necessary to may be considered medically necessary. Policy statement on partial breast IMRT remains investigational. Description section rewritten|
|04/11/13||Replace policy||Policy updated with literature search through March 11, 2013. References 11, 21, 23, 28, and 32-34 added; practice guidelines updated and other references renumbered. No change to policy statements.|
|05/09/13||Replace policy-- correction only||Language was added to the Rationale section to clarify that Jiang et al. (reference 32) is a follow-up study by the same group of investigators (Liao and colleagues).|
|4/10/14||Replace policy||Policy updated with literature review through March 20, 2014. References 35-36 added; reference 39 updated. Policy statement added stating other indications not meeting the criteria for medical necessity are considered not medically necessary.|
|1/2/15||coding update only||add 77385, 77386|
This policy was originally created in 2005 and was regularly updated with searches of the MEDLINE database. The most recent literature review was performed for the period of March 11, 2013, through March 20, 2014. The following is a summary of the key findings to date.
Intensity-modulated radiotherapy (IMRT) methods to plan and deliver RT are not uniform.(3-5) IMRT may use beams that remain “on” as multileaf collimator (MLC) devices move around the patient (dynamic MLC), or that are off during movement and turn on once the MLC reaches prespecified positions (“step and shoot” technique). A third alternative uses a very narrow single beam that moves spirally around the patient (tomotherapy). Each of these methods uses different computer algorithms to plan treatment and yields somewhat different dose distributions in and outside the target.
Patient position is another variable that can alter target shape and thus affect treatment plans. Some investigators and clinicians deliver 3-dimensional conformal radiation therapy (3D-CRT) and IMRT with the patient prone,(6) while most treat supine patients as in conventional (2D) external beam radiotherapy (EBRT). A recent comparative dosimetric analysis (published only as an abstract) concluded that target coverage is similar with either position, but plans generated for the prone position spared more lung tissue than those generated if the same patient was supine.(7) However, data are unavailable to compare clinical outcomes for patients treated in prone versus supine positions, and consensus is lacking.
Respiratory motion of the breast and internal organs (heart and lung) during radiation treatments is another concern when using 3D-CRT or IMRT to treat breast cancer.(8,9) Treatment plans are usually based on 1 scan, a static 3D image. They partially compensate for day-to-day (interfraction) variability in patient set-up, and for (intrafraction) motion of the target and organs at risk, by expanding the target volume with uniform margins around the tumor (generally 0.5-1 cm for all positional uncertainty).
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. Investigators are exploring an active breathing control device combined with moderately deep inspiration breath-holding techniques to improve conformality and dose distributions during IMRT for breast cancer.(8,9) Techniques presently being studied with other tumors (eg, lung cancer )(10) either gate beam delivery to the patient’s respiratory movement or continuously monitor tumor (by in-room imaging) or marker (internal or surface) positions to aim radiation more accurately at the target. The impact of these techniques on outcomes of 3D-CRT or IMRT for breast cancer is unknown. However, it appears likely that respiratory motion alters the dose distributions actually delivered while treating patients from those predicted by plans based on static computed tomography (CT) scans, or measured by dosimetry using stationary (nonbreathing) targets. In addition, non-small-cell lung cancer (NSCLC) 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 CRT 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 RT) is unknown.
These considerations emphasize the need to compare clinical outcomes rather than treatment plan predictions to determine whether 1 RT method is superior to another.
The literature search found no reports directly comparing health outcomes of IMRT with those of 3D-CRT for either breast or lung cancer treatment. There were no prospective comparative trials (randomized or nonrandomized). Because available data are scant, the report summarizes the studies that reported health outcomes.
In 2012, Dayes et al published a systematic review that examined the evidence for IMRT for whole-breast irradiation in the treatment of breast cancer to quantify its potential benefits and to make recommendations for radiation treatment programs.(11) Based on a review of 6 published reports through March 2009 (1 randomized controlled trial [RCT], 3 retrospective cohort studies, 1 historically controlled trial, 1 prospective cohort) including 2012 patients, the authors recommended IMRT over tangential RT after breast-conserving surgery to avoid acute adverse effects associated with radiation. There were insufficient data to recommend IMRT over standard tangential RT for reasons of oncologic outcomes or late toxicity. The RCT included in this review was the Canadian multicenter trial by Pignol et al reported next. In this RCT, IMRT was compared with 2D-RT, and CT scans were used in treatment planning for both arms of the study; the types of tangential RT regimens were not reported for the other studies.(2)
Two (of 6) cohort studies reviewed by Dayes et al reported on breast cancer-related outcomes.(11) Neither of these studies reported statistically significant differences between treatment groups for contralateral breast cancer rates, clinical recurrence-free survival or disease-specific survival. Despite differences in reported outcomes, all 6 studies reported reductions in at least 1 measure of acute toxicity as a result of IMRT-based breast radiation. These toxicities typically related to skin reactions during the course of treatment, with reductions being in the order of one-third. The RCT by Pignol et al (reported next), for example, found a reduction in moist desquamation specific to the inframammary fold by 39%. Only 2 retrospective cohort studies reported on late toxicity effects; 1 cohort study reported a significant difference between IMRT and tangential RT in favor of IMRT for breast edema (IMRT, 1% vs 25%, p<0.001), and the other study found a trend toward a reduction in lymphedema rates (p=0.06). No differences were observed across both studies in other late effects including fat necrosis or second malignancies.(11)
In 2010, Staffurth et al conducted a review of clinical evidence from studies on IMRT.(12) Included in the portion of the review addressing IMRT for breast cancer were 6 studies comparing the results of IMRT and 2D-RT for postoperative RT, including 2 RCTs [Donovan and Pignol, noted next(1,2)] and 4 nonrandomized comparative trials). The authors reported that the studies showed improvements in long-term cosmesis and toxicity when IMRT was used for breast cancer. However, health-related quality of life did not improve with forward-planned IMRT when compared with conventional tangential breast 2D-RT. Despite the lack of long-term health outcomes, the authors concluded reductions in radiation-induced adverse effects were sufficient to warrant the use of IMRT.
Randomized and nonrandomized studies
Donovan et al reported the treatment planning and dosimetry results from an ongoing RCT comparing outcomes of RT for breast cancer using conventional 2D-RT with wedged, tangential beams or IMRT (n=300) in 2002.(13) In an abstract, these investigators reported interim cosmetic outcomes at 2 years after randomization for 233 evaluable patients. Changes in breast appearance were noted in 60 of 116 (52%) randomly assigned to conventional EBRT and in 42 of 117 (36%) randomly assigned to IMRT (p=0.05). Other outcomes were not reported. In 2007, Donovan et al published a subsequent report on this trial. (1) Enrolled patients had ‘higher than average risk of late radiotherapy-adverse effects’, which included patients having larger breasts. The authors stated that while breast size is not particularly good at identifying women with dose inhomogeneity falling outside current International Commission on Radiation Units and Measurements guidelines, their trial excluded women with small breasts (≤500 cm3), who generally have fairly good dosimetry with standard 2D compensators. All patients were treated with 6 or 10 MV photons to a dose of 50 Gy in 25 fractions to 100% in 5 weeks followed by an electron boost to the tumor bed of 11.1 Gy in 5 fractions to 100%. The primary end point was change in breast appearance scored from serial photographs taken before RT and at 1, 2, and 5 years’ follow-up. Secondary end points 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%) allocated standard 2D treatment compared with 47 of 118 (40%) patients allocated 3D IMRT. Significantly fewer patients in the 3D IMRT group developed palpable induration assessed clinically in the center of the breast, pectoral fold, inframammary fold and at the boost site. No significant differences between treatment groups were found in patient-reported breast discomfort, breast hardness, or quality of life. The authors concluded that the analysis suggests that minimization of unwanted radiation dose inhomogeneity in the breast reduces late adverse effects. While the change in breast appearance was statistically different, a beneficial effect on quality of life was not demonstrated. Because whole-breast radiotherapy (WBRT) is now delivered by 3D-conformal techniques, these comparison data are of limited value. As the authors note, quality-of-life changes were not noted. No other clinical outcomes were reported.
In a 2008 study, Donovan et al evaluated methods for breast cancer IMRT planning and compared IMRT methods with conventional wedge planning in 14 patients.(14) Most IMRT plans were found to improve dose homogeneity over wedge-only treatment plans. In patients with a breast size of 500 cm3 or greater, the dose distribution improved between 5.6% and 11.1% (p<0.05), regardless of the planning method used. The authors noted in the discussion that IMRT may be inappropriate for patients with a breast volume of less than 1000 cm3.
In another RCT, IMRT was compared with 2D-RT, and CT scans were used in treatment planning for both arms of the study. Thus, this is close to the ideal comparison of 3D-CRT and IMRT. In 2008, Pignol et al reported on a multicenter, double-blind RCT that was performed to determine if breast IMRT would reduce the rate of acute skin reaction (moist desquamation), decrease pain, and improve quality of life compared with RT using wedges.(2) Patients were assessed each week during and up to 6 weeks after RT. A total of 358 patients were randomly assigned between July 2003 and March 2005 in 2 Canadian centers, and 331 were included in the analysis. The authors noted that breast IMRT significantly improved the dose distribution compared with 2D-RT. They also noted a lower proportion of patients with moist desquamation during or up to 6 weeks after their radiation treatment; 31% with IMRT compared with 48% with standard treatment (p=0.002). A multivariate analysis found the use of breast IMRT and smaller breast size were significantly associated with a decreased risk of moist desquamation. The use of IMRT did not correlate with pain and quality of life, but the presence of moist desquamation did significantly correlate with pain and a reduced quality of life. The focus on short-term outcomes (6 weeks) is a limitation when assessing net health outcome.
Barnett et al have published baseline characteristics and dosimetry results of a single-center randomized trial of IMRT for early breast cancer after breast-conserving surgery.(15) In this trial, 1145 patients with early breast cancer were evaluated for EBRT. Twenty-nine percent had adequate dosimetry with standard RT. The other 815 patients were randomly assigned to receive either IMRT or conventional 2D-RT. In this study, inhomogeneity occurred most often when the dose-volume was greater than 107% (V107) of the prescribed dose to greater than 2 cm3 breast volume with conventional radiation techniques. When breast separation was 21 cm or more, 90% of patients had received greater than V107 greater than 2 cm3 with standard radiation planning. Subsequently, in 2012, Barnett et al reported on the 2-year interim results of the trial. (16) The incidence of acute toxicity was not significantly different between groups. Additionally, photographic assessment scores for breast shrinkage were not significantly different between groups. The authors noted overall cosmesis after RT or IMRT was dependent on surgical cosmesis, suggesting breast shrinkage and induration were due to surgery rather than RT, thereby masking the potential cosmetic benefits of IMRT.
Several other publications report findings from single institutions from patients who received IMRT compared with patients who received 2D-RT (nonrandomized studies). The grading of acute radiation dermatitis is relevant to these studies. Acute radiation dermatitis is graded on a scale of 0 to 5, with 0 as no change and 5 as death. Grade 2 is moderate erythema and patchy moist desquamation, mostly in skin folds; grade 3 is moist desquamation in other locations and bleeding with minor trauma.
McDonald et al reported on a single institution retrospective review of patients who received RT after conservative surgery for stages 0-III breast cancer from January 1999 to December 2003.(17) Computed tomography simulation was used to design standard tangential breast fields with enhanced dynamic wedges for 2D-RT and both enhanced dynamic wedges and dynamic MLCs for IMRT. In this report, 121 breasts were treated with IMRT and 124 with 2D-RT. Median breast dose was 50 Gy in both groups. Median follow-ups were 6.3 years (range, 3.7-104 months) for patients treated with IMRT and 7.5 years (range, 4.9-112 months) for those treated with 2D-RT. Decreased acute skin toxicity of Radiation Therapy Oncology Group (RTOG) grade II or III was observed with IMRT treatment compared with 2D-RT (39% vs 52%, respectively; p=0.047). For patients with stages I-III (n=199), 7-year Kaplan-Meier freedom from ipsilateral breast tumor recurrence (IBTR) rates were 95% for IMRT and 90% for 2D-RT (p=0.36). For patients with stage 0 (ductal carcinoma in situ, n=46), 7-year freedom from IBTR rates were 92% for IMRT and 81% for 2D-RT (p=0.29). There were no statistically significant differences in overall survival (OS), disease-specific survival, or freedom from IBTR, contralateral breast tumor recurrence, distant metastasis, late toxicity, or second malignancies between IMRT and 2D-RT. The authors concluded that patients treated with breast IMRT had decreased acute skin toxicity, and long-term follow-up showed excellent local control. Interpretation of this study is limited by its retrospective design and limited outcome measures (no quality-of-life measures).
Kestin et al reported they had treated 32 patients with early stage breast cancer using multiple static MLC segments to deliver IMRT for WBRT.(18) With at least 1 month of follow-up on all patients, they observed no grade III or greater acute skin toxicity (using RTOG criteria). However, follow-up was inadequate to assess other health outcomes.
A subsequent report from Vicini et al included 281 patients with early breast cancer treated with the same IMRT technique.(19) Of these, 102 (43%) experienced RTOG grade II, and 3 (1%) experienced grade III skin toxicity. Cosmetic results at 1 year after treatment were reported for 95 patients and were good to excellent in 94 (99%). No patients had skin telangiectasias, significant fibrosis, or persistent breast pain. Other primary or secondary outcomes were not reported.
Many reports in the literature described changes in radiation dose delivered for IMRT compared with other techniques. For example, Selvaraj reported on 20 patients with breast cancer randomly selected for comparison who received IMRT or 3D-CRT.(20) In this study, the mean dose for the ipsilateral lung and the percentage of volume of contralateral volume lung receiving greater than 5% of prescribed dose with IMRT were reduced by 9.9% and 35% compared with 3D-CRT. The authors note that the dosimetric data suggest improved dose homogeneity in the breast and reduction in the dose to lung and heart for IMRT treatments, which may be of clinical value in potentially contributing to improved cosmetic results and reduced late treatment-related toxicity.
Hardee et al compared the dosimetric and toxicity outcomes after treatment with IMRT or 3D-CRT for whole-breast irradiation in a consecutive series of 97 patients with early stage breast cancer, who were assigned to either approach after segmental mastectomy based on insurance carrier approval for reimbursement for IMRT.(21) IMRT significantly reduced the maximum dose to the breast (Dmax median, 110% for 3D-CRT vs 107% for IMRT; p<0.001, Wilcoxon test) and improved median dose homogeneity (median, 1.15 for 3D-CRT vs 1.05 for IMRT; p<0.001, Wilcoxon test) when compared with 3D-CRT. These dosimetric improvements were seen across all breast volume groups. Grade 2 dermatitis occurred in 13% of patients in the 3D-CRT group and 2% in the IMRT group. IMRT moderately decreased rates of acute pruritus (p=0.03, c2 test) and grade 2 to 3 subacute hyperpigmentation (p=0.01, Fisher exact test). With a minimum of 6 months’ follow-up, the treatment was reported to be similarly well-tolerated in either group, including among women with large breast volumes.(21)
Freedman et al studied the time spent with radiation-induced dermatitis during a course of RT for women with breast cancer treated with conventional RT (2D-RT) or IMRT.(22) For this study, the population consisted of 804 consecutive women with early stage breast cancer treated with breast-conserving surgery and radiation from 2001 to 2006 at the Fox Chase Cancer Center. All patients were treated with WBRT followed by a boost to the tumor bed. WBRT consisted of conventional wedged photon tangents (n=405) earlier in the study period, and mostly of photon IMRT (n=399) in later years. All patients had acute dermatitis graded each week of treatment. The breakdown of cases of maximum toxicity by technique was as follows: 48%, grade 0/1, and 52%, grade 2/3, for IMRT; and 25%, grade 0/1, and 75%, grade 2/3, for conventional RT (p<0.001). The IMRT patients spent 82% of weeks during treatment with grade 0/1 dermatitis and 18% with grade 2/3 dermatitis, compared with 29% and 71% of patients, respectively, treated with conventional radiation (p<0.001). From this pre/post study, the authors concluded that breast IMRT is associated with a significant decrease both in the time spent during treatment with grade 2/3 dermatitis and in the maximum severity of dermatitis compared with that associated with conventional radiation. Interpretation of these results is limited by lack of a contemporaneous comparison. The investigators have subsequently reported on 5-year outcomes of the Fox Chase Cancer Center experience using whole-breast IMRT for the treatment of early stage breast cancer; the 5-year actuarial ipsilateral breast tumor recurrence and locoregional recurrence rates were 2.0% and 2.4%, respectively. In terms of treatment-related effects, edema and erythema were consistently noted early after breast IMRT and peaked at 3 to 6 months from the start of whole-breast IMRT. Infection was rare, with less than 1.5% of the patient population experiencing this adverse effect; telangiectasia was noted to develop in approximately 8% of patients, and fibrosis in 7% of patients, at 36 months or more from the start of whole-breast IMRT.(23)
Publications also report on the potential ability of IMRT to reduce radiation to the heart (left ventricle) in patients with left-sided breast cancer and unfavorable cardiac anatomy.(24) This is a concern because of the potential development of late cardiac complications, such as coronary artery disease, following RT to the left breast.
IMRT has also been investigated as a technique of partial-breast irradiation, as an alternative to WBRT after breast-conserving surgery. Breast brachytherapy (see Policy No. 8.01.13) is another technique of partial-breast irradiation therapy. Leonard et al reported on 55 patients treated with partial-breast IMRT who had mean follow-up of 10 months.(25) At the short-term follow-up, the dose delivery and clinical outcomes were considered acceptable; however, long-term follow-up is needed.
In 2010, Livi et al reported on preliminary results of 259 patients randomized in a phase 3 trial, that began in September 2008, to compare conventional fractionated whole-breast treatment (n=128) with accelerated partial-breast irradiation plus IMRT (n=131).(26) RTOG grade 1 and 2 skin toxicity was observed at a rate of 22% and 19% in the whole-breast treatment group versus 5% and 0.8% in the partial-breast treatment group, respectively. The authors concluded partial-breast irradiation with IMRT is feasible but noted long-term results on health outcomes are still needed. Additionally, 18 months after RT, 1 case of contralateral breast cancer was diagnosed in the partial-breast irradiation group, creating concern from the authors that it may be related to the high dosage of IMRT.
Few studies have examined the use of IMRT for chest wall irradiation in postmastectomy breast cancer patients and no studies were identified that reported on health outcomes for this indication. Available studies have focused on treatment planning and techniques to improve dose distributions to targeted tissues while reducing radiation to normal tissue and critical surrounding structures, such as the heart and lung. An example of 1 available study was published by Rudat et al in which treatment planning for chest wall irradiation with IMRT was compared with 3D-CRT in 20 postmastectomy patients.(27) The authors reported IMRT resulted in significantly decreased heart and lung high-dose-volume with a significantly improved conformity index when compared with 3D-CRT. However, there was no significant difference reported in the homogeneity index. The authors noted longer term prospective studies are needed to further assess cardiac toxicity and secondary lung cancer risk with multifield IMRT, which while reducing high dose-volume, increases mean heart and lung dose. As noted, health outcomes were not reported in this study.
In 2012, Bezjak et al published a systematic review that examined the evidence for the use of IMRT in the treatment of lung cancer to quantify its potential benefits and make recommendations for RT programs considering adopting this technique within Ontario, Canada.(28) This review consisted of 2 retrospective cohort studies (through March 2010) reporting on cancer outcomes, which was considered insufficient evidence on which to make evidence-based recommendations. These 2 cohort studies reported on data from the same institution (M.D. Anderson Cancer Center); the study by Liao et al (2010, reported next)(29) acknowledged that patients included in their cohort (n=409) were previously reported on in the earlier cohort by Yom et al (n=290), but it is not clear exactly how many patients were added in the second report. However, due to the known dosimetric properties of IMRT and extrapolating from clinical outcomes from other disease sites, the review authors recommended that IMRT should be considered for lung cancer patients where the tumor is in close proximity to an organ at risk, where the target volume includes a large volume of an organ at risk, or in scenarios where dose escalation would be potentially beneficial while minimizing normal tissue toxicity.(28)
Randomized and nonrandomized studies
Holloway et al reported on a phase 1 dose escalation study of IMRT for patients with lung cancer that was terminated after the first 5 patients received 84 Gy in 35 fractions (2.4 Gy per fraction).(30) 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 II dysphasia, 1 with grade I odynophagia, and 1 with grade I 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.
Noting that the use of IMRT for inoperable NSCLC had not been well-studied, Sura et al reviewed their experience with IMRT for patients with inoperable NSCLC.(31) They reported a retrospective review of 55 patients with stage I-IIIB inoperable NSCLC treated with IMRT between 2001 and 2005. The study end points were toxicity, local control, and OS. With a median follow-up of 26 months, the 2-year local control and OS rates for stage I/II patients were 50% and 55%, respectively. For the stage III patients, 2-year local control and OS 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.
Liao et al report on a nonrandomized comparative study of patients who received one of these forms of RT, along with chemotherapy, for inoperable NSCLC at 1 institution (M.D. Anderson Cancer Center).(29) This study involved a retrospective comparison of 318 patients who received CT/3D-CRT and chemotherapy from 1999 to 2004 (mean follow-up, 2.1 years) to 91 patients who received 4-dimensional computed tomography (4DCT)/IMRT and chemotherapy from 2004 to 2006 (mean follow-up, 1.3 years). Both groups received a median dose of 63 Gy. Disease end points were locoregional progression, distant metastasis, and OS. Disease covariates were gross tumor volume (GTV), nodal status, and histology. The toxicity end point was grade III or greater radiation pneumonitis; toxicity covariates were GTV, smoking status, and dosimetric factors. Data were analyzed using Cox proportional hazards models. The hazard ratios for IMRT were less than 1 for all disease end points; the difference was significant only for OS. The median survival was 1.40 (SD=1.36) years for the IMRT group and 0.85 (SD=0.53) years for the 3D-CRT group. The toxicity rate was significantly lower in the IMRT group than in the 3D-CRT group. The V20 (volume of the lung receiving 20 Gy) was higher in the 3D-CRT group and was a factor in determining toxicity. Freedom from distant metastasis was nearly identical in both groups. The authors concluded that treatment with 4DCT/IMRT was at least as good as that with 3D-CRT in terms of the rates of freedom from local/regional progression and metastasis. This retrospective study found a significant reduction in toxicity and improvement in survival. The nonrandomized, retrospective aspects of this study from 1 center limit the ability to draw definitive conclusions from this report.
In a 2012 follow-up study, Liao et al (Jiang et al) published long-term follow-up data from the M.D. Anderson Cancer Center on the use of definitive IMRT, with or without chemotherapy, for newly diagnosed, pathologically confirmed, inoperable NSCLC from 2005 to 2006.(32) This retrospective review included 165 patients, 89% of whom had stage III to IV disease. The median radiation dose was 66 Gy given in 33 fractions. Median OS time was 1.8 years; the 2-year and 3-year OS rates were 46% and 30%, respectively. Rates of grade 3 or greater maximum treatment-related pneumonitis were 11% at 6 months and 14% at 12 months. At 18 months, 86% of patients had developed grade 1 or greater maximum pulmonary fibrosis, and 7% grade 2 or greater fibrosis. The median times to maximum esophagitis were 3 weeks (range, 1-13 weeks) for grade 2 and 6 weeks (range, 3-13 weeks) for grade 3. These rates of treatment-related toxicities with IMRT have been reported in other series to be no different than that in patients treated with 3D-CRT.(33,34)
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‒Medicare database.(35) 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.(36) 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).
Ongoing Clinical Trials
A search of online site ClinicalTrials.gov on March 20, 2014 identified at least 3 randomized phase 3 studies comparing IMRT with 3D-CRT for breast cancer after breast-conserving surgery. One study addresses partial-breast RT (NCT01185132), and 2 studies address WBRT (NCT01322854, NCT01349322). In addition, a follow-up study of the Canadian RCT by Pignol et al (2008) is being undertaken to assess the long-term outcomes of breast irradiation using IMRT (NCT01803139). In this study, investigators will recall all patients (n=358) enrolled in the original trial at 8 years to assess whether this technique also reduces permanent adverse effects including pain and cosmesis. This study will be open for recruitment in April 2013, with the estimated completion date of June 2014.
A randomized intergroup trial that compared whole-breast and accelerated partial-breast irradiation, including IMRT, sponsored by the U.S. National Cancer Institute and led by the National Surgical Adjuvant Breast and Bowel Project and the RTOG opened in early 2005 (NCT00103181). The trial is randomly assigning 4300 patients (2150 per treatment arm) to whole-breast or partial-breast irradiation after lumpectomy with tumor-free margins verified by histologic examination. The primary objective is to compare in-breast tumor control (ie, recurrence rates) for whole-breast versus partial-breast irradiation. Investigators anticipate accrual will be completed within 4.6 years (June 2015) from the trial‘s start date. Lacking data with adequate follow-up from this or similar RCTs, there is inadequate published evidence to permit scientific conclusions about partial-breast irradiation, regardless of whether it is delivered by IMRT or breast brachytherapy.
One randomized phase 3 trial for limited-stage small cell lung cancer treatment was identified comparing 3 different chest RT regimens, including IMRT (NCT00632853). This U.S. multicenter trial has an estimated enrollment of 729 patients and is sponsored by the Cancer and Leukemia Group B, in collaboration with the Radiation Therapy Oncology Group and the National Cancer Institute. The primary outcome measure is OS time between 3 treatment arms. This study is currently recruiting participants with the estimated completion date of June 2023. In addition, a phase 3 study from the M.D. Anderson Cancer Center is comparing 3D-CRT versus IMRT using 4-dimensional CT planning and image guided adaptive RT in 168 patients with locally advanced NSCLC receiving concurrent chemoradiation. The primary outcome measure is time to grade 3 pneumonitis. This study has closed but the results have not been published (NCT00520702).
Clinical Input Received Through Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 1 physician specialty society and 2 academic medical centers (3 reviewers) while this policy was under review in 2010. Those providing input suggested that IMRT should be utilized in select patients with breast cancer (eg, some cancers involving the left breast) and lung cancer (eg, some large cancers).
In response to requests, input was received from 2 physician specialty societies and 3 academic medical centers (3 reviewers) while this policy was under review in 2011. There was near uniform consensus in responses that suggested whole-breast and lung IMRT are appropriate in select patients with breast and lung cancer. Respondents noted IMRT may reduce the risk of cardiac, pulmonary, or spinal cord exposure to radiation in some cancers such as those involving the left breast or large cancers of the lung. Respondents also indicated whole-breast IMRT may reduce skin reactions and potentially improve cosmetic outcomes. Partial-breast IMRT was not supported by the respondents, and the response was mixed on the value of chest wall IMRT postmastectomy.
For the treatment of breast cancer, based on randomized and nonrandomized comparative studies, whole-breast intensity-modulated radiotherapy (IMRT) appears to produce clinical outcomes comparable with that of 3D-conformal radiation therapy (3D-CRT). In addition, there is some evidence for decrease in acute skin toxicity with IMRT compared with 2D radiotherapy (2D-RT). Dosimetry studies have demonstrated that IMRT reduces inhomogeneity of radiation dose, thus potentially providing a mechanism for reduced skin toxicity. One randomized controlled trial (RCT) reported improvements in moist desquamation of skin, but did not report differences in grade 3 to 4 skin toxicity, pain symptoms, or quality of life. Another RCT reported no differences in cosmetic outcome at 2 years for IMRT compared with 2D-RT. There was strong support through clinical vetting for the use of IMRT in breast cancer for left-sided breast lesions in which alternative types of RT cannot avoid toxicity to the heart. Based on the available evidence and results of input from clinical vetting, in conjunction with a strong indirect chain of evidence and the potential to reduce harms, IMRT may be considered medically necessary for whole-breast irradiation when (1) alternate forms of RT cannot avoid cardiac toxicity and (2) IMRT dose planning demonstrates a substantial reduction in cardiac toxicity.
Studies on IMRT for partial-breast irradiation are limited and have not demonstrated improvements in health outcomes. Therefore, partial-breast IMRT in the treatment of breast cancer is considered investigational.
No studies have reported on health outcomes after IMRT for chest wall irradiation in postmastectomy breast cancer patients. Available studies have only focused on treatment planning and techniques. The risk of secondary lung cancers and cardiac toxicity needs to be further evaluated. Therefore, IMRT for chest wall irradiation in postmastectomy breast cancer patients is considered investigational.
For the treatment of lung cancer, based on nonrandomized comparative studies, IMRT appears to produce clinical outcomes comparable with that of 3D-CRT. Dosimetry studies report that IMRT can reduce radiation exposure to critical surrounding structures, especially in large lung cancers. Results of clinical vetting indicate strong support for IMRT when alternative RT dosimetry exceeds a threshold of 20 Gy dose-volume (V20) to at least 35% of normal lung tissue. As a result of available evidence and clinical vetting, in conjunction with a strong indirect chain of evidence and potential to reduce harms, IMRT of the lung may be considered medically necessary for lung cancer when: (1) RT is given with curative intent, (2) alternate RT dosimetry demonstrates radiation dose exceeding 20 Gy dose-volume (V20) for at least 35% of normal lung tissue, and (3) IMRT reduces the 20-Gy dose-volume (V20) of radiation to the lung at least 10% below the V20 of 3D-CRT (eg, 40% reduced to 30%). IMRT for the palliative treatment of lung cancer is considered not medically necessary because conventional radiation techniques are adequate for palliation.
Practice Guidelines and Position Statements
The current National Comprehensive Cancer Network (NCCN) guidelines for breast cancer indicate that for whole-breast irradiation, uniform dose distribution and minimization of toxicity to normal tissue are the objectives and list various approaches to achieve this, including IMRT.(37) The guidelines note accelerated partial-breast irradiation is generally considered investigational and should be limited to use in clinical trials. Additionally, IMRT is not mentioned as a technique in partial-breast irradiation. The guidelines indicate chest wall and regional lymph node irradiation may be appropriate postmastectomy in select patients, but IMRT is not mentioned as a technique for irradiation in these circumstances.
Current NCCN guidelines for NSCLC indicate that “more advanced technologies are appropriate when needed to deliver curative radiation therapy safely. These technologies include (but are not limited to) IMRT…. Nonrandomized comparisons of using advanced technologies versus older techniques demonstrate reduced toxicity and improved survival.”(38)
The current NCCN guidelines for small cell lung cancer indicate “use of more advanced technologies is appropriate when needed to deliver adequate tumor dose while respecting normal tissue dose constraints.” IMRT is included in the technologies listed.(39)
The American Society for Radiation Oncology published consensus guidance on radiation to the lung in 2010. The guidance recommends limiting the 20-Gy dose-volume (V20) of radiation to the lung to less than or equal to between 30% to 35% or less and mean lung dose to 20 to 23 or less Gy (with conventional fractionation) to reduce the risk of radiation pneumonitis to 20% or less.(40)
Medicare National Coverage
No national coverage determination (NCD) was identified. In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
Some local medical review policies, published by Medicare Part B carriers, have indicated that IMRT for the lung is considered medically necessary. These documents do not provide a detailed rationale for this conclusion.