Subject:
Radiation Therapy for Breast Cancer
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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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. Earlier methods involved 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. These methods were collectively termed conventional external beam radiation therapy (EBRT).
Subsequent enhancement evolved 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. Radiation oncologists used these images, displayed from a "beam's-eye-view", 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 beam). The planner/radiotherapist modified one or more parameters and recalculated 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).
Other methods were subsequently developed to permit beam delivery with non-uniform cross-sectional intensity. This often relies on a device (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. Beams may remain on as MLCs move around the patient (dynamic MLC), or they may be off during movement and turned on once the MLC reaches prespecified positions ("step and shoot" technique). Another method of delivering radiation beam uses a small radiation portal emitting a single narrow beam that moves spirally around the patient, with intensity varying as it moved. This method, also known as tomotherapy or helical tomotherapy, is described as the use of a linear accelerator inside a large "donut" that spirals around the body while the patient laid on the table during treatment. 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 that 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).
Policy:
(NOTE: This policy only applies to adult members. It does not apply to pediatric members.
NOTE: For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)
I. Whole breast irradiation following breast-conserving surgery
A. The use of up to 16 fractions of three-dimensional conformation radiation therapy (3DCRT) followed by up to 5 fractions of electrons or photons as a boost to the surgical bed is considered medically necessary for radiation treatment to the whole breast with or without treatment to the low axilla.
B. The use of up to 28 fractions of 3DCRT followed by up to 8 fractions of electrons or photons as a boost to the surgical bed is considered medically necessary for ANY of the following:
1. Regional lymph node radiation requiring a separate supraclavicular, axillary, and/or internal mammary node field
2. Collagen vascular disease
3. Breast augmentation
C. Note that the boost to the surgical bed is planned using either electrons (CPT®77321) or if using photons, a complex isodose technique (CPT®77307). A brachytherapy boost is not considered medically necessary. The use of electronic brachytherapy or AccuBoost® is considered investigational.
D. The use of intensity modulated radiation therapy (IMRT) for treatment of the whole breast is not considered medically necessary.
II. Partial breast irradiation following breast-conserving surgery
A. Accelerated partial breast irradiation using 10 fractions delivered twice daily or 5 fractions delivered once daily with 3DCRT, IMRT or high dose rate (HDR) brachytherapy (intracavitary or interstitial) is considered medically necessary.
B. Partial breast irradiation using 15 or 16 fractions delivered once daily with 3DCRT is considered medically necessary.
C. The use of electronic brachytherapy or AccuBoost® is considered investigational.
III. Intraoperative radiation therapy (IORT)
A. For single fraction IORT at the time of breast conserving surgery in a node-negative individual 50 years of age or older with invasive cancer and negative surgical margins, the use of electron-beam IORT and low-energy x-ray IORT using the INTRABEAM® device are considered medically necessary.
B. In an individual who is found to have adverse pathologic features, supplemental radiation using up to 28 fractions of 3DCRT is considered medically necessary.
C. IORT not done at the time of lumpectomy (i.e., as a boost after whole breast irradiation) is not considered medically necessary.
D. The use of other forms of intraoperative brachytherapy, including but not limited to electronic brachytherapy, is considered investigational.
IV. Post-mastectomy radiation is considered medically necessary in an individual with positive axillary lymph node(s), a primary tumor greater than 5 cm or positive or close (< 1 mm) surgical margins
A. The use of up to 28 fractions of 3DCRT to the chest wall and, if needed, to regional nodes followed by up to 8 fractions of an electron boost is considered medically necessary.
B. The use of IMRT is not considered medically necessary.
V. Locoregional radiation therapy in an individual with metastatic disease who has no evidence of clinical disease following surgery and/or chemotherapy.
A. The use of up to 25 fractions of 3DCRT is considered medically necessary.
VI. Palliation
A. The use of up to 10 fractions of 3DCRT is considered medically necessary.
Medicare Coverage:
There is no National Coverage Determination (NCD) for Radiation Therapy. In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for radiation therapy. However, Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has issued a determination for Intensity-Modulated Radiation Therapy (IMRT). For additional information and eligibility, refer to Local Coverage Determination (LCD): Intensity Modulated Radiation Therapy (IMRT) (L36711) and Local Coverage Article: Billing and Coding: Intensity Modulated Radiation Therapy (IMRT) (A56725). Available at: https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=36711&ver=18&name=314*1&UpdatePeriod=749&bc=AAAAEAAAAAAAAA%3d%3d&
Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy for Radiation Treatment of Breast Carcinoma other than IMRT.
Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.
FIDE-SNP Coverage:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.
[INFORMATIONAL NOTE: Early stage breast cancer is typically treated with mastectomy with or without radiotherapy to the chest wall, or lumpectomy followed by radiotherapy. Indications for post-mastectomy radiotherapy include the presence of multiple positive axillary lymph nodes, positive or narrow margins (< 1 mm), or large primary tumor size (> 5 cm). In breast-conserving therapy, radiotherapy is indicated for most women after local excision of ductal carcinoma in situ (DCIS) or invasive carcinoma. In some women over the age of 70 who have been diagnosed with invasive breast cancer, radiation therapy may be safely omitted, especially if they have comorbidities.
Hypofractionated Whole Breast Irradiation (HF-WBI)
Several randomized trials have confirmed the efficacy of a hypofractionated regimen in the adjuvant treatment of breast cancer. In the Ontario trial, Whelan et al. (2010) randomized 1234 women with invasive carcinoma, negative axillary nodes and negative margins to 50 Gy in 25 fractions or to 42.5 Gy in 16 fractions to the whole breast. At 10 years, the hypofractionated regimen was not inferior to standard fractionation with respect to recurrence, survival or toxicity.
The START-B trial enrolled, 2215 women with stage pT1-3a, pN0-1 invasive carcinoma who were randomized to 50 Gy in 25 fractions or to 40 Gy in 15 fractions. At a median follow up of 6 years, there was no statistical difference in the rate of locoregional recurrence (LRR) between the groups (Yarnold et al., 2008). At a median follow up of 9.9 years, there remained no difference in LRR. The hypofractionated regimen was associated with higher rates of disease-free survival (DFS) and overall survival (OS) as well as reduced rates of breast shrinkage, telangiectasia and breast edema.
Brunt et al (2020) published “3 weeks (FAST-Forward): 5-year efficacy and late normal tissue effects results from a multicentre, non-inferiority, randomized, phase 3 trial.” In this randomized phase III trial, 4096 patients with early stage invasive breast cancer (pT1–3, pN0–1, M0) who had undergone breast conservation surgery or mastectomy were randomized to receive 1 week of radiation versus 3 weeks of radiation therapy. Patients were allocated to receive 40 Gy in 15 fractions of 2.67 Gy (3 weeks); 27 Gy in five fractions of 5.4 Gy (1 week); or 26 Gy in five fractions of 5.2 Gy (1 week). For patients undergoing breast conservation, a sequential tumor boost was allowed (10 Gy of 16 Gy in 2 Gy fractions). With a median follow-up of 71.5 months, 27 Gy and 26 Gy in five fractions were non inferior to 40 Gy in 15 fractions in terms of ipsilateral breast tumor relapse. The cumulative number of ipsilateral breast tumor relapse was 79 (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group). The HRs versus 40 Gy in 15 fractions were 0.86 (95% CI 0.51 to 1.44) for 27 Gy in five fractions and 0•67 (0.38 to 1.16) for 26 Gy in five fractions). There was a significant difference in late onset normal tissue effects between 40 Gy and 27 Gy (p=0.0003) but there was no significant difference in late normal tissue effects between 40 Gy and 26 Gy (p=0.17). The authors concluded that a 1 week schedule of radiation was non-inferior to a 3 week schedule of radiation in terms of ipsilateral breast tumor relapse and late onset tissue effects were similar for patients receiving 40 Gy and 26 Gy (Brunt et al., 2020).
In 2018, updated evidence-based guidelines on radiation therapy for the whole breast were published by the American Society for Radiation Oncology to provide guidance on fractionation for whole breast irradiation (Smith et al., 2018). The guideline recommends a hypofractionated regimen for all age groups and all stages, including DCIS, as long as additional fields are not used to encompass regional lymph nodes. DCIS may be included for hypofractionated regimens. The tangent fields may encompass the low axilla, as clinically necessary. The recommended dose regimens are 4000 cGy in 15 fractions or 4250 cGy in 16 fractions for whole breast. When tumor bed boost is being used, 1000 cGy in 4 to 5 fractions is suggested as the standard tumor bed boost. 3DCRT with field-in-field technique is recommended. The volume of breast tissue receiving greater than 105% of the dose should be kept to a minimum. The contoured tumor bed should receive a minimum of 95% of the prescribed dose. Breast size and mid-plane separation should not be determining factors as long as dosimetric homogeneity guidelines are met. The use of chemotherapy prior to radiation or the use of concurrent treatment with hormonal therapy or trastuzumab is not a contraindication to hypofractionation (Smith et al., 2018).
Radiation Planning Techniques
Whole Breast
The updated guideline referenced above also provided guidelines around treatment technique and planning for women receiving whole breast irradiation. The authors state that “…3-dimensional conformal treatment planning with a ‘field-in-field’ technique is recommended as the initial treatment planning approach.” Further, “(d)eep inspiration breath hold, prone positioning, and/or heart blocks are recommended to minimize heart dose.” They also state that “(f)or patients with significant daily positioning variations, daily imaging may be used.”
As a participant in the Choosing Wisely® campaign, ASTRO recommended not to “…routinely use intensity modulated radiotherapy (IMRT) to deliver whole breast radiotherapy as part of breast conservation therapy.” They further state that “…the term ‘IMRT’ has generally been applied to describe methods that are more accurately defined as field-in-field 3-D conformal radiotherapy.” And “…while IMRT may be of benefit in select cases where the anatomy is unusual, its routine use has not been demonstrated to provide a significant clinical advantage.”
Therefore, in treatment of the whole breast, the use of 3DCRT without IGRT is considered medically necessary. The use of IMRT is considered not medically necessary, though an exception will be considered if an optimized 3D conformal plan fails to meet tolerances of nearby organs at risk (OARs).
Boost
The guideline also discusses recommendations concerning a boost. Specifically, “…a tumor bed boost is recommended for patients with invasive breast cancer who meet any of the following criteria: age < 50 years with any grade, age 51 to 70 years with high grade, or a positive margin.” They also state that “…omitting a tumor boost is suggested in patients…age >70 with hormone receptor-positive tumors of low or intermediate grade resected with widely negative (>2 mm) margins.”
The dose recommended “(i)n the absence of strong risk factors for local recurrence (is)…1000 cGy in 4 to 5 fractions…(i)n the presence of strong risk factor(s) for local recurrence…a higher radiation boost dose of 1400 to 1600 cGy in 5 fractions may also be used.”
With respect to timing and technique, the guideline states that a “…sequential boost is currently recommended” and that “…external beam treatment is recommended…” Given this, the use of a photon or electron boost is considered medically necessary. The use of brachytherapy, including but not limited to interstitial, intracavitary, or intraoperative, for a boost is considered not medically necessary.
Partial Breast Irradiation
The IMPORT LOW trial is a multicenter, randomized phase 3 trial which demonstrated non-inferiority for partial breast radiation therapy using standard external beam radiation therapy techniques (Coles et al., 2017). Between May 2007 and October 2010, 2018 women with low risk, early stage breast cancer who underwent breast conserving surgery were randomized to whole breast radiation therapy versus partial breast radiation. Patients were randomized to receive 40 Gy in 15 fractions to the whole breast, 36 Gy in 15 fractions to the whole breast, or 40 Gy in 15 fractions to the partial breast. The study required that all patients receive 3D conformal radiation therapy using forward-planned, field in field radiation techniques. The treatment was delivered with medial and lateral tangential beams to minimize dose to surrounding lung and heart and to ensure that the beams exit within the breasts. At a median follow-up of 72.2 months, there was no difference in the 5 year local relapse rate (whole breast 1.1% vs partial breast 0.5%, p=0.42). The estimated 5-year absolute differences in local relapse compared with the control group were -0.38% (-0.84 to 0.90) for the partial breast group and -0.73% (-0.99 to 0.22) for the reduced-dose group. The patients in the partial breast group reported statistically significant fewer adverse cosmetic events (change in breast appearance, p=0.007 and breast harder or firmer, p=0.002) compared to the whole breast group. As this study used the same dose fractionation scheme for the whole breast and the partial breast group, this study concluded that partial breast radiation using standard external beam radiation therapy techniques is non-inferior to standard dose whole breast radiation therapy in terms of local relapse and resulted in a lower rate of adverse late tissue effects.
Accelerated Partial Breast Irradiation (APBI) is a technique in which the target of the radiation is only a portion of the breast with the greatest likelihood of harboring residual cancer cells after lumpectomy. The technique is called “accelerated” because it is given twice daily for five days, with each fraction delivering a relatively higher dose.
Correa et al. (2017) recently published an update of an ASTRO evidence-based consensus statement for APBI. In this update, a “Suitable Group” was defined as eligible for APBI. The “Suitable Group” included those with stage T1s or T1, age 50 or greater, and with negative margins by at least 2 mm. The DCIS group now considered “Suitable” must include all of the following: screen-detected, low to intermediate nuclear grade, no more than 2.5 cm, and have a resection margin of at least 3 mm. Definition of both the “Cautionary” and “Unsuitable” Groups are defined in the updated ASTRO consensus statement. These updates were accepted by the National Comprehensive Cancer Network (NCCN®) which further recommends 10 fractions twice daily using brachytherapy or external beam photon therapy. Typical doses cited in the NCCN Guidelines® are 34 Gy in 10 fractions with twice daily treatment using brachytherapy. External beam treatment is recommended with 38.5 Gy in 10 fractions with twice daily treatment. They also indicate that “…other fractionation schemes are currently under investigation.” Therefore, up to 10 fractions (whether photon or brachytherapy) for APBI is considered medically necessary.
The American Brachytherapy Society issued their consensus statement for APBI in early 2018. They reviewed guidelines and consensus statements from ASTRO, GEC-ESTRO, the American Society of Breast Surgeons as well as their own previous guidelines. Seven randomized trials of APBI and two trials evaluating intraoperative radiation, the TARGIT-A and ELIOT clinical trials were reviewed. The new consensus statement criteria include age 45 years or older; size 3 cm or less; all invasive subtypes and DCIS; positive or negative ER status; negative surgical margins with no tumor on ink for invasive cancers and at least a 2 mm margin for DCIS; no evidence of lymphovascular space invasion and negative lymph node status. Recommendations on treatment technique with strong or moderate evidence include multicatheter interstitial brachytherapy; external beam techniques of IMRT and 3DCRT; and applicator brachytherapy. Participation in clinical trials and protocols was recommended for proton beam, intraoperative radiation therapy, and electronic brachytherapy. In considering electronic brachytherapy as an APBI technique and intraoperative technique, the review centered on the reports of 702 patients and a group of 146 DCIS patients and concluded that electronic brachytherapy should not be used outside of a clinical trial.
Most recently, data from NSABP B39/RTOG 0413 was presented at the 2018 SABCS conference. In this trial, 4216 patients with DCIS or stage I-II (≤ 3cm and 0-3 positive axillary nodes) invasive adenocarcinoma were randomized to whole breast irradiation (WBI) or APBI (using MammoSite® or 3D conformal external beam radiotherapy) after lumpectomy. The primary endpoint was rate of ipsilateral breast tumor recurrence (IBTR) while secondary endpoints included relapse free survival (RFI), distant disease free survival (DDFI) and overall survival (OS). At 10 years, 95.2% of APBI patients were IBTR-free vs. 95.9% of WBI patients. Though this was not statistically significantly different, the “hazard ratio did not meet the statistical criteria for treatment equivalence.” Further, the 10-year RFI was statistically improved with WBI as compared to APBI (93.4% vs. 91.9%). There was no difference, however, in DDFI, DFS or OS. Given the small differences in IBTR and RFI, “PBI may be an acceptable alternative to WBI for a proportion of women who undergo breast-conserving surgery.”
At the 2019 San Antonio Breast Cancer Symposium, Meattini et al. presented “Accelerated partial breast or whole breast irradiation after breast conservation surgery for patients with early breast cancer: 10-year follow up results of the APBI IMRT Florence randomized phase 3 trial.” In the APBI IMRT Florence phase 3 trial, women with breast cancer age>40 years, pT<25 mm, and final surgical margins > 5 mm were randomized to APBI using IMRT to 30 Gy in 5 fractions and to conventional fractionation whole breast irradiation (WBI) to 50 Gy in 25 fractions followed by tumor bed boost to 10 Gy in 5 fractions. At a median follow-up of 10 years, there was no significant difference in ipsilateral tumor recurrence (IBTR) in APBI vs. WBI 3.9% vs. 2.6% with the HR for APBI patients compared with WBI patients was 1.57 (p=0.39; 95% CI: 0.56-4.41). There was no significant difference between the treatment arms in overall survival or in breast cancer specific survival. The authors conclude that ABPBI using IMRT in 5 once daily fractions (30 Gy in 5 fractions) results in a low 10 year cumulative IBTR that is not significantly different from patients treated with WBI.
AccuBoost® Non-Invasive Image-Guided Breast Brachytherapy (NIIGBB) (Advanced Radiation Therapy, Inc., Billerica, MA) is a method of IGRT that incorporates a real-time image guidance mammography-based system to deliver noninvasive brachytherapy. The breast is immobilized using moderate compression. Digital mammography provides localization of the target volume. Custom applicators, ranging from 4 to 8 cm in diameter, are designed to deliver a highly collimated beam, which are used with an HDR remote afterloading system. The applicators are mounted on mammography paddles, centered on the target to deliver HDR IR-192 along two intersecting orthogonal axes sequentially. To use AccuBoost®, the tumor bed must be visible on mammogram, the planning target volume (PTV) must be less than or equal to 8 cm, and the breast must be compressible to a plate separation less than or equal to 7 cm. There is limited clinical data on AccuBoost®. The data is primarily dosimetric or feasibility studies. In “Breast boost using noninvasive image-guided breast brachytherapy vs. external beam: a 2:1 matched-pair analysis,” Leonard KL et al (2013) provide a retrospective analysis of 47 patients treated with AccuBoost® compared to 94 matched controls treated with standard electrons or photons. This study is limited by short follow-up (median follow-up of 13.6 months) and that it is retrospective in nature. In the publication “The rationale, technique, and feasibility of partial breast irradiation using noninvasive image-guided breast brachytherapy,” Schuster et al. (2016) report a multicenter study examining the feasibility of AccuBoost® in 518 patients. This is feasibility study. This study does not compare AccuBoost® against the standard of care which is radiation therapy to the boost using photons or electron.
Sioshansi et al. (2011) conducted a study of dose modeling of NIIGBB, compared with electron beam and 3DCRT partial breast radiation. This study modeled the NIIGBB dose distributions as a point source. Dose volume comparisons were evaluated in eight patients and compared to 3DCRT and electron boost simulations. Patient eligibility required a clearly defined target cavity identified on CT, > 5 mm distance between the posterior aspect of the cavity and the chest wall, and a breast that could be compressed in < 8 cm. The authors reported that the NIIGBB PTVs were significantly less than those of the 3DCRT and electron boost, allowing for more normal tissue sparing. Because NIIGBB directs radiation parallel to the chest wall, there is negligible dose delivered to the chest wall and lung. NIIGBB, compared to electrons and 3DCRT, resulted in lower maximum dose to the skin (60% and 10% respectively), and chest wall/lung (70 to 90%).
There is, as yet, little clinical information available on the long-term results in patients treated with this technique. A multi-institutional study showed acceptable rates of acute skin toxicity and a high rate of excellent or good cosmetic results at 6 months. In a study from Tufts Medical Center (Leonard et al., 2012), the cosmetic results and skin and subcutaneous toxicities were similar in 18 matched pairs of patients with more than 6 months follow up treated with either AccuBoost® or a conventional electron boost. This device has also been used for APBI, again with very limited follow up of small numbers of patients. Hepel et al. presented the results of the patient registry for APBI at the 2018 ASTRO meeting and concluded longer follow up is needed to confirm late end points. Given the paucity of data regarding the use of NIIGBB, particularly on local control, additional research is necessary prior to widespread approval of NIIGBB. Therefore, NIIGBB is considered investigational.
IORT
The use of IORT for the treatment of breast cancer has been evaluated in two prospective randomized clinical trials, TARGIT-A which utilized low-energy xrays (using INTRABEAM®) and ELIOT, which utilized electrons.
TARGIT-A
In the TARGIT-A trial, patients 45 years or older with unifocal invasive ductal carcinoma (preferably less than 3.5 cm) were randomized to receive IORT (to the lumpectomy bed) or external beam radiation therapy (EBRT) to the whole breast (with or without a boost). Those receiving IORT were stratified by timing of the IORT (pre-pathology versus post-pathology) and by facility. For pre-pathology patients randomized to IORT, supplemental EBRT to the whole breast (without a boost) was given when pathology from the lumpectomy revealed either invasive lobular carcinoma, extensive intraductal component or another adverse criterion (i.e. high-grade, lymphovascular invasion, nodal involvement). In this setting, IORT was considered the boost. The primary outcome evaluated was local control in the conserved breast.
Initial results were published in 2010 at which time data was presented on 2232 patients, 862 who had a median follow up of 4 years and 1514 who had a median follow up of 3 years. Of the 1113 patients randomized to IORT, 996 received the allocated treatment. Of the 1119 patients randomized to EBRT, 1025 received the allocated treatment. At four years, there was no significant difference in the estimate of local recurrence between IORT and EBRT (1.2% versus 0.95%, p = 0.41). It is noted that in the pre-pathology IORT group, 14.2% of patients received supplemental EBRT.
In a more recent update published in 2014, a total of 3451 patients randomized to IORT and 1730 patients randomized to EBRT were evaluated. Within the IORT group, 2298 were randomized prior to the lumpectomy (pre-pathology strata) and 1153 were randomized after lumpectomy (post-pathology strata). Median follow-up of the 3451 patients who had received IORT was two years and five months. 2020 patients had a median follow up of four years and 1222 patients had a median follow up of five years (note that only 611 patients [18%] had 5-year follow up). At five years, the risk for local recurrence with IORT was significantly higher as compared to EBRT (3.3% versus 1.3%, p = 0.042). When considering the pre-pathology strata, the risk of local recurrence was 2.1% with IORT versus 1.1% (p = 0.31). This contrasts with the post-pathology strata where the recurrence was 5.4% with IORT versus 1.7% with EBRT (p = 0.069). Based on this data, the authors conclude that “TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative external beam breast radiotherapy.”
In response to this publication, several authors have criticized the statistical analysis. For example, Cuzick (2014) states “…there are several major deficiencies in the analysis…” including “…the misuse of the non-inferiority criterion…” which “…clearly fails…” as the ‘…Kaplan-Meier estimates… establish a 2% superiority of external beam radiotherapy (p = 0.04) and a CI extending beyond 2.5%.’” Cuzick further states the “…protocol clearly states that the primary analysis population includes all randomized patients. However, the report concentrates on the prepathology group.”
Haviland et al. (2014) stated that “…assessment of local recurrence at 5 years by comparison of binomial proportions is appropriate only if 5-year follow-up is available for all patients, whereas only 611 of 3451 patients have reached this point. This analysis, including the non- inferiority test statistic, is therefore unreliable.” The authors conclude that “…the TARGIT-A trial remains inconclusive, and intraoperative radiotherapy using TARGIT remains an experimental treatment.”
Finally, Silverstein et al. (2014) indicated that “…the results of the TARGIT-A trial, with a median follow-up (FU) of 29 months, is still well below the median time when breast recurrences can be expected, especially since more than 90 % of TARGIT-A women were estrogen receptor positive, and at least 65% received adjuvant hormonal therapy, a treatment well-known to delay recurrences in ER+ women.” In addition, they note that “…overall breast recurrence rates in the TARGIT group also exceeded rates in the EBRT group, a difference at borderline statistical significance (p = 0.053).” They conclude that “…with 29 months of median follow-up, the TARGIT data are still immature and risk-adapted IORT with 50-kV X-rays is still too early in follow-up to select the subset of women whose local control will be within their noninferiority criteria margin of 2.5%. Until the data are more mature, 50-kV patients should be treated under strict institutional protocols.”
ELIOT
In the ELIOT trial, 1305 patients 48 years or older with tumors 2.5 cm or smaller were randomized to receive IORT with electrons or EBRT. Patients were stratified by tumor size (<1.0 cm vs. 1.0 to 1.4 cm vs. 1.5 cm). The primary endpoint was the occurrence of ipsilateral breast tumor recurrences (IBTR), which included true local relapse plus new ipsilateral breast tumor. Median follow up for all patients was 5.8 years.
Results revealed that there was a significantly greater occurrence of IBTR in the IORT group compared to the EBRT group at five years (4.4% versus 0.4%, p = 0.0001). The five-year rate of true local recurrence (occurring in the index quadrant) was also significantly higher in the IORT group compared to the EBRT group (2.5% versus 0.4%, p = 0.0003). The rate of new ipsilateral breast carcinoma was also significantly higher in the IORT group compared to the EBRT group (1.9% versus 0%, p = 0.0001). Finally, it was noted that the IORT group developed a significantly higher rate of axillary or other regional lymph node metastases (1% versus 0.3%, p = 0.03). At five years, overall survival did not differ between the two groups.
In a multivariate analysis of the IORT group, tumor size greater than 2 cm, presence of four or more positive lymph nodes, a poorly differentiated tumor and triple negative subtype were associated with nearly twice the risk of IBTR. The risk of IBTR at five years was 11.3% if any one of these unfavorable characteristics was present versus 1.5% in those without these features (p < 0.0001). It is noted that this group of patients with a low risk of IBTR is similar to that of the “suitable” APBI group as defined by ASTRO.
ASTRO CONSENSUS STATEMENT
ASTRO recently released an Evidence-Based Consensus Statement for APBI. In this statement, the authors recommend that patients “…be counseled that in 2 clinical trials the risk of IBTR was higher with IORT.”
With respect to IORT using electrons, the authors state that “ELIOT has a median of 5.8 years follow up (n = 1305). However, ELIOT patients with invasive cancer fitting the ’suitability’ criteria had a very low rate of IBTR. Among these patients, the 5-year occurrence of IBTR was approximately 1.5%, pointing out the importance of patient selection.” Hence the recommendation that “…electron beam IORT should be restricted to women with invasive cancer considered “suitable” for PBI.”
With respect to IORT using low-energy x-rays, the authors recommend that “…low-energy x-ray IORT for PBI should be used within the context of a prospective registry or clinical trial, per ASTRO Coverage with Evidence Development (CED) statement. When used, it should be restricted to women with invasive cancer considered ’suitable’ for partial breast irradiation based on the data at the time of this review.”
When further detailing their recommendations, the authors note that “…the five-year IBTR risk is based on the overall short follow up of the TARGIT trial, which limits precision of the five-year risk estimates. Although there was no statistically significant difference in IBTR risk for patients treated with IORT versus WBI in the TARGIT prepathology subgroup, the task force thought greater weight should be placed on evaluation of the efficacy of IORT in the prespecified primary analysis population that included all patients.” Given this and the concern of “…misuse of the noninferiority criterion…,” the authors “…felt low-energy x-ray IORT should continue to be used within the context of a prospective registry or clinical trial to ensure long-term local control and toxicity outcomes are prospectively monitored.” In addition, “…given the increased risk of IBTR, the task force advised that low-energy x-ray IORT, when used, be confined to patients with the lowest risk of IBTR, specifically those in the ’suitable’ group.”
In response to the Consensus Statement, Small et al. (2017) reiterated that the “TARGIT-A trial specified stratification between pre- and post-pathology before randomization…” and that “…the panel’s recommendations regarding IORT should have acknowledged the results for the pre-specified analysis for the primary end-point of IORT treatment in the whole trial (n = 3451, a difference of 2 % p = 0.04), as well the pre-pathology stratum (n = 2298, a difference of 1% p = 0.31)."
Conclusion
When considering all published data and editorials, electron beam and low-energy x-ray (INTRABEAM®) IORT are considered medically necessary for a node-negative individual with invasive cancer when used in accordance with the updated ASTRO Evidence-Based Consensus Statement for APBI.
Electronic Brachytherapy
The updated American Brachytherapy Society Consensus Statement recommends patients treated with electronic brachytherapy should not be offered…outside of clinical trial. Therefore, until such evidence is available, electronic brachytherapy for APBI or IORT is considered investigational.
Palliation
Primary therapy for women with metastatic breast cancer (M1 stage) is systemic therapy. However, if there is symptomatic breast or chest wall disease, a short course of radiotherapy may alleviate symptoms (i.e. 10 fractions). Evidence is limited with regard to the role of locoregional radiotherapy for M1 stage disease in the absence of symptomatic locoregional disease. Locoregional radiation therapy may be considered for women who initially present with metastatic disease but after surgery and/or chemotherapy are found to have no clinical evidence of disease. In such a scenario, the use of up to 25 fractions is considered medically necessary.]
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Radiation Therapy for Breast Cancer
Radiation Treatment of Breast Carcinoma
Breast Carcinoma, Radiation Treatment
Radiotherapy of Breast Carcinoma
References:
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2. Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med. 2001 Nov 8; 345(19):1378-1387.
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12. Harness JK, Silverstein MJ, Wazer DE, et al. Correspondence: Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014 May 17; 383(9930): 1718-1719.
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14. Hepel JT, Listo M, Leonard KL, et al. Multi-Institutional Registry Study of Accelerated Partial Breast Irradiation (APBI) Using Non-Invasive Image-Guided Breast Brachytherapy (NIBB). 2018 Nov 1, 102(3):e576. https://doi.org/10.1016/j.ijrobp.2018.07.1593.
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18. Leonard KL, Wazer DE, Styczynski JR, et al. Breast boost using noninvasive image-guided breast brachytherapy versus en face electrons: a matched pair analysis. Int J Radiat Oncol Biol Phys. 2012;84(3S suppl):S226 (abstract 2023).
19. Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using intensity modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial. Eur J Cancer. 2015 Jan;51: 451-463. doi: http://dx.doi.org/10.1016/j.ejca.2014.12.013.
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21. Meattini I, Saieva C, Livi, L. Letter to the editor: Authors reply to comments on our phase 3 trial comparing whole breast irradiation (WBI) to accelerated partial breast irradiation (APBI) using IMRT technique for low risk breast cancer (BC) patients. Eur J Cancer. 2015;51:1478-1479. doi: http://dx.doi.org/10.1016/j.ejca.2015.04.019.
22. Meattini I, Saieva C, Lucidi S, lo Russo M, et al. (2019). Accelerated partial breast or whole breast irradiation after breast conservation surgery for patients with early breast cancer: 10-year follow up results of the APBI IMRT Florence randomized phase 3 trial. 2019 San Antonia Breast Cancer Symposium. Eur J Cancer. 2015 Mar;51(4): 451-463. doi: 10.1016/j.ejca.2014.12.013.
23. Meattini I, Saieva C, Miccinesi G, et al. Accelerated partial breast irradiation using intensity modulated radiotherapy versus whole breast irradiation: Health-related quality of life final analysis from the Florence phase 3 trial. Eur J Cancer. 2017 Jan;76: 17-26. doi: http://dx.doi.org/10.1016/j.ejca.2017.01.023.
24. Moran MS, Truong PT. Intraoperative accelerated partial breast irradiation: caution still warranted. Int J Radiat Oncol Biol Phys. 2014 Jul 1; 89(3):496-498.
25. National Comprehensive Cancer Network (NCCN) Guidelines® Breast Cancer Version 3.2020 – March 24, 2020. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer Version 3.2020. ©2020 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN®. To view the most recent and complete version of the NCCN Guidelines®, go online to NCCN.org.
26. Roof KR, Marks LB. Breast intensity modulated radiation therapy versus tissue compensation: what’s in a name? Pract Radiat Oncol. 2014 Jan-Feb; 4(1):3-5.
27. Schuster J, Chipko C, Kasper M, et al. Updated feasibility and reproducibility results of multi-institutional study of noninvasive breast tumor bed boost. Brachytherapy. 2016;15(6):804-811. doi: 10.1016/j.brachy.2016.09.003.
28. Shah C, Vicini F, Shaitelman, et al. The American Brachytherapy Society consensus statement for accelerated partial-breast irradiation. Brachytherapy. 2018 Jan-Feb;17(1):154-170.
29. Shah C, Vincini F, Wazer, DE, et al. The American Brachytherapy Society consensus statement for accelerated partial breast irradiation. Brachytherapy. 2013 Jul-Aug; 12(4):267-277.
30. Silverstein MJ, Gastner G, Maluta S, et al. Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials. Part 1—ELIOT. Ann Surg Oncol. 2014 Nov; 21(12):3787-3792.
31. Silverstein MJ, Gastner G, Maluta S, et al. Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials. Part 2—TARGIT. Ann Surg Oncol. 2014 Nov; 21(12):3793-3799.
32. Sioshansi S, Rivard MJ, Hiatt JR, et al. Dose modeling of noninvasive image-guided breast brachytherapy in comparison to electron beam boost and three-dimensional conformal accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2011 Jun 1; 80(2):410-416.
33. Small W Jr., Alvarado M, Baum M, et al. Commentary on Accelerated partial breast irradiation consensus statement: update of an ASTRO evidence based consensus statement. Practical Radiat Oncol. 2017 May-Jun; 7(3):e159-163.
34. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 2009 Jul 15; 74(4):987-1001.
35. Smith BD, Bellon JR, Blitzbau R, et al. Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidenced-based guideline. Pract Radiat Oncol. 2018;8(3):145-152. doi: 10.1016/j.prro.2018.01.012.
36. Smith BD, Bentzen SM, Correa CR, et al. Fractionation for whole breast irradiation: an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011 Sep 1; 81(1)59-68.
37. Syed AMN, Chang H, Schwartzberg BS S, et al. Two-year follow-up results a multi-center trial of intra-operative electronic brachytherapy during breast conservation surgery for early stage breast cancer. 2016 San Antonio Breast Cancer Symposium. Cancer Res. 2017 Feb 15 77 (4 Supplement) P1-10-19.
38. Taunk NK, Prosnitz RG. Planning comparison of intensity modulated radiation therapy delivered with 2 tangential fields versus 3-dimensional conformal radiotherapy for cardiac sparing in women with left-sided breast cancer. Pract Radiat Oncol. 2012 October-December; 2(4):248-256.
39. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomized, non-inferiority trial. Lancet. 2010 Jul 10; 376(9735):91-102.
40. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial. Lancet. 2014 Feb 15; 383(9917):603-613.
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42. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Lancet Oncol. 2013 Dec; 14(13):1269-1277.
43. Vicini FA, Arthur D, Wazer D, et al. Limitations of the American Society of Therapeutic Radiology and Oncology consensus panel guidelines on the use of accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys. 2011 Mar 15; 79(4):977-984.
44. Wazer DE. Technological Updates on Targeting Partial Breast Dose via Non-Invasive Brachytherapy. AccuBoost Webinar. 2013 Apr 23.
45. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med. 2010 Feb 11; 362(6):513-520.
46. Yarnold JR, Offersen BV, Olivotto I, et al. Correspondence: Radiotherapy for breast cancer, the TARGIT-A trial. Lancet. 2014 May 17; 383(9930):1717-1718.
Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
HCPCS
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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