Intraoperative radiation therapy and brachytherapy in early-stage breast cancer: a narrative review of their role in the era of modern hypofractionated whole-breast irradiation

Introduction

Background

Breast-conserving therapy (BCT) is established as a safe and effective alternative to mastectomy for early-stage breast cancer. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis of 17 randomized trials and 10,801 women demonstrated that adjuvant whole-breast irradiation (WBI) following lumpectomy reduced the 10-year risk of any first recurrence from 35.0% to 19.3% and the 15-year risk of breast cancer death from 25.2% to 21.4% (1).

Conventional WBI was historically delivered over 5–7 weeks. The duration prompted decades of effort to develop accelerated alternatives, both to improve patient convenience and access, and to reduce healthcare costs. Two parallel strategies emerged. The first was accelerated partial breast irradiation (APBI), supported by pathologic data from mastectomy specimens demonstrating that the majority of clinically significant residual microscopic disease in early-stage breast cancer is located within approximately 1 cm of the index tumor (2). The seminal Holland series found that, of 282 invasive cancers ≤4 cm in size, 4–9% had occult invasive cancer foci more than 2 cm from the reference tumor and an additional 4–9% had non-invasive disease at that distance, supporting the rationale for partial-volume irradiation in carefully selected patients but also documenting a non-trivial residual rate of multifocal and multicentric disease (2). Modern breast magnetic resonance imaging (MRI) series likewise show occult multifocal or multicentric disease in approximately 9–16% of women otherwise judged to be candidates for breast conservation, with detection rates rising in dense breasts, lobular histology, and younger women (3).

The second strategy was hypofractionated WBI (HF-WBI). The Canadian trial (Whelan et al.) demonstrated 10-year non-inferiority of 42.5 Gy in 16 fractions vs. 50 Gy in 25 fractions, with ipsilateral breast tumor recurrence (IBTR) rates of 6.2% vs. 6.7% (4). The UK START A and B trials confirmed equivalent local control and improved late normal tissue effects with 40 Gy in 15 fractions over 3 weeks (5,6). FAST-Forward subsequently established that 26 Gy in 5 fractions over 1 week is non-inferior to 40 Gy in 15 fractions for both local control and late normal tissue effects (7). The Mayo MC1635 phase III randomized trial of 25 Gy in 5 fractions vs. 40 Gy in 15 fractions confirmed acceptable toxicity and patient-reported outcomes for ultrahypofractionation in a United States (U.S.) population (8).

Rationale, knowledge gap, and objective

Within this evolving landscape, intraoperative radiation therapy (IORT), balloon brachytherapy, and multicatheter brachytherapy continue to be offered at a subset of centers. An October 2025 National Broadcasting Company (NBC) News story characterized reduced U.S. adoption of IORT as principally driven by financial considerations rather than clinical evidence. The story featured a patient who had received IORT but ultimately required additional WBI following final pathology and reported notable late effects, including induration consistent with fibrosis at the lumpectomy site. That clinical course is an illustrative example of the limitations of risk-adapted IORT discussed in detail below: even when selection and risk-adaptation are applied prospectively, a meaningful proportion of patients ultimately require supplemental WBI and may experience cumulative toxicity at the operative bed.

Several narrative reviews and meta-analyses (9-17) have evaluated partial breast irradiation (PBI) relative to WBI, but most predate the maturation of both UHF-WBI (5-fraction regimens) and the 10-year results of the European Group of Curietherapy-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) and Florence APBI trials (18,19). No prior review has directly compared all four modalities—IORT, brachytherapy-based APBI, external beam APBI, and HF-WBI/ultrahypofractionated WBI (UHF-WBI)—alongside a structured engagement with the published health-economic literature in the context of a recent public media narrative attributing IORT underutilization to financial motives.

This review critically examines comparative oncologic and toxicity outcomes of IORT, brachytherapy, and external beam APBI relative to contemporary HF-WBI and UHF-WBI. We deliberately address the published health-economic literature alongside the clinical data. The financial and clinical narratives are independent variables: both can simultaneously be true, and a clinically rigorous response to the media coverage requires engaging with both. This article is presented in accordance with the Narrative Review reporting checklist (available at https://abs.amegroups.com/article/view/10.21037/abs-2026-0016/rc).

Methods

PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched, supplemented by hand-searching of the reference lists of major reviews and American Society for Radiation Oncology (ASTRO), ESTRO, American Society of Breast Surgeons (ASBrS), and GEC-ESTRO consensus documents. Only English-language publications were included. The search strategy is summarized in Table 1.

Comparative evidence

Radiobiologic considerations

Breast cancer is sensitive to dose per fraction. Estimates from the START and other trials place the breast tumor α/β ratio at approximately 4.0 Gy (range, 1.5–10 Gy across analyses), late-responding breast normal tissue at approximately 3.4 Gy, and acute-responding tissue at approximately 10 Gy (5,6,20). These values are similar to those of late-responding normal tissues, providing the radiobiologic justification for hypofractionation.

Direct comparisons of dose across fractionation schemes require conversion to biologically effective dose (BED) and equivalent dose in 2 Gy fractions (EQD2). Using α/β = 3.4 Gy for breast late effects (5):

• FAST-Forward 26 Gy/5 fractions: BED_3.4 = 26 × (1 + 5.2/3.4) ≈ 65.7 Gy; EQD2 ≈ 41.4 Gy.
• 40 Gy/15 fractions: BED_3.4 = 40 × (1 + 2.67/3.4) ≈ 71.4 Gy; EQD2 ≈ 45.0 Gy.
• TARGIT 50 kVp 20 Gy surface dose (single fraction): BED_3.4 = 20 × (1 + 20/3.4) ≈ 137.6 Gy; EQD2 ≈ 86.8 Gy at the applicator surface, but falling to <5 Gy at 1 cm depth.
• ELIOT 21 Gy single-fraction electron IORT to the prescription depth: BED_3.4 = 21 × (1 + 21/3.4) ≈ 150.7 Gy; EQD2 ≈ 95.0 Gy.

These calculations make explicit a feature that is sometimes obscured: at the applicator surface, IORT delivers a far higher BED than fractionated WBI, while delivering essentially no dose to the remaining breast volume. Because the linear-quadratic (LQ) model becomes increasingly uncertain at single-fraction doses above approximately 8–10 Gy, BED/EQD2 values for IORT should be interpreted as illustrative rather than definitive (21). Modifications to the LQ model and alternative formulations (e.g., universal survival curve, modified LQ) have been proposed for the high single-fraction range and yield somewhat different estimates.

Three radiobiologic implications follow. First, the apparent paradox that single-fraction IORT achieves clinically meaningful local control at the tumor bed is consistent with the very high local BED. Second, the entire remainder of the breast receives essentially no irradiation, and therefore any occult disease beyond approximately 1 cm of the cavity (present in 4–9% of cT1–2 N0 patients in the Holland series and 9–16% by modern MRI) is untreated by IORT alone (2,3). Third, comparing single-fraction IORT to fractionated WBI on the basis of EQD2 alone is not by itself sufficient to predict either tumor control or late toxicity, and any radiobiologic discussion at IORT dose levels must explicitly state the model’s limitations (21,22).

Differentiation of IORT platforms: TARGIT vs. ELIOT

Throughout the literature TARGIT and ELIOT are sometimes discussed interchangeably as “IORT”, but the platforms differ substantially. TARGIT-IORT uses the Intrabeam device (Carl Zeiss Meditec, Jena, Germany), which delivers low-energy 50 kVp photons via a spherical applicator placed in the lumpectomy cavity, with a prescription dose of 20 Gy at the applicator surface and a steep depth fall-off such that the dose at 1 cm depth is roughly 5–6 Gy (23,24). The relative biologic effectiveness of low-energy photons exceeds that of megavoltage beams, and the dose distribution is highly heterogeneous across the cavity wall (21).

ELIOT, by contrast, employs a mobile linear accelerator delivering 6–9 MeV electrons through a Lucite collimator applied directly to the surgically dissected tumor bed, with a prescription dose of 21 Gy in a single fraction and substantially deeper penetration than 50 kVp photons (25,26). The two devices therefore differ in beam quality, dosimetric profile, target volume definition, and operative workflow. They are appropriately considered separately when interpreting comparative outcomes.

TARGIT-A: risk-adapted IORT

TARGIT-A randomized 2,298 women aged ≥45 years with cT1–2 cN0–1 unifocal invasive ductal carcinoma to risk-adapted single-dose 20 Gy 50 kVp IORT vs. standard WBI between 2000 and 2012, with results reported initially in 2010 (23) and updated in 2014 (24). Two design features are essential to interpretation. First, randomization could occur “pre-pathology” (intraoperative IORT delivered concurrent with lumpectomy) or “post-pathology” (IORT delivered after final pathology in a subsequent procedure). Second, the trial was risk-adapted: any patient assigned to IORT who, on final pathology, was found to have unfavorable features (e.g., lobular histology, extensive in-situ component, lymphovascular invasion, close margins, large size, or grade 3 disease, depending on local protocol) received supplemental WBI. The proportion of IORT-arm patients who ultimately received supplemental WBI was approximately 15–20% across centers.

The 2020 BMJ long-term update reported, in the pre-pathology stratum (the protocol-intended population of concurrent IORT), 5-year complete-follow-up local recurrence of 2.11% with risk-adapted IORT vs. 0.95% with WBI [difference 1.16%; 90% confidence interval (CI): 0.32–1.99], within the pre-specified non-inferiority margin of 2.5% (27). With longer follow-up, 24 of 1,140 IORT patients vs. 11 of 1,158 WBI patients experienced local recurrence; mortality outcomes diverged in the opposite direction, with 42 vs. 56 deaths reported. Non-breast-cancer mortality in the IORT arm was lower than in the WBI arm (1.4% vs. 3.5% in the original 2014 update), driven primarily by reductions in cardiovascular and other-cancer deaths (24,27). If replicated in independent randomized data this signal would be of substantial clinical importance, particularly for left-sided cancers and women with cardiac risk factors. Independent reanalysis of the TARGIT-A data has, however, raised methodologic concerns regarding censoring and competing-risks handling that affect the magnitude of the local control difference and the interpretation of the mortality signal (28), and these critiques should be acknowledged.

Several caveats follow. First, the post-pathology stratum showed substantially worse local control with delayed IORT than the pre-pathology stratum, and that difference is design-relevant rather than treatment-effect-relevant. Second, the trial’s non-inferiority margin of 2.5% in absolute IBTR is wider than many oncologists consider clinically acceptable, and the IBTR difference observed in the pre-pathology stratum (1.16%) is, in absolute terms, larger than the difference between FAST-Forward 26 Gy and 40 Gy/15 fractions (1.4% vs. 2.1%; difference 0.7%) or between Florence APBI and WBI at 10 years (3.7% vs. 2.5%; difference 1.2%) (7,18). This review applies consistent quantitative standards across all modalities in order to allow direct comparison. Third, the risk-adapted nature of the IORT arm complicates direct comparison with single-modality APBI: TARGIT-A is properly understood as a comparison of a treatment strategy (IORT ± WBI based on pathology) to single-modality WBI.

ELIOT: electron IORT

ELIOT randomized 1,305 women aged 48–75 years with unifocal cT1–2 invasive carcinoma to single-fraction 21 Gy electron IORT vs. 50 Gy WBI plus 10 Gy boost. The 5-year IBTR rate was 4.4% with ELIOT vs. 0.4% with WBI [hazard ratio (HR) =9.3; P<0.0001] (25). The 15-year update reported 15-year cumulative IBTR of 12.6% (95% CI: 9.8–15.9%) with ELIOT vs. 2.4% (95% CI: 1.4–4.0%) with WBI (26). Overall survival did not differ significantly, although the trial was not powered for survival differences in this favorable population.

Subgroup analyses identified higher recurrence in patients with larger tumors, grade 3 disease, lymphovascular invasion, hormone-receptor-negative disease, or ≥4 positive nodes, supporting selective use in low-risk patients only (25). The ELIOT investigators explicitly recommend that ELIOT be offered to selected patients at low risk of IBTR (26). The 15-year recurrence differential is substantially larger than that observed with risk-adapted TARGIT-IORT, multicatheter brachytherapy, or intensity-modulated radiation therapy (IMRT)-APBI, and this difference is one principal driver of the 2023 ASTRO recommendation against routine IORT outside of a clinical trial or registry (29).

Brachytherapy-based APBI

Multicatheter interstitial brachytherapy (GEC-ESTRO)

The GEC-ESTRO phase III non-inferiority trial randomized 1,184 women with low-risk early breast cancer to multicatheter interstitial brachytherapy APBI vs. WBI plus boost. The 5-year update found IBTR of 1.44% with APBI vs. 0.92% with WBI (30). The 10-year update by Strnad and colleagues reported cumulative IBTR of 3.51% (95% CI: 1.99–5.03%) vs. 1.58% (95% CI: 0.37–2.80%), difference 1.93% (P=0.074), within the pre-specified non-inferiority margin (19). Regarding late toxicity, grade 2–3 late skin toxicity occurred in 6.9% of the APBI arm vs. 10.7% of the WBI arm (P=0.04); subcutaneous toxicity rates were similar between arms (19,31). Physician-rated cosmesis was rated excellent or good in 75.4% of APBI patients vs. 71.5% of WBI patients at 5 years (P=0.04), with the cosmetic advantage of APBI persisting at long-term follow-up; patient-rated cosmesis similarly favored APBI (31). GEC-ESTRO provides the most mature randomized evidence for brachytherapy-based APBI, with 10-year data demonstrating non-inferior local control and superior late toxicity and cosmesis compared with WBI.

Single-entry (balloon and strut-based) brachytherapy

Single-entry catheter brachytherapy devices (e.g., MammoSite, Contura, SAVI) are typically placed at the time of lumpectomy or, more commonly, in a delayed fashion. Treatment can be delivered as long as the cavity remains open and skin spacing is adequate, generally up to approximately 4 weeks following surgery. The fractionated nature of brachytherapy [typically 34 Gy in 10 twice-daily (BID) fractions over 5 days] preserves the option, in trials such as NSABP B-39 and the ASBrS Registry, to deliver supplemental WBI based on final pathology; however, in routine practice this risk-adapted approach is less rigorously applied than in TARGIT-A. ASTRO conditionally recommends single-entry catheter brachytherapy in appropriately selected patients (29).

NSABP B-39/RTOG 0413

NSABP B-39/RTOG 0413 randomized 4,216 women with stage 0–II breast cancer to APBI (multicatheter brachytherapy, single-entry brachytherapy, or 3D-CRT external beam APBI 38.5 Gy/10 BID fractions) vs. 50 Gy/25 fractions WBI ± boost (32). The trial’s eligibility was substantially broader than other modern APBI trials and included women aged ≥18 years with up to 3 positive axillary nodes, ductal carcinoma in situ, and unfavorable histologic features. At 10.2 years of median follow-up, IBTR was 4.6% in the APBI arm and 3.9% in the WBI arm (HR =1.22; 90% CI: 0.94–1.58); although the absolute difference was less than 1%, APBI did not meet the protocol-defined criteria for equivalence (HR 90% CI bounded by 0.667–1.5) (32).

Key features of the NSABP B-39 patient population should be highlighted when the trial is interpreted alongside other randomized APBI trials. Median age was younger (54 vs. ≥50 years in GEC-ESTRO and Florence), 10% had DCIS, approximately 25% had ER-negative disease, and a meaningful minority had 1–3 positive nodes. These patient characteristics differ materially from the strictly low-risk populations of GEC-ESTRO and Florence, and the broader population in NSABP B-39 likely contributes to the higher IBTR in both arms and to the failure to meet equivalence. Patient-reported quality-of-life outcomes in NSABP B-39 favored APBI for cosmesis-related domains and treatment burden (33).

External beam IMRT-based APBI: the Florence trial

The Florence/APBI-IMRT trial (Livi et al.) randomized 520 women aged ≥40 years with low-risk early breast cancer to APBI 30 Gy in 5 once-daily fractions delivered with IMRT vs. 50 Gy/25 fractions WBI with boost (34). At 10.7 years of median follow-up, the 10-year cumulative incidence of IBTR was 3.7% with APBI vs. 2.5% with WBI (HR =1.56; 95% CI: 0.55–4.37; P=0.40) (18). Acute and late toxicity and cosmesis significantly favored the APBI arm: grade ≥2 acute skin toxicity was significantly lower with APBI (P<0.001), late subcutaneous fibrosis and skin toxicity were significantly lower in the APBI arm at 5 and 10 years, and physician-rated cosmesis (excellent or good) was achieved in 95% of APBI patients vs. 88% of WBI patients at 5 years (P=0.043) (18,34); see also Table 2. The Florence regimen has been widely adopted in Europe and increasingly in the U.S. and is now an acceptable APBI option in the 2023 ASTRO guideline (29).

Florence is particularly important in the present discussion because it provides a non-invasive, externally delivered, fractionated APBI option with mature 10-year randomized data not included in many prior narrative reviews of PBI. The 1.2% absolute difference in 10-year IBTR (favoring WBI but well within the non-inferiority margin) and the favorable toxicity and cosmesis profile are directly relevant to the current clinical decision space.

HF-WBI and UHF-WBI

The Canadian (Whelan) and UK START A and B trials established 15- to 16-fraction WBI as standard of care, with 10-year IBTR of 6.2% vs. 6.7% in the Canadian trial, and similarly low IBTR with comparable or improved late tissue effects in START (4–6%). The FAST-Forward trial randomized 4,096 women to 40 Gy in 15 fractions vs. 27 Gy in 5 fractions vs. 26 Gy in 5 fractions delivered over 1 week. At 5 years, IBTR was 2.1% (95% CI: 1.4–3.1%) with 40 Gy/15 fractions, 1.7% (95% CI: 1.2–2.6%) with 27 Gy, and 1.4% (95% CI: 0.2–2.2%) with 26 Gy; both 5-fraction regimens met the pre-specified non-inferiority margin of ≤1.6% excess IBTR, and 26 Gy/5 fractions is the recommended schedule on the basis of comparable late normal tissue effects (7). The 10-year FAST-Forward update presented at ESTRO 2025 confirmed durable non-inferiority (35).

The Mayo MC1635 trial randomized 107 women with localized breast cancer (pT0–3 pN0–1) to 40 Gy in 15 fractions vs. 25 Gy in 5 fractions, with optional simultaneous integrated boost. The trial was designed primarily to assess physician- and patient-reported toxicity and quality-of-life outcomes; mature IBTR data are still emerging. Grade 2 dermatitis was 7.4% in the moderately hypofractionated arm vs. 3.7% in the ultrahypofractionated arm, with no grade ≥3 toxicity in either arm, and patient-reported skin burns were 3.7-fold less common with 25 Gy/5 fractions (8). MC1635 is therefore cited primarily for its toxicity and patient-reported outcomes; for IBTR data, FAST-Forward provides the higher-quality evidence base.

Comparative local control across major phase III trials

Table 3 presents IBTR data from the major modern phase III trials; quoted values are extracted directly from each cited primary publication. Because trials differ in patient eligibility, follow-up duration, and statistical design, cross-trial comparisons should be interpreted as descriptive only.

Quantitative comparison of toxicity

Quantitative toxicity data from major phase III trials are summarized in Table 2.

Several patterns are clinically relevant. First, multicatheter brachytherapy APBI and IMRT-based APBI are associated with measurably better late toxicity and cosmesis than WBI, in addition to being acceptable on local control. Second, the fundamental tradeoff for IORT, particularly in risk-adapted protocols such as TARGIT, is that the subset of patients who require supplemental WBI on the basis of final pathology experience the cumulative toxicity of both modalities at the operative bed; this is consistent with the clinical course of the patient highlighted in the October 2025 NBC News story, who received both IORT and subsequent WBI and reported notable late induration. Third, the convenience advantage of IORT (a single intraoperative fraction) is now substantially reduced compared with the era in which TARGIT-A and ELIOT were designed: 5-fraction WBI delivered over 1 week, followed by zero in-room time for the patient, is an alternative that did not exist in 2000.

Patient selection and society guidance

ASTRO published consensus criteria stratifying patients into “suitable”, “cautionary”, and “unsuitable” categories for APBI, with the 2017 update extending suitability to include women ≥50 years with cT1 (≤2 cm) cN0 ER-positive unifocal invasive ductal carcinoma with negative margins (≥2 mm), no lymphovascular invasion, and no neoadjuvant therapy (36). The 2023 ASTRO guideline (Shaitelman et al.) updated these criteria with the following key recommendations: (I) PBI is recommended (not just an option) for women with the suitable factors above; (II) three-dimensional conformal radiation therapy (3D-CRT), IMRT, and multicatheter interstitial brachytherapy are recommended techniques; (III) single-entry catheter brachytherapy is conditionally recommended; (IV) IORT (electron or 50 kVp photon) is not recommended outside a clinical trial or registry; and (V) once-daily or every-other-day APBI is preferred to BID fractionation (29). The 2025 ASBrS update broadly aligns with the 2023 ASTRO guideline (37). The GEC-ESTRO patient suitability framework, which informed the GEC-ESTRO trial eligibility criteria, defines low-, intermediate-, and high-risk groups and recommends APBI alone only for low-risk patients (38).

It is important to note that ASTRO and ASBrS guidelines are multidisciplinary and developed with explicit conflict-of-interest management. The 2023 ASTRO PBI Task Force included radiation oncologists, surgical oncologists, medical oncologists, a patient representative, and methodologists; recommendations were classified by strength and quality of evidence per the established ASTRO methodology (29). The author of this review participates in clinical care of breast cancer patients at Mayo Clinic Arizona and discloses, in the Conflicts of Interest section, the absence of industry relationships related to IORT, brachytherapy, or external beam radiation device manufacturers. The recommendation that IORT not be used routinely outside a clinical trial or registry is therefore a multidisciplinary, evidence-based position rather than a single-institution preference.

It is also important to distinguish APBI from radiation omission. The PRIME II, IDEA, LUMINA, and CALGB 9343 trials addressed whether radiation can be safely omitted entirely in highly selected older women with low-risk hormone receptor-positive disease who receive endocrine therapy (39,40). Those data, which support radiation omission as a reasonable shared-decision option in selected women aged ≥65–70 years with grade 1–2, T1, ER⁺ tumors, do not bear directly on the choice between IORT, brachytherapy, APBI, or HF-WBI when radiation is being delivered. Conflating APBI and radiation omission has caused confusion in some prior reviews.

Health-economic evidence

The October 2025 NBC News story argued that financial considerations are the principal driver of limited U.S. IORT adoption. A clinically rigorous response to that argument requires engagement with the published health-economic literature. The principal published economic analyses are summarized below.

• Alvarado et al. [2013] constructed a Markov decision-analytic model and concluded that, from a societal perspective over a 10-year horizon, IORT was the dominant strategy vs. 6-week whole-breast external beam radiation therapy (WB-EBRT), with greater quality-adjusted life years (QALYs) at lower cost (41).
• Patel et al. [2017] extended the analysis to a lifetime horizon and again found IORT to be dominant over EBRT (lifetime cost $53,179 vs. $63,828; QALYs 17.86 vs. 17.06) (42).
• Shah et al. [2014] reported that, on cost-minimization analysis, IORT yielded cost savings of $1.6–8.2 million per 1,000 patients depending on comparator; however, when downstream medical and non-medical costs were included, WBI and APBI represented more cost-effective modalities on a per-QALY basis, illustrating the sensitivity of these models to assumptions about recurrence rates, salvage costs, and health-state utilities (43).
• Golshan et al. [2021] performed a systematic review of cost-effectiveness analyses of IORT vs. EBRT and concluded that IORT can be a potential cost-saving strategy if delivered to eligible patients in a routine setting, while cautioning that heterogeneity of underlying clinical assumptions and possible publication bias limit confidence in the conclusion (44).
• Silverstein et al. [2025] reported a final analysis of 1,828 IORT cases at a single high-volume U.S. center and explicitly addressed reimbursement, capital cost, and operating-room logistical barriers to IORT adoption in the U.S. environment, concluding that reimbursement was initially inadequate and never substantially improved despite the development of dedicated CPT codes (45).

Several conclusions follow. First, when IORT achieves recurrence rates approaching those of WBI in carefully selected patients, modeling generally supports cost savings, particularly in single-payer or socialized systems. Second, U.S. reimbursement for IORT, including both physician work and facility/capital costs, has historically been low relative to multi-fraction external beam therapy, and the absence of dedicated CPT codes until comparatively recently was a documented barrier to adoption (45). Third, the cost-effectiveness of IORT depends critically on the assumed local recurrence rate; small differences in IBTR (and the cost of salvage mastectomy and systemic therapy in those who recur) can flip the cost-effectiveness conclusion (43,44). Fourth, the universal availability of 5-fraction WBI through FAST-Forward (a 1-week regimen delivered without a capital outlay for IORT equipment or modification of operative workflow) has dramatically narrowed the convenience and cost gap on which the original IORT economic case rested.

Critically, financial barriers and clinical evidence are independent variables. The reduced adoption of IORT in many U.S. centers reflects both: (I) the published clinical data showing higher IBTR with IORT than with WBI, particularly for ELIOT and for the post-pathology TARGIT-A stratum; and (II) documented reimbursement and infrastructure barriers identified in the peer-reviewed health-economic literature (45). A binary clinical-vs.-financial framing misrepresents the multifactorial reality. The present review does not contend that financial factors are unimportant; rather, it contends that, even when financial factors are set entirely aside, the clinical evidence does not support IORT as equivalent to modern HF-WBI in the general early-stage breast cancer population. Conversely, we acknowledge that, for individual patients in geographies with limited radiation oncology access, IORT may remain a clinically and economically reasonable option, particularly within the carefully selected populations described in the GEC-ESTRO and Florence trial frameworks. The 2023 ASTRO guideline’s recommendation to deliver IORT only on a clinical trial or registry, rather than a recommendation against IORT in any context, reflects this nuance (29).

The October 2025 NBC News narrative

The October 2025 NBC News story contended that limited U.S. IORT adoption is principally explained by financial considerations adverse to IORT. Three elements of that narrative warrant comment.

First, the story’s central financial claim is supported in part by the peer-reviewed literature: U.S. reimbursement for IORT is, in fact, substantially lower than for multi-fraction external beam radiation, capital costs are non-trivial, and operating-room logistical barriers exist (45). The clinical community should not dismiss these realities.

Second, the story’s framing implicitly assumes that, in the absence of financial barriers, IORT would be straightforwardly preferred clinically. This assumption does not engage with the randomized data demonstrating higher IBTR with IORT than with WBI, particularly for ELIOT and for delayed (post-pathology) TARGIT, nor with the convergence of professional society recommendations that IORT be used only on a clinical trial or registry (29,37).

Third, the patient highlighted in the story is, on the basis of the publicly reported clinical course, an illustrative example of the tradeoffs inherent in even risk-adapted IORT. According to public reporting, she received single-fraction IORT at the time of lumpectomy and was subsequently found on final pathology to have features that prompted supplemental WBI, and she has reported notable induration consistent with fibrosis at the lumpectomy site. This sequence is not an outlier: in TARGIT-A, approximately 15–20% of women in the IORT arm ultimately received supplemental WBI on the basis of risk-adapted criteria, and patients receiving both IORT and subsequent WBI have, by definition, the cumulative dose and toxicity of both at the operative bed. Risk-adapted IORT, in other words, does not eliminate the clinical compromise of single-fraction radiation; it ports the compromise to the subset of patients who, by virtue of unfavorable final pathology, ultimately receive both modalities.

Taken together, these considerations argue for the conclusion that the current clinical position on IORT in the U.S. is appropriately characterized as evidence-based caution, not as financially motivated suppression. The financial factors are real and are addressed in the peer-reviewed economic literature; the clinical factors are real and are addressed in the randomized trial literature; both contribute to current U.S. utilization patterns.

Strengths and limitations

Several limitations of the included literature warrant explicit discussion. First, cross-trial comparisons of IBTR rates (Table 3) are confounded by differences in patient eligibility, tumor characteristics, systemic therapy use, surgical margins, and follow-up duration. No single trial randomizes all four modalities head-to-head; the comparative evidence base consists of independent randomized trials evaluated against a common reference modality (WBI) with heterogeneous control arm outcomes. Second, most trials evaluating IORT and brachytherapy were designed in an era when conventional 25-fraction WBI was the comparator; the trials do not directly compare IORT or brachytherapy with 5- or 15-fraction WBI, and indirect comparisons therefore carry substantial uncertainty. Third, FAST-Forward provides only 5-year IBTR data for the 5-fraction regimen (10-year data presented at ESTRO 2025 but not yet published in full); the long-term local control trajectory of UHF-WBI continues to mature. Fourth, health-economic analyses of IORT are highly model-dependent, and conclusions about cost-effectiveness are sensitive to assumed local recurrence rates, salvage costs, and health-state utilities; the heterogeneity of modeling assumptions limits the generalizability of any single economic analysis.

This review has several strengths. It incorporates the most recent long-term follow-up data from both ELIOT (15-year) and GEC-ESTRO (10-year) available at the time of writing, and it includes Florence/APBI-IMRT data that are absent from many prior reviews. It is also one of the first narrative reviews to systematically address the published health-economic evidence alongside randomized clinical trial data in the context of a public media narrative, providing a framework for distinguishing financial from clinical determinants of modality utilization. The review is limited by its sole-author design, which is consistent with a narrative rather than systematic methodology but means that study selection was not independently adjudicated. Inclusion of randomized trials was prioritized; single-institution retrospective series, which may introduce selection bias, were excluded per the prespecified criteria in Table 1. Finally, this review does not incorporate patient preferences or shared decision-making frameworks in depth, which represent an important dimension of modality selection that is complementary to the evidence synthesis provided here.

Conclusions

Modern HF-WBI and UHF-WBI provide excellent local control over 1–3 weeks with a favorable toxicity profile and have substantially narrowed the convenience and cost gap that motivated the development of IORT in an earlier era. Multicatheter brachytherapy APBI (GEC-ESTRO) and external beam IMRT-APBI (Florence) achieve IBTR rates within an acceptable range of WBI at 10 years, with measurably better late toxicity and cosmesis, and are recommended in current ASTRO and ASBrS guidance for appropriately selected patients. NSABP B-39/RTOG 0413, with broader eligibility, did not meet protocol-defined equivalence at 10 years and should be interpreted with attention to its more heterogeneous patient population.

Single-fraction IORT, whether delivered as 50 kVp photons (Intrabeam, TARGIT) or megavoltage electrons (ELIOT), is associated with higher IBTR than WBI in randomized data, with the largest absolute difference for ELIOT at 15 years. The risk-adapted approach pioneered in TARGIT-A reduces but does not eliminate this gap; a meaningful proportion of patients ultimately receive supplemental WBI and accumulate the toxicity of both modalities at the lumpectomy bed. The 2023 ASTRO and 2025 ASBrS guidelines therefore recommend IORT only on a clinical trial or registry.

The most meaningful priorities for early breast cancer radiation oncology in the U.S. are the continued expansion of convenient, high-quality external beam radiation—including UHF-WBI, IMRT-APBI, and multicatheter brachytherapy in well-selected patients—with patient-centered shared decision-making that maximizes local control, minimizes toxicity, and respects access and convenience. The reduced U.S. adoption of IORT is appropriately characterized as evidence-based caution shaped jointly by clinical and financial considerations, and not as financially motivated suppression.

Acknowledgments

None.

Footnote

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at https://abs.amegroups.com/article/view/10.21037/abs-2026-0016/rc

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