Radiotherapy for women with breast cancer has evolved significantly over the last 3 decades. Since the seminal findings of NSABP B-06, further supported by EBCTCG meta-analysis, adjuvant whole breast radiotherapy (WBRT) after breast-conserving therapy is established as the standard of care for most women.1,2 Radiation to the breast was traditionally delivered in “conventional” fractions of 1.8 to 2 Gray (Gy) per fraction to a total dose of 45 to 50 Gy. These fraction sizes were chosen based on the historic dogma that smaller fractions were necessary for normal tissue sparing. Subsequent radiobiologic advances challenged the dogma and treatment schemata with higher dose-per-fraction in the less total number of fractions, called hypofractionation, which began to be explored.3 In the late 1980s, Royal Marsden Hospital in the UK compared 2 hypofractionated whole breast regimens, 42.9 Gy in 13 fractions and 39 Gy in 13 fractions, to 50 Gy in 25 fractions.4 In this study, oncologic outcomes of hypofractionated arms were equivalent to conventionally fractionated arms and with improved cosmetic outcomes in the 39 Gy arm. Over the next decade, a series of hypofractionation trials including the Canadian Ontario Clinical Oncology Group trial and the UK “START A” and “START B” trials demonstrated similar oncologic and cosmetic equivalence of hypofractionated radiation in 13 to 16 fractions compared with conventional regimens.5,6 These positive trials galvanized further efforts to maximize dose-per-fraction. The UK “FAST” and “FAST-Forward” trials built off START A and B but condensed WBRT into 5 treatments.7,8 With 10 years of follow-up, locoregional recurrences in the hypofractionated whole breast arms of UK FAST were noninferior compared with conventionally fractionated radiation, however, there were significantly increased adverse cosmetic effects in the 30 Gy in 5 weekly fraction arm that was not seen in the 28.5 Gy in 5 weekly fractions. UK FAST-Forward compared hypofractionated 40 Gy/15 fractions with 2 “accelerated” hypofractionated whole breast irradiation (WBI) where 5-fraction treatment was completed in 1 week. Significantly more adverse events were seen in the 27 Gy/5 fractions arm compared with the 40 Gy/15 fractions arm and 26 Gy/5 fractions arm, but there was no significant difference in ipsilateral breast tumor relapse. Herein, we learned a total difference of 1 Gy (or 0.2 Gy/fraction) in daily, hypofractionated radiation resulted in a 50% increased odds ratio of significant adverse breast or chest wall events. These results suggest that delivering WBI in <5 fractions would likely result in poor cosmetic outcomes and should not be pursued.

Alongside the development of hypofractionated WBI, it was noted that most breast cancer recurrences were in the same breast quadrant after lumpectomy and that most malignant cells are within 1 cm of the tumor cavity.9,10 These findings suggested adjuvant radiation could be limited to a partial, high-risk volume immediately surrounding the lumpectomy cavity in some women, termed partial breast irradiation. These observations were very attractive to radiation oncologists given the general principle that less volume of irradiated tissue will translate to less adverse normal tissue effects and accelerated partial breast irradiation (APBI) was conceived. In line with accelerated hypofractionated WBI, APBI reduces the number of treatments to 1 to 5 fractions. APBI has since been investigated using a variety of delivery methods including interstitial or intracavitary brachytherapy,11–14 intraoperative radiation therapy,15,16 and 3-dimensional conformal radiation therapy.17–20

However, less tissue required for APBI suggested that the dose could be further escalated. Stereotactic ablative radiation, or stereotactic body irradiation, has been successfully applied to other disease sites, such as early-stage lung cancer, with remarkable local tumor control.21,22 As a result of improved precision of radiation delivery to submillimeter levels by incorporating stereotactic localization and advanced image guidance, ablative doses of radiation can be achieved. Thus, stereotactic partial breast irradiation (SPBI) has inspired novel delivery methods, including Cyberknife(Accuray), Gammapod(Xcision), and heavy ion therapy.23–25 In seminal dose-finding studies, dose escalation with SPBI was achieved with acceptable tumor control and cosmetic outcomes (Table 1).26–34 Doses up to 40 Gy in 5 fractions and 30 Gy in a single fraction were achieved without significant acute or late toxicity, unlike the accelerated hypofractionated WBRT experience from UK FAST-Forward.

TABLE 1 - Ongoing Adjuvant APBI/SPBI Trials Institution ClinicalTrials.gov identifier Principal Investigator Study Design Study Start Date Anticipated Accrual Georgetown University NCT02365714 Sonali Rudra, MD Phase I-II trial of adjuvant 30 Gy/5Fx SPBI February 2015 Enrolled 2 (status: terminated due to slow accrual) Georgetown University NCT02457117 Olusola Obayomi-Davies, MD Multiinstitutional registry of adjuvant 30 Gy/5Fx SPBI May 2015 200 University of Texas Southwestern NCT02685332 Asal Rahimi, MD Phase I dose-escalation trial of adjuvant SPBI (22.5, 25, 27.5, and 30 Gy in 1 fraction) March 2016 75 Yonsei University NCT03568981 Yong Bae Kim, MD, PhD Observational cohort of adjuvant 5-fraction SPBI and WBI April 2018 200 University of Texas Southwestern, University of Maryland NCT03581136 Asal Rahimi, MD Phase II trial of adjuvant 40 Gy/5Fx postoperative SPBI through GammaPod to CTV (1 cm expansion) and 30 Gy/5Fx to PTV (0.3 cm expansion) March 2019 40 University of Alabama RAD 1802 NCT03643861 Drexell Hunter Boggs, MD Trial of adjuvant 30 Gy/5Fx through LINAC based SPBI August 2019 40 Azienda Ospedaliero Universitaria Careggi EUROPA trial NCT04134598 Icro Meattini, MD Phase III randomized controlled trial of adjuvant endocrine therapy versus PBI in women ≥70 y February 2021 926 University of North Carolina CAMERAN trial NCT05472792 Dana Casey MD Phase II randomized trial of adjuvant endocrine therapy versus APBI in women >65 with grade 1-2, <2 cm tumors, and node negative disease after lumpectomy May 2022 90

APBI indicates accelerated partial breast irradiation; CTV, clinical target volume; LINAC, linear accelerator; PBI, partial breast irradiation; PTV, planning target volume; SPBI, stereotactic partial breast irradiation; WBI, whole breast irradiation.

The interplay of radiation and surgery continues to be optimized. Sequencing radiation before surgery has become a general trend in many disease sites, notably rectal and esophageal cancer, and aims to decrease toxicity associated with postoperative radiation. Traditionally breast radiotherapy has been adjuvant to breast-conserving therapy, however, postoperative cavities are often larger and more amorphous than an intact tumor, particularly with the increased use of oncoplastic techniques in reconstruction after lumpectomies. Intraoperative APBI trials have failed to show noninferiority to WBI techniques for women with high-risk features due to small, but significant, ipsilateral breast tumor recurrence rates, and postoperative external beam techniques are preferred.15,16 Further, intraoperative radiation therapy is difficult to generalize given the specialized equipment required. Given the points above, a paradigm shift to sequence radiotherapy before surgery has been explored. Initially explored by a French group and then expanded upon by physicians at Duke, the concept of preoperative single-fraction SPBI has expanded greatly since conception.35–39 Subsequent trials have shown acceptable toxicity and cosmetic outcomes. Further, studies showed favorable imaging response to preoperative SPBI and, using magnetic resonance-guided radiation techniques, a 42% pathologic complete response rate after 20 Gy single fraction, ablative radiation.40–42 These groundbreaking studies have paved the way for a portfolio of provocative preoperative trials, which may radically change the standard of care set by NSABP B-06 (Table 2).

TABLE 2 - Ongoing Preoperative (Definitive or Neoadjuvant) SPBI Trials Institution ClinicalTrials.gov identifier Principal Investigator Study Design Study Start Date Anticipated Accrual Juravinski Cancer Center ARTEMIS Trial NCT02065960 Julie Arsenault, MD Do-Hoon Kim, MD Timothy Whelan, MSc Phase I trial of preoperative 40 Gy/5Fx SPBI February 2014 32 Laurentian University, Jewish General Hospital SIGNAL Trial NCT02212860 Muriel Brackstone, MD, PhD Phase II trial of preoperative 21 Gy/1Fx SPBI March 2015 120 Duke University NCT02482376 Rachel Blitzblau, MD, PhD Phase II trial of preoperative 21 Gy/1Fx SPBI October 2015 100 H Lee Moffit Cancer Center NCT03137693 Michael Montejo, MD Phase II trial of preoperative 3-fraction SPBI April 2017 40 Johns Hopkins Univeristy NCT03043794 Jean Wright, MD Phase II trial of preoperative SPBI of 21 Gy/1Fx August 2017 40 Azienda Opsedaliero-Universitaria Careggi ROCK trial NCT03520894 Lorenzo Livi, MD Single-arm phase II trial of 21 Gy/1Fx preoperative SPBI May 2018 25 Toronto Sunnybrook Regional Cancer Centre NCT03585621 Danny Vesprini, MD Phase I/II study evaluating SPBI 36—48 Gy in 4 fractions for inoperable patients July 2018 24 Jules Brodet Institute, Belgium Neo-CheckRay Trial NCT03875573 Alex De Caluwe, MD Phase II trial of neoadjuvant SPBI 24 Gy/3 fractions with or without immunotherapy after 5 wk of neoadjuvant chemotherapy November 2019 147 Univerity of Texas Southwestern Medical Center NCT04040569 Asal Rahimi, MD Phase I dose-escalation trial of preoperative ablative SPBI 30-38 Gy December 2019 70 University of Miami SABER study NCT04360330 Cristiane Takita MD, MBA Phase I study of preoperative SBPI 35-50 Gy/5 fractions August 2020 18 Stony Brook University SBRT BREAST trial NCT04532177 Alexander Stessin, MD Phase I trial of safety and efficacy of SPBI 40 Gy/5 fx in breast cancer patients who do not get surgery August 2020 15 Lawson Health Research Institute SIGNAL series, TRIO study NCT03978663 Muriel Brackstone, MD, PhD Single-arm trial for patients with high-risk breast cancer to receive SPBI 8 Gy/3 fractions before neoadjuvant chemotherapy followed by surgery and whole breast radiation September 2020 40 University of Rome Tor Vergata NCT05071105 Rolando Maria D'Angelillo, MD Phase I trial of omission of surgery with SPBI 40-45 Gy/5 fractions and endocrine therapy for women >70 who cannot undergo surgery January 2021 30 Centre Hospitalier Universitaire Vaudois NCT04807192 Khalil Zaman, MD Phase II study of preoperative SPBI 8 Gy/1 fraction with or without study drug CMP-001 to evaluate for increase in tumor interstitial lymphocyte activity and evaluate toxicty/response April 2021 40 European Institute of Oncology CRYSTAL study NCT04679454 Cristina Leonardi, MD Phase I/II single-arm studying evlauating pathologic complete response of preoperative single-fraction 18-24 Gy SPBI July 2021 79 Thomas Jefferson University SABR-CaRe NCT04959474 Nicole Simone, MD Phase II study of preoperative SPBI with or without caloric restriction August 2021 80 University of Maryland NCT04234386 Elizabeth Nichols, MD Phase Ib dose-escalation trial of single-fraction SPBI 21-30 Gy September 2021 50 Shengjing Hospital NCT05132790 Nan Niu, MD Cai-Gang Liu, MD Phase I study evaluating pathologic response and toxicity of SPBI in combination with neoadjuvant systemic therapy with investigational drugs SHR1316 (triple negative) or SHR6390 (HER2−/HR+) patients November 2021 24

SPBI indicates stereotactic partial breast irradiation.

So where is APBI going? It is clear adjuvant APBI is a safe and effective treatment for appropriately risk-stratified women. Further refinement of the suitability criteria of APBI may expand access to a set of women who are not “suitable”, including younger women, those with larger tumors, different histologic subtypes, or those who have received neoadjuvant chemotherapy with favorable pathologic responses. Radiation omission with adjuvant endocrine trials showed no significant difference in overall survival in elderly, low-risk women, however, there is equipoise whether APBI may supplant 5 years of adjuvant endocrine therapy in this same group of women; the “CAMERAN” and “EUROPA” trials are currently recruiting patients to answer this open question, though EUROPA includes non-APBI courses per institutional preference (NCT05472792, NCT04134598). The role of adjuvant SPBI in the setting of positive margins in women unable to undergo reresection to ablate microscopic or gross tumors could also be considered. However, it is our opinion SPBI is most likely to flourish in the preoperative setting. At the extreme, SPBI may become the definitive therapy for pathologic complete responders, as suggested by Vasmel et al.41 Defining clinical, translational, and radiomic features that correlate with pathologic response rates after preoperative SPBI is necessary to create a roadmap for the omission of surgery. Moffitt studied a preoperative SPBI regimen of 28.5 Gy in 3 fractions and showed an excellent correlation of 6-week post–radiotherapy magnetic resonance imaging features with pathologic partial response, however, no patients had a complete response in this single dose-level study.42 In our (University of Texas Southwestern) single-fraction ablative preoperative SPBI dose-escalation study, we aim to explore how those features change with ablative doses, in addition to assessing toxicity, tumor control, on multiple SPBI platforms including Cyberknife, Gammapod, and magnetic resonance linear accelerator (NCT04040569). Similarly designed phase I/II dose-escalation studies are currently open at the University of Miami (NCT04360330), Stony Brook University (NCT04532177), Toronto Sunnybrook (NCT03585621), European Institute of Oncology (NCT04679454), and University of Maryland (NCT04234386), with the latter utilizing the Gammapod platform. Phase II preoperative single-fraction studies using a previously validated dose of 21 Gy are currently recruiting at Duke (NCT02482376), Johns Hopkins (NCT03043794), Italy (NCT03520894), and in Canada (NCT02212860). However, in higher-risk women, SPBI is being leveraged in the neoadjuvant setting, with or without immunotherapy, as is the subject of Neo-CheckRay (NCT03875573) and TRIO (NCT03978663), respectively. Effectively, preoperative SPBI serves as the boost dose routinely given at the end of a course of WBI, however, the advantages to performing preoperatively are an easily defined tumor, synergistic effects with immunotherapy, and removal of irradiated tissue thereby potentially decreasing radiation-induced late normal tissue effects. Furthermore, new investigational agents in combination with SPBI are being evaluated in phase I/II studies in high-risk patients (NCT05132790, NCT04807192) or the role of calorie restriction on the efficacy of preoperative SPBI (NCT04959474). Critically, ablative doses must not cause untoward toxicity. Exit doses of photons and deeply seated tumors are potential limitations of dose escalation of photon radiation, particularly for left-sided tumors, and particle therapy may prove superior in these situations. Karasawa and colleagues showed durable responses of breast tumors treated definitively to 60 Gy (relative biological efficacy) in 4 fractions with carbon ion therapy with a minimum 4 years of follow-up, with only 1 local failure in a patient with triple-negative histology. Having shown efficacy, the unique dosimetry of particle-based radiation may be leveraged in these unique situations, however, larger, prospective studies are necessary to validate these therapies.

Overall, we expect an expanded role of APBI, both in the adjuvant and preoperative settings, with or without neoadjuvant systemic therapy, and even the omission of surgery or adjuvant endocrine therapy in selected patients. SPBI, by incorporating advanced radiation treatment techniques, allows for the safe escalation of dose without significant increases in normal tissue toxicity. The therapeutic index of SPBI will be further improved with continued advances in radiation delivery, such as online adaptive radiation therapy. We believe SPBI is convenient, has lower time-associated toxicity and thereby less financial toxicity, and is well tolerated by our patients.

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