Adjuvant radiation therapy (RT) after breast conserving surgery has been consistently shown to reduce local recurrence and to improve breast cancer survival after breast conserving surgery.1 Traditionally, adjuvant RT consisted of standard fractionation whole breast irradiation (WBI), which required daily treatment for 5 to 7 weeks. As such, this led to noncompliance, increased costs of care, as well as patients electing to pursue mastectomy to avoid such long durations of therapy.2 In addition, the burdens of such an approach led to many early deintensification trials in low-risk patients evaluating the omission of RT in lieu of endocrine therapy alone.3,4

The last 2 decades has brought a plethora of new radiotherapy approaches for patients which are forcing clinicians to rethink the assumptions made based on standard fractionation WBI. With respect to WBI, mature outcomes have supported the transition to moderately hypofractionated WBI and more recently, ultrashort WBI, though long-term outcomes with 5 fraction WBI remain limited.5–8 Concurrently, multiple randomized trials have evaluated the utilization of partial breast irradiation (PBI), allowing for a reduction in treatment volumes and therefore the potential for reduced toxicities and treatment duration.9 The purpose of this review is to evaluate outcomes with PBI (not including intraoperative RT) while evaluating the role of therapeutic de-escalation for early-stage breast cancers. Only the PBI techniques for which the definitive pathology is available at the time of the RT delivery have been considered to tailor the treatment to the individual, according to the principle of high-precision medicine.

DISCUSSION Outcomes

Over the past decade, multiple randomized trials have been published comparing WBI with various modern PBI techniques with long-term follow-up. Outcomes from these studies are summarized in Table 1 and consistently demonstrate low rates of local recurrence with both PBI and WBI at 5 to 20 years of follow-up; in addition, these studies have identified either no statistically significant difference or <1% in local recurrence between approaches.10–17 For example, Polgar et al10 recently published 20-year outcomes from their randomized trial comparing interstitial/electron PBI to WBI; no difference in local control was noted (9.6% PBI vs. 7.9% WBI, P=0.59). Similar results have been seen in the NSABP B-39 trial, which did not meet equivalence at 10 years with a 0.7% difference in local control (4.6% vs. 3.9%), as well as the Randomized Trial of Accelerated partial breast irradiation (RAPID) trial that demonstrated no difference in local recurrence at 8 years (3.0% vs. 2.8%).11,17 Importantly, the randomized trial data have shown that local control is comparable with PBI irrespective of technique (brachytherapy and external beam RT).

TABLE 1 - Randomized Trials Evaluating Partial Breast Irradiation No. Patients Partial Breast Technique(s) Follow-up (y) Inclusion Criteria Local Recurrence Toxicity/Cosmetic Outcomes NSABP B-3911 4216 Interstitial, applicator, 3D-CRT 10.2 18 y or older, pTis, pT1-2 (≤3 cm), N0-1, negative margins 3.9% WBI vs. 4.6% PBI Grade 3: 7% WBI vs. 10% PBI RAPID17 2135 3D-CRT 8.6 40 y or older, pTis, pT1-2 (≤3 cm), N0-mi, negative margins; no ILC 2.8% WBI vs. 3.0% PBI Late toxicity grade 2+: 13% WBI vs. 32% PBI Adverse cosmesis 18% worse with PBI at 7 y GEC-ESTRO12 1184 Interstitial 6.6 40 y or older, pTis, pT1-2 (≤3 cm), N0-mi, negative margins (2 mm, 5 mm ILC); no LVSI 0.9% WBI vs. 1.4% PBI Late grade 2-3 toxicity: 5.7% PBI vs. 3.2% PBI Florence16 520 IMRT 10.7 40 y or older, pT1-2 (≤2.5 cm), N0-1, negative margins (5 mm); no EIC, multifocal 2.5% WBI vs. 3.7% PBI PBI reduced acute, chronic toxicity, improved cosmetic outcomes IMPORT-LOW14 2018 IMRT 6.0 50 y or older, pT1-2 (≤3 cm), N0-1, negative margins (2 mm) 1.1% WBI vs. 0.5% PBI vs. 0.2% SIB PBI less change in breast appearance Barcelona15 102 3D-CRT 10.3 60 y or older, pT1-2 (≤3 cm), N0, negative margins (3 mm), grade 2 or less; no ILC, no EIC 4% both arms Similar excellent/good cosmesis, No difference late skin toxicity NIO10 258 Interstitial brachytherapy/electron 17 40 y or older, pT1, N0-1mi, negative margins, No ILC/DCIS, No EIC, grade 1-2 7.9% WBI vs. 9.6% PBI Improved cosmetic outcomes with HDR PBI

3D-CRT indicates 3-dimensional conformal radiotherapy; DCIS, ductal carcinoma in situ; EIC, extensive intraductal component; GEC-ESTRO, Groupe Européen de Curiethérapie- European SocieTy for Radiotherapy and Oncology; HDR, high dose rate; ILC, invasive lobular carcinoma; IMPORT-LOW, Intensity modulated partioal organ radiotherapy trial; IMRT, intensity-modulated radiotherapy; LVSI, lymphovascular invasion; PBI, partial breast irradiation; RAPID, Randomized Trial of Accelerated partial breast irradiation; SIB, simultaneous integrated boost; WBI, whole breast irradiation.

Beyond local control, PBI has demonstrated the ability to improve toxicity and cosmetic outcomes. For example, Polgar et al10,18 found that with long-term follow-up, PBI was associated with improved rates of excellent/good cosmesis, whereas the Groupe Européen de Curiethérapie- European SocieTy for Radiotherapy and Oncology (GEC-ESTRO) trial demonstrated reduced breast pain with PBI, with no difference in quality of life. More recently, using advanced techniques including intensity-modulated radiation therapy (IMRT), the Florence trial demonstrated reduced rates of acute and chronic toxicity, as well as improved cosmetic outcomes. Similar outcomes were seen in the IMPORT-LOW trial, which used intensity modulated PBI, with reduced changes in breast appearance, and breast firmness. Quality of life data from Intensity modulated partioal organ radiotherapy trial demonstrated fewer adverse events with PBI as well, which is consistent with quality of life data from the Florence trial.19,20 The data have also demonstrated that when using less advanced techniques to deliver PBI (eg, 3-dimensional conformal RT) that outcomes may be worse with PBI as compared with WBI though this was not seen in NSABP B39;21 data from RAPID and RTOG 0319 have demonstrated increased toxicity and deteriorated cosmetic outcomes though accurate dosimetric evaluation and once a day fractionation may minimize late toxicity and provide satisfactory cosmesis.17,22 The use of more advanced techniques, such as IMRT, can increase the confidence of radiation oncologists in prescribing PBI, especially when ultrashort fractionations are applied.

Utilization

With comparable clinical outcomes and reduced toxicity rates, one would expect that PBI would represent the most common strategy utilized in women with early-stage breast cancer, particularly given current guidelines that support its utilization in women 45 to 50 years or older with early-stage node negative breast cancers or ductal carcinoma in situ.23,24 This is consistent with data that have demonstrated up to 75% of patients with early-stage breast cancer would be eligible for PBI.25 However, recent data have demonstrated that only 15% of patients who may be eligible for accelerated PBI receive the treatment with additional data demonstrating no increase in PBI utilization since 2008 despite the growing data supporting its utilization.26,27 These findings support that there remains an opportunity for clinicians to greater embrace PBI as an approach for women with early-stage breast cancer after breast-conserving surgery. As PBI enables the delivery of RT in a short, safe, and effective manner, the controversial question of RT-related risks outweighing the benefits will fade, alongside the decisional conflict of both clinicians and patients.28,29

As patient selection is at the core of risk-adapted RT options, consistent with American Society for Radiation Oncology and GEC-ESTRO criteria, assessment of HER2 and KI-67 might contribute to better assesment of optimal candidates;30 for example, the APT trial demonstrated that use of HER2-targeted therapies for HER2 over-expressed cancers led to local recurrence rates approximating luminal A breast cancers, allowing for risk adoption to PBI in these patients.31 In addition, the LUMINA trial (NCT01791829) is currently testing the role of these immunohistochemical biomarkers to identify Luminal A breast cancers, avoiding the cost of gene expression profiling for all patients, whereas deintensification based on multigene assays such as Prosigna and Oncotype Dx to define the risk of recurrence score is also being investigated in the EXPERT trial (NCT02889874) and IDEA Study (NCT02400190).

Rethinking Deintensification

For decades, when evaluating options to deintensify therapy for patients with low-risk early-stage breast cancer, the focus has been removing RT.3,4 Meta-analyses have demonstrated that RT omission while increasing the risk of local recurrence, did not impact survival.32,33 Given the duration of the historical RT regimens and potential radiation-induced toxicities, this seemed appropriate. However, with modern RT approaches including short-course PBI and significant reductions in toxicities, reevaluation of deintensification should occur; this is particularly relevant, given growing data on long-term toxicities of endocrine therapy, as well as noncompliance.34,35 Importantly, previous data have shown that in low-risk patients, endocrine therapy does not impact the rates of distant metastases as compared with RT alone;36,37 in addition, RT provides improved local control as compared with endocrine therapy alone with modest increases in contralateral breast cancers.36,38 Population data have shown no difference in outcomes with RT alone as compared with endocrine therapy alone in low-risk breast cancer patients with modeling studies demonstrating comparable costs and quality of life outcomes.38–40 Because of the non-negligible rate of endocrine therapy discontinuation over time, a propensity score matching analysis using the National Cancer Data Base found that patients undergoing RT alone had better overall survival than those receiving endocrine therapy alone.41 Murphy and colleagues confirmed the association of endocrine therapy nonadherence with distant metastases and disease-free survival, stressing the importance of considering RT alone for elderly women.42 In a survey of elderly women with biologically favorable tumors, 71% of whom received both RT and endocrine therapy, respondents noted they would rather receive RT than endocrine therapy, which was perceived as having the most negative effect on their quality of life.43

PBI Planning

PBI planning will be dependent on the technique utilized; however, the use of smaller targets than WBI allows for sparing of organs at risk including the heart, lung, skin, chest wall, and uninvolved breast tissue. In addition, the use of PBI may be associated with reduced risk of secondary cancers.44,45 For interstitial, and applicator brachytherapy techniques, after placement of catheters or applicators, patients should undergo computed tomography–based planning. Volume expansions range from 1.5 to 2 cm beyond the cavity and optimization can be utilized to meet/exceed standardized constraints from randomized and prospective trials, as well as guidelines to ensure target coverage while limiting dose to critical structures including the skin and chest wall.46

External beam PBI represents an opportunity to use noninvasive techniques to improve the therapeutic ratio of breast radiation; more advanced RT modalities such as IMRT may allow for the optimal balance between target volume coverage and organ at risk sparing, paving the way for lower rates of toxicity and dose-escalation regimens. As such, more recent trials have incorporated use of IMRT to allow for improved homogeneity, as well as conformality, reducing hot spots and dose to uninvolved breast tissue, which may be the reason that these trials demonstrated reduced toxicities as compared with WBI while older PBI techniques did not. Moving beyond IMRT, newer techniques have been reported. Data from the Cleveland Clinic incorporated deep inspiratory breath hold in conjunction with daily cone-beam computed tomography; incorporating advanced planning and treatment delivery allowed for reductions in target margins from 2 to 1 cm.47 The transition to conformal, highly accurate delivery of external beam PBI that delivers high doses in as few as 5 fractions requires complex planning and delivery which can be considered consistent with stereotactic body RT (SBRT), which the American Association of Physicists in Medicine defines as, “the delivery of large doses in a few fractions, which results in a high biological effective dose (BED). In order to minimize the normal tissue toxicity, conformation of high doses to the target and rapid fall-off doses away from the target is critical. The practice of SBRT therefore requires a high level of confidence in the accuracy of the entire treatment delivery process.48” For example, the regimen used in the Florence trial was 30 Gy in 5 fractions, which is comparable to 50 Gy in 25 fractions with a 5 fraction boost additionally.16 These doses/fraction coupled with reduced margins in order to provide a highly conformal low side-effect treatment is consistent with SBRT use in the management of lung and brain tumors.

Future Directions

At this time, the role of PBI continues to evolve. With respect to deintensification, the EUROPA trial is comparing RT alone to endocrine therapy alone.49 Likewise, the GEC-ESTRO Breast Cancer Working Group has conceived a phase III randomized trial using multicatheter interstitial brachytherapy, EPOPE, which is designed to test 30 to 32 Gy in 7 to 8 fractions versus 16 Gy in a single fraction, with the primary endpoint of disease-free survival.50 In addition, trials are evaluating shorter courses of PBI. For example, initial outcomes from the TRIUMPH-T trial demonstrated the safety and feasibility of a 3 fraction PBI approach with further outcomes expected in the years to come; in addition, advances in treatment technology have allowed for the evaluation of a single-fraction postoperative PBI approach.51,52 Studies are ongoing evaluating the use of SBRT to deliver PBI with outcomes demonstrating the safety and efficacy of this approach while proceeding with dose escalation; the safety of dose escalation has also led to increased use of SBRT-like approaches preoperatively which are being evaluated in prospective trials at this time.53,54

CONCLUSIONS

PBI has demonstrated comparable clinical outcomes as compared with whole breast irradiation, with new techniques demonstrating reduced toxicity profiles. This transition allows for the reevaluation of treatment deintensification approaches in the management of early-stage breast cancer. To maximize therapeutic ratios with PBI, complex treatment planning incorporating stereotactic body RT approaches should be considered.

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