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To evaluate the clinical outcomes of a very-accelerated partial breast irradiation (vAPBI) in the elderly based on a single fraction of multicatheter interstitial high-dose rate brachytherapy (MIB). Mature results with a median follow-up of 5 years.
Methods and Materials
From November 2012 to September 2014, 26 patients (pts) (≥70) with early breast cancer were enrolled in a prospective phase II trial (NCT01727011). After lumpectomy, intraoperative catheter implant was performed for postoperative APBI (single fraction 16 Gy). Surveillance was performed twice a year after APBI. Oncologic outcome (local [LRFS], metastasis-free survival, cancer-specific survival, and overall survival [OS]) as well as late toxicity and cosmetic outcome were investigated.
Results
Median age was 77 years [69–89]. After a median follow-up of 63 months [60–68], 5-year LRFS, metastasis-free survival, cancer-specific survival, and overall survival rates were 100%, 95.5%, 100%, and 88.5%, respectively. Late toxicity was observed in 5 pts (19.2%) with a total of five events: 3 pts G1 (60%); and 2 pts G2 (40%). The observed late side effects were breast pain in 1 pt (G2 cytosteatonecrosis with occasional acetaminophen consumption), hypopigmentation (puncture site) in 2 pts (G1) and breast fibrosis in 2 pts (G1: 1 pt; G2: 1 pt). Cosmetic evaluation was excellent for 21 pts (81%) and good for 2 pts (19%).
Conclusion
For elderly with early breast cancer, a vAPBI using a single fraction of postoperative MIB (16 Gy) provides excellent oncologic results, mainly in terms of local control and cancer death. Late toxicity and cosmetic profile are acceptable.
At this moment, there is no clear consensus regarding the real oncologic impact of adjuvant radiation therapy for low-risk breast cancer in the elderly. In this patient subgroup, four phase III randomized trials compared hormonal therapy with or without adjuvant whole breast irradiation (WBI) based on conventional or slightly hypofractionated regimens (
PRIME II Investigators Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): A randomised controlled trial.
). All of them confirmed that adjuvant WBI significantly improved local control, with no impact on overall survival (OS). The dilemma that patients (pts), care providers, and care payers have to face is to choose between “achieving an optimal local control after a constraining and costly treatment” or “assuming a significant higher risk of local relapse without these constraints” (
). However, some more convenient irradiation techniques allow to escape from this “all-or-nothing” law. According to the American Society of Therapeutic Radiation Oncology (ASTRO) recommendations, the Choosing wisely campaign advises to consider shorter treatment schedules for women over 50 years with early-stage breast cancer (
). Keeping this in mind, accelerated partial breast irradiation (APBI) based on multicatheter brachytherapy (MIB) represents a smart and validated option to shorter radiation therapy from 4 to 6 weeks to 4 to 5 days, especially for low-risk breast cancer (
Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO). 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: A randomised, phase 3, non-inferiority trial.
). More specifically for the elderly, considering different associated comorbidity factors playing a deleterious impact on the treatment observance, APBI allows to reduce the overall treatment time and the number of transportations without any significant alteration of the patient's functional status (
GERICO-03 phase II trial of accelerated and partial breast irradiation in elderly women: Feasibility, reproducibility, and impact on functional status.
). In the frame of APBI, intraoperative radiation therapy also represents an attractive solution by combining at the same time, breast surgery and adjuvant irradiation (
TARGIT Trialists' Group 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.
). However, despite the debatable results of the different randomized trials, at least 15% of the pts will need postoperative WBI due to the definitive pathologic results. As we wanted to preserve the benefits of a one APBI day (very APBI—vAPBI) within a fully compatible treatment for eligible pts (low-risk elderly breast cancer), we conducted a phase I/II prospective trial (single fraction early breast irradiation—SiFEBI) based on a postoperative single fraction of high-dose rate brachytherapy (
Accelerated partial breast irradiation for suitable elderly women using a single fraction of multicatheter interstitial high-dose-rate brachytherapy: Early results of the Single-Fraction Elderly Breast Irradiation (SiFEBI) Phase I/II trial.
). Updated results of the SiFEBI trial are reported.
Methods and materials
SiFEBI trial was a phase I/II, interventional open-label prospective single-institution study (Clinical.gov #NCT01727011). The primary objective was to investigate the early toxicity occurring during the first 180 days following a single fraction of MIB APBI for elderly women presenting an early-stage breast cancer. Oncologic outcomes, cosmetic results, quality of life, and impact on self-assessment by oncogeriatric esthetic result analysis were considered as secondary objectives.
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All pts signed informed consent, and the protocol was approved by responsible investigational review boards.
Data related to patient selection, treatments, follow-up/evaluation, and statistical analysis are briefly reported (
Accelerated partial breast irradiation for suitable elderly women using a single fraction of multicatheter interstitial high-dose-rate brachytherapy: Early results of the Single-Fraction Elderly Breast Irradiation (SiFEBI) Phase I/II trial.
Patients who are 70-year-old and older, Balducci Score I/II, presenting a low-risk breast cancer, were passed initial screening, and prospectively enrolled in this phase I/II trial. Definitive inclusion was validated after obtaining the final postoperative pathologic report, which confirmed the “low-risk” features for APBI according to the classification of Groupe Européen de Curiethérapie European SocieTy for Radiotherapy and Oncology (GEC-ESTRO) (
GEC-ESTRO Breast Cancer Working Group Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: Recommendations of the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009).
At the time of breast surgery (lumpectomy + clips in the tumor bed) and sentinel lymph node biopsy, interstitial brachytherapy procedure was performed (intraoperatively) in respect with the Paris system geometric rules (Fig. 1) (
). Once the final pathologic results confirmed the indication of APBI, CT-based treatment planning was performed. The clinical target volume (CTV) was delineated with a safety margin of 2 cm from the clips minus the surgical margins described by the pathologist in every direction redefined as 5 mm below the skin surface and 5 mm above the underlying ribs (
Recommendations from GEC ESTRO Breast Cancer Working Group (I): Target definition and target delineation for accelerated or boost Partial Breast Irradiation using multicatheter interstitial brachytherapy after breast conserving closed cavity surgery.
). The treatment planning was performed in the respect of dose constraints (D90 ≥ 105%, V100 ≥ 95%, V150 ≤ 35%, V200 ≤ 15%, DNR [V150/V100] ≤ 35%, and maximal skin dose ≤ 75%). A single fraction of 16 Gy was prescribed on the reference isodose.
Fig. 1Frontal (a) and lateral (b) views of the final position of breast catheters.
Hormonal treatments were dispensed according to the protocols used in the Antoine Lacassagne Cancer Center.
Follow-up and evaluation
After the completion of vAPBI, pts were followed up every 6 months during 5 years, then annually alternatively between the radiation oncologist and the breast surgeon (clinical examination and yearly mammogram). Toxicity and cosmetic results were assessed according to the third version of the Common Toxicity Criteria for Adverse Events and Harvard criteria, respectively (
Quality of life (QLQ-C30V3; QLQ-BR23) and geriatric assessment were performed by the geriatric oncology team (MMSE, MNA, GDS, ADL, and IADL). The median follow-up (MFU) was calculated from the day of vAPBI to the date of last follow-up.
Statistical analysis
Quantitative data were described by using median and range and qualitative data by using absolute and relative frequencies. Survival time will be defined between the inclusion starting date and the event onset date. Survival curves and local (LRFS) and metastasis-free survival, cancer-specific survival (CSS), and OS rates (confident intervals 95%) were estimated according to the Kaplan-Meier method. All statistical analyses will be performed using R.3.0.2 software for Windows.
Results
Patients and treatments
From November 2012 to September 2014, 47 elderly pts matched the preinclusion criteria and were prescreened in the SiFEBI trial. Among them, 10 pts were initially excluded (Balducci III status: 3 pts; consent withdrawal: 2 pts; bilateral breast cancer: 3 pts; preplastic surgery of the breast: 1 pt; adjuvant chemotherapy: 1 pt). Among the 37 remaining pts, 11 pts (29.7%) were excluded due to postoperative pathologic exclusion criteria (pT > 20 mm [6 pts]; pN+ [3 pts]), lymphovascular invasion (2 pts). Twenty-six pts were definitively included and evaluable (Fig. 2).
Patient and treatment characteristics are reported in Table 1. Median age was 76.6 years [69.4–88.9]. Median tumor size was 10.4 mm [4–17]. Histologic type was mainly invasive ductal carcinoma (76.5%), with low histologic grade (65%) and positive hormonal receptor status (96%). Median surgical margins were 4 mm [2–10]. Median time interval between surgery and vAPBI was 7 days [6–15]. The median number of brachytherapy catheters and planes were 12 [7–15] and 2 [2–3], respectively. Dosimetric data regarding CTV and organs at risk (skin and thoracic wall) were previously reported with a median CTV of 41 cc [22–95], median V100 of 97% [89–100], and median DNR of 0.35 [0.27–0.45] (Table 2) (
Accelerated partial breast irradiation for suitable elderly women using a single fraction of multicatheter interstitial high-dose-rate brachytherapy: Early results of the Single-Fraction Elderly Breast Irradiation (SiFEBI) Phase I/II trial.
CTV = clinical target volume; V100 = volume receiving 100% of the prescribed dose; V150 = volume receiving 150% of the prescribed dose; V200 = volume receiving 200% of the prescribed dose; DNR = dose nonuniformity ratio = V150/V100; D90 = dose delivered to 90% of the CTV; D100 = dose delivered to 100% of the CTV; EQD2αβ4 = equivalent dose at 2 Gy per fraction for α/β = 4 (breast tissue).
After an MFU of 63 months [CI-95%: 60–68], 5-year LRFS, metastasis-free survival, CSS, and OS rates were 100%, 95.5% (IC 95%: 0.87–1), 100%, and 88.5% (IC95%: 0.77–1), respectively (Fig. 3). One patient presented an ipsilateral supraclavicular recurrence 40 months after vAPBI.
Fig. 35-year cause-specific and overall survivals after very-accelerated partial breast irradiation.
Acute toxicity occurring up to 180 days after vAPBI was observed in 18 pts (70%) with a total of 44 events (Grade ≥ 3: 4.5%). Acute side effects occurred mainly during the first month after vAPBI (68.2%), while at 6 months, only five (11.3%) side effects were observed (G1: 4; G2: 1). Breast fibrosis (31.8%), puncture site inflammation (13.6%), and skin hyperpigmentation (11.4%) were the most frequent acute side effects (
Accelerated partial breast irradiation for suitable elderly women using a single fraction of multicatheter interstitial high-dose-rate brachytherapy: Early results of the Single-Fraction Elderly Breast Irradiation (SiFEBI) Phase I/II trial.
Late toxicity was observed in 5 pts (19.2%) with a total of five events: 3 pts G1 (60%); 2 pts G2 (40%) with no Grade ≥ 3. The observed late side effects were breast pain in 1 pt (G2 cytosteatonecrosis with occasional acetaminophen consumption), hypopigmentation (puncture site) in 2 pt (G1), and breast fibrosis in 2 pts (G1: 1 pt; G2: 1 pt). Cosmetic evaluation was excellent for 21 pts (80.8%) and good for 5 pts (19.2%).
Discussion
Adjuvant radiation therapy for elderly breast cancer remains a predicament. Indeed, a potential antagonism can be observed between achieving an optimal local control rate and, mainly for some frail pts with comorbidity factors, assuming the burden of irradiation (
). The frequency and difficulty of transportation from the patient's home to the radiotherapy facility were also described as being a limiting factor to the treatment compliance, leading some pts to prefer mastectomy without radiotherapy rather than conservative treatment, entailing many long and expensive transports (
). In this setting, and especially for low-risk breast cancer, at the beginning of the 90s, the hypothesis of adjuvant irradiation avoidance was tested in four phase III randomized trials (hormonal therapy with or without adjuvant WBI) (
PRIME II Investigators Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): A randomised controlled trial.
). While all these studies highlighted the significant benefit of adjuvant WBI on local control, the lack of significant impact on OS constituted an argument to consider hormonal therapy alone as a valid option. However, other large series reported a significant deleterious impact of WBI avoidance on OS, so that the debate remains open (
Outcomes in real-world practice are different than cooperative trial for elderly patients with early breast cancer treated with adjuvant radiation therapy.
To offer the most appropriate treatment to the elderly with breast cancer, adapting adjuvant radiation therapy to the patient's Balducci status is highly recommended (
). The breast working-group of the GEC-ESTRO reported excellent local control rates in a phase III trial, which were achieved after APBI (MIB) for low-risk breast cancer, which is now considered as a validated and standard technique (
Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO). 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: A randomised, phase 3, non-inferiority trial.
). To evaluate more precisely the impact of APBI in the elderly, we recently used the Albert nomogram, which calculates the 10-year mastectomy-free survival rate with or without adjuvant WBI (
). Our results suggested that the 10-year mastectomy-free survival rate observed after APBI was 97.4% vs. 96.3% after WBI (p = 1) and 92.7% without irradiation (p = 0.27), leading to consider APBI, at least, as effective as WBI, but without the burden of 4–6 treatment weeks (
Accelerated partial breast irradiation for elderly women with early breast cancer: A compromise between whole breast irradiation and omission of radiotherapy.
Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO). 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: A randomised, phase 3, non-inferiority trial.
Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer. SABCS 2018, Abstract GS4-04.
Three-fraction accelerated partial breast irradiation (APBI) delivered with brachytherapy applicators is feasible and safe: First results from the TRIUMPH-T trial.
). The results of these prospective studies are presented in Table 3. In these series, the overall treatment time varied from 1 to 3 consecutive days with twice-daily fractionation. However, in this important and commendable goal to offer a more convenient treatment by reducing the number of fractions (and transportation), why did protocols and research stop after achieving 2–3 treatment days? Could not we think of taking one step further to reach a single fraction regimen (
)? As far as we know, SiFEBI trial is the first APBI trial evaluating a postoperative single fraction regimen. In the SiFEBI trial, we reported excellent local control rate without in-breast recurrence after an MFU of 63 months. After an MFU of 74 months, Wilkinson et al. (
) reported no local relapse in a cohort of 45 pts treated with a total dose of 28 Gy in four fractions over 2 days. Furthermore, and especially in the oncogeriatric setting, CSS seems more relevant compared with OS, acknowledging the fact that the treatment is not specifically performed to avoid overall cause of death (including competing causes) rather than to prevent cancer-specific death (
Three-fraction accelerated partial breast irradiation (APBI) delivered with brachytherapy applicators is feasible and safe: First results from the TRIUMPH-T trial.
Three-fraction accelerated partial breast irradiation (APBI) delivered with brachytherapy applicators is feasible and safe: First results from the TRIUMPH-T trial.
The acute toxicity profile of vAPBI reported in the SiFEBI trial was mainly observed during the first month after radiosurgical procedure with less than 5% of G3 complications. In this study, brachytherapy implant was performed intraoperatively so that it made difficult to distinguish acute side effects specifically due to surgery rather than to brachytherapy. The rate of G ≥ 3 acute toxicity after vAPBI described in the literature varied from 0 to 13.3% (
Three-fraction accelerated partial breast irradiation (APBI) delivered with brachytherapy applicators is feasible and safe: First results from the TRIUMPH-T trial.
) used an intraoperative HDR brachytherapy using a flap device to deliver a single fraction of 20 Gy. Due to an unexpected high rate of acute toxicity observed in the first 18 treated pts, the authors reduced the total delivered dose from 20 to 18 Gy, to obtain more acceptable results. Currently, there are few data related to vAPBI late toxicity profile. In the SiFEBI trial, we did not observe any G ≥ 3 late toxicity, while Wilkinson et al. (
) reported 2% of G ≥ 3 late side effects after 74 months of MFU. The excellent/good cosmetic result observed after vAPBI is 100% in our study and 91% in the Wilkinson et al. publication (
Permanent breast seed implant for partial breast radiotherapy after partial mastectomy for favorable breast cancer: Technique, results, and applications to various seroma presentations.
) recently reported acute and late tolerance for 67 permanent breast seed implants performed for postmenopausal women with low-risk breast cancer. The implant used stranded Pd-103 seeds (90 Gy delivered to the seroma). Acute reactions observed at 6 weeks were 51% grade 1 erythema and 12% focal desquamation. Late reactions consisted in 43% localized fibrosis, 20% mild telangiectasia, and 22% contour change.
There are some limitations of the SIFEBI trial. This vAPBI single fraction regimen enrolled a small number of patients. But it remains important to notice that, even with a careful preoperative screening, final pathologic report remains crucial and leads to approximately 25–30% of patient exclusion from APBI indication. Furthermore, in a phase I/II study evaluating efficacy and toxicity of a brand-new protocol, it remains difficult to expose numerous patients to a potential risk of local relapse and/or side effects. In the frame of breast cancer research study, a minimum MFU of 60 months remains highly recommended to provide acceptable results. But for vAPBI, longer follow-up is needed to use this new regimen in routine clinical practice. Last but not least, the biologic rational supporting the 16 Gy single fraction delivered dose remains debatable. Indeed, not only, Biological Equivalent Dose (BEDα∕β4 = 80 Gy) and Equivalent Dose at 2 Gy (EQD2α∕β4 = 53 Gy) are calculated using linear quadratic model calculation, which is not validated for dose per fraction higher than 8 Gy but impact of hyperdosed volumes with MIB HDR brachytherapy on BED/EQD2 calculation is also not consider in this model (
According to the very last “Trend in population aging report” published by the United Nations, the population aged ≥65 years is growing faster than all other age groups (
). According to these data, by 2050, 1/6 people in the world will be ≥ 65 years (16%), up from 1/11 in 2019 (9%). The number of elderly persons (≥80 years) is projected to triple, from 143 million in 2019 to 426 million in 2050. According to these trends, the International Agency for Research on Cancer considers that breast cancer incidence rates for women ≥70 years will increase by 104% from 445,081 in 2018 to 908,119 in 2040 (
). Elderly breast cancer treatment is rapidly mutating and must properly answer epidemiologic, oncologic, and financial problematics. Adjuvant radiation therapy remains crucial to reach an optimal local control rate but new adapted regimens are required. vAPBI based on a single fraction represents a promising answer, which should be tested in phase III randomized trial.
References
Fyles A.W.
McCready D.R.
Manchul L.A.
et al.
Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.
Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): A randomised controlled trial.
Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO). 5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: A randomised, phase 3, non-inferiority trial.
GERICO-03 phase II trial of accelerated and partial breast irradiation in elderly women: Feasibility, reproducibility, and impact on functional status.
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.
Accelerated partial breast irradiation for suitable elderly women using a single fraction of multicatheter interstitial high-dose-rate brachytherapy: Early results of the Single-Fraction Elderly Breast Irradiation (SiFEBI) Phase I/II trial.
Patient selection for accelerated partial-breast irradiation (APBI) after breast-conserving surgery: Recommendations of the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) breast cancer working group based on clinical evidence (2009).
Recommendations from GEC ESTRO Breast Cancer Working Group (I): Target definition and target delineation for accelerated or boost Partial Breast Irradiation using multicatheter interstitial brachytherapy after breast conserving closed cavity surgery.
Outcomes in real-world practice are different than cooperative trial for elderly patients with early breast cancer treated with adjuvant radiation therapy.
Accelerated partial breast irradiation for elderly women with early breast cancer: A compromise between whole breast irradiation and omission of radiotherapy.
Primary results of NSABP B-39/RTOG 0413 (NRG Oncology): A randomized phase III study of conventional whole breast irradiation (WBI) versus partial breast irradiation (PBI) for women with stage 0, I, or II breast cancer. SABCS 2018, Abstract GS4-04.
Three-fraction accelerated partial breast irradiation (APBI) delivered with brachytherapy applicators is feasible and safe: First results from the TRIUMPH-T trial.
Permanent breast seed implant for partial breast radiotherapy after partial mastectomy for favorable breast cancer: Technique, results, and applications to various seroma presentations.
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