Accelerated Partial Breast Irradiation in the Elderly:8-year Oncological Outcome and Prognostic Factors

Introduction: To evaluate long term clinical outcome and prognostic factors after accelerated partial breast irradiation (APBI) in the elderly using high-dose-rate interstitial multi-catheter brachytherapy (HIBT). Material and methods: Between 2005 and 2018, 109 patients underwent APBI using HIBT (34 Gy/10f/5d or 32 Gy/8f/4d). Based on a prospective database, outcomes were retrospectively analyzed (local relapse-free survival (LRFS), metastatic-free survival (MFS), specic survival (SS) and overall survival (OS). Prognostic factors were investigated. Late toxicity and cosmetic evaluation were reported. Results: With a median follow-up of 97 months [7–159], median age was 81.7 years [58-89]. According to the GEC-ESTRO APBI classication, 72.5%, 11.9% and 15.6% were classied as low, intermediate and high-risk respectively. The histological type was mainly invasive ductal carcinoma (87.1%). The median tumor size was 10 mm [range 1-35]. Eight-year LRFS, SS and OS were 96.7% [95% CI [0.923; 1]), 96.7% [95% CI [0.924; 1] and 72%[95% CI [0.616; 0.837] respectively. In univariate analysis, APBI classication was not cosidered as prognostic factor, whilemolecular classication was prognostic factor for OS (p<0.0001), SS (p=0.007) and MFS (p=0.009) but not for LR (p=0.586). No Grade ³3 late toxicity was observed while 61 patients (88.4%) and 8 patients (11.6%) presented grade 1 and 2 toxicities respectively. Cosmetic outcome was excellent/good for 96.4%. Conclusion: Long-term follow-up conrms that HIBT is safe and for elderly early breast cancer. Our results suggest that selected elderly women presenting with high-risk breast cancer be also


Introduction
Breast cancer has been recognized as a major public health problem for many years. The global incidence of breast cancer has been rising with an average annual increases of 3.1%, beginning with 641,000 cases in 1980 and increasing to about 2.1 million in 2018 (1). Currently, life expectancy is growing and the incidence of breast cancer in women increases with age. An aging population could explain in part why more than 40% of breast cancers occur in women over 65 years (2).
A meta-analysis of randomized studies with 10,801 patients showed that radiation therapy (RT) after breast-conserving surgery reduces the risk of all recurrences including ipsilateral breast tumor recurrence and improves overall survival (OS) by increasing breast cancer-speci c survival (3). However, for elderly women speci cally, whole breast irradiation (WBI), which can last 6-7 weeks or 4-5 weeks in case of a hypofractionated regiment, may be challenging to perform due to their potential comorbidities and the treatment inconveniences (4)(5)(6). In order to reduce discomfort and expenses induced by adjuvant RT in low-risk breast cancer (elderly/postmenopausal women), 5 randomized trials comparing adjuvant endocrine therapy alone with or without post-operative external WBI were conducted. They con rmed that a combined treatment does not signi cantly impact on OS rate, while it signi cantly reduces the rate of Page 3/21 local recurrence (LR) (7)(8)(9)(10)(11)(12). Based on these results, the National Comprehensive Cancer Network concluded that RT could be omitted in women aged 70 and older with hormonal receptor (HR) positive stage I breast cancer, receiving endocrine therapy, while, in some cases, a non-compliance with endocrine therapy is observed due to its side effects (13).
For the elderly, is it possible to propose a compromise between WBI, which is a long but e cient treatment in terms of local control, and endocrine therapy as a sole adjuvant treatment, but with signi cant associated risks in terms of LR? During the last decade, accelerated and partial breast irradiation (APBI) techniques have emerged, as an attractive alternative to WBI for patients with early breast cancer and low-risk of LR (14)(15)(16). The volume of breast tissue irradiated is smaller, the course of treatment is shortened and therefore is generally a more suitable treatment for elderly patients (17,18). APBI appears to be an appropriate solution, decreasing the risk of LR rate whilst, at the same time, preserving oncological outcome and quality of life as well as reducing expenses for the healthcare reimbursement system.
We have previously reported the 5-year clinical outcome of a cohort of elderly women treated with APBI based on a high-dose rate interstitial multicatheter brachytherapy (HIBT), but a longer follow-up was needed to assess the consistency of our results. The aim of this report was to update the clinical outcome after APBI in our previously published cohort and discuss prognostic factors (19).

Material And Method
All materials and methods sections were previously described in details (19).
This observational, single-center, retrospective study was performed in the Antoine Lacassagne Center in Nice, France, from 2005 to 2018. Data were collected from patients' les.

Patient features
Target population were women who underwent breast conservative surgery. All along the study period, the Bethesda workshop (20) and then the GEC-ESTRO recommendations (21) were used for the selection of elderly women who could be good candidates for adjuvant APBI using HIBT. However, for some frail patients presenting comorbidity factors, APBI was proposed without strong adherence to the APBI recommended criteria. This study was approved by the Institutional Review Board of Antoine Lacassagne Cancer Centre (n°17013) which approved the ethical aspect of the protocol. The board waived the requirement for informed consents because of the retrospective design of this study.

Treatment features
Breast surgery Patients underwent lumpectomy with axillary management through sentinel lymph node or axillary dissection. Four to ve clips were clamped by the surgeon to mark the tumor bed before closing the Page 4/21 lumpectomy cavity.

Brachytherapy
Vector implantation for HIBT was performed pre-or postoperatively following the Paris System geometric recommendations (22). The implant was performed under local anesthesia in case of post-operative procedure. A post-implant CT-scan was performed in order to delineate the clinical target volume (CTV).
The CTV delineation consisted in an expansion of 1 cm around the clips. The CTV was rede ned as 5 mm below the skin-surface and 5 mm above the underlying ribs for super cial and deep tumors, respectively (23,24).
The dose distribution was optimized manually by varying time and stop position of the radio-active source. Dose constraints were: dose delivered to 90% of the CTV more than 105% (D90 > 105%), part of the CTV receiving 100% of the prescribed dose more than 95% (V100 > 95%), V150 < 35%, V200 < 15% (with no con uence of two consecutive V200 isodoses and V200 isodose diameter < 10 mm) and DMskin (maximal dose delivered to the skin) < 75%. Two protocols were applied delivering 2 fractions per day, 6 hours apart, up to a total dose of 34 Gy (3.4 Gy/fraction over 5 consecutive days) or 32 Gy (4 Gy/fraction over 4 consecutive days). Irradiation was performed with an after-loading device using a 10 Ci 192Ir source (Microselectron™; Nucletron, an Elekta company, Elekta AB, Stockholm, Sweden and Saginova™, Eckert and Ziegler BEBIG company, Berlin, Germany). The irradiation was performed in an out-patient hospitalization way.

Adjuvant treatments
Endocrine therapy, chemotherapy, or anti-HER2-targeted therapy were used according to our center guidelines.

Follow-up
All patients were followed up closely. Patients were systematically examined by the radiation oncologist one month after brachytherapy to evaluate early toxicity. Afterwards, patients were seen every 6 months by the surgeon, the medical or radiation oncologist, during a clinical examination. Mammograms were obtained yearly. Late toxicities evaluation used the Common Classi cation for Adverse Events 4.0. Cosmetic results were assessed at every follow-up visit by the physician according to the Harvard criteria (25): excellent (treated breast nearly identical to untreated breast), good (treated breast slightly different from untreated), fair (treated breast clearly different from untreated but not seriously distorted), and poor (treated breast seriously distorted). All patients were included in the follow-up. The median follow-up was calculated from the day of last brachytherapy fraction to the date of the last follow-up.

Statistical analysis
Data were analyzed using the R 3.5.1 Windows software. The description of the study population and the different parameters consisted of absolute and relative frequencies for qualitative data, and descriptive statistics such as median and range for quantitative data. Local recurrence-free survival (LRFS) was de ned as the time between the date of surgery and the date of ipsilateral LR. Metastatic disease-free survival (MFS) rate was de ned as the time between the date of surgery and the date of metastatic disease occurrence. Speci c survival (SS) and OS were de ned as the time between the date of surgery and death from cancer or any cause respectively. These data were estimated and plotted at different time intervals with their 95% con dence using the Kaplan-Meier method. Patients were censored at the time of death or at last follow-up. In univariate analysis, the survival curves were compared using the log-rank test. The level of signi cance was set at a p-value of less than 0.05. Univariate and multivariate analysis were performed in order to nd some independent prognostic factors for oncological outcomes (LRFS, MFS, SS, OS).    The observed complications consisted mainly in breast brosis (60.8%), while telangiectasia (17.4%), hyper-pigmentation (7.2%), deformation (8.7%) and pain (5.8%) were less frequent.

Patient and tumor characteristics
Regarding cosmetic outcome, the rates of excellent and good cosmetic outcomes were 57.8% and 38.6% respectively, while a fair result was observed for 2 patients (1.8%). There was no poor cosmetic outcome (Table 4).

Discussion
Breast conserving treatment is the standard of care for early stage breast cancer (26). RT is a mainstay of this conserving approach, not only allowing a threefold reduction in LR but also improving OS (3,27). Patients aged 70 years and over, who are in good health condition, have a median life expectancy about 15 years and half of them will live much longer.
Elderly breast cancer represents a public health challenge, which will become more and more critical with the upcoming increasing life expectancy during the next decades and the impact of a potential acceptance of breast cancer screening for patients older than 75. For elderly patients presenting with early breast cancer, choosing the appropriate adjuvant treatment remains di cult, and we need to promote more accurate strategies taking into account oncological outcome and treatment toxicity as well as quality of life and health care expenditure.
In order to nd an acceptable compromise between no breast irradiation, as suggested in randomized trials (7)(8)(9)(10)(11)(12), and 3-5 weeks of WBI, the concept of APBI emerged and has been presented as a good option speci cally for the elderly population with breast cancer at low-risk of LR (17,18). The rationale for investigating partial-breast radiotherapy is based on the fact that after breast-conserving surgery, most LR occur at or near the primary site of the cancer (tumor bed) (28,29). Indeed, irradiation is limited to the higher risk area of LR. By increasing the radiation fraction size and decreasing the target volume and consequently decreasing the volume of irradiated normal tissue, APBI represents an alternative for the local treatment of breast cancer, and our extended follow-up enables us to look at the long-term impact of this approach.
Many techniques of APBI have been developed: HIBT, external breast RT and intraoperative radiation therapy. HIBT is one of the rst APBI technique used and has the longest follow-up (30,31). The two last trials which reported the comparison between external partial breast RT to WBI con rmed the noninferiority of the APBI technique in the RAPID trial, (but with a signi cant deleterious impact in terms of cosmetic outcome) (32,33) but not in the NSABP B-39/RTOG 0413 trial (34). Two trials of intraoperative radiotherapy reported higher rates of LR compared with conventional WBI (35,36). The GEC-ESTRO APBI phase III compared WBI versus APBI for selected primary early-stage breast cancer (low and intermediaterisk groups) (37) and the 5-year LRFS was 98.6%, which is similar to our 5-year LRFS of 98.1% previously described (19). With a 12-year median follow-up, Polgar et al. (38) reported a 5-year LR rate of 4.7% with 77% of good/excellent cosmetic results. This update con rms the outcome of our cohort while HIBT remains as an attractive technical option (19). In our study, regarding the oncological outcomes of the whole cohort and taking into account that in speci c circumstances, we were led to propose APBI even for patients belonging to the APBI GEC-ESTRO high-risk group, the 8-year LRFS, MFS, SS and OS rates were 96.7%, 95.7%, 96.7% and 71.8%, respectively.
Focusing on local control, Polgar et al. reported a 10-year LR rate of 9.3% but in a lower risk breast cancer population and younger cohort (median age: 56 years) (38). Our results lead to consider that, in an elderly population presenting with an early breast cancer, APBI could be reasonably proposed for intermediate and even high-risk patients in order to achieve optimal local control rate. Comparing with external beam APBI phase III randomized trials, we observed similar results in terms of local control. With a median follow-up of 10.2 years, the NSABP B-39/RTOG 0413 (34) reported a LRFS rate of 95.4%. With a similar 8- year median follow-up, the LRFS rate reported in the RAPID trial was 97% (32).
In our cohort, we observed that the majority of the patients died from other causes than cancer (Fig. 2). In phase III randomized trials comparing surgery plus endocrine therapy with or without adjuvant WBI, a signi cant over-risk of LR without breast irradiation was reported (9,11). Due to the deleterious impact of aromatase inhibitors on the quality of life (43), it is currently discussed to promote adjuvant breast irradiation without endocrine therapy in the elderly with low-risk breast cancer (44,45). In our population study, 5 patients refused and 12 patients stopped the treatment prematurely due to poor tolerance. For selected patients, APBI could also be considered as a viable alternative to the omission of adjuvant RT which has been considered for elderly patients, as it drastically reduces the number of transportations, alleviates the treatment related constraints, in particular for elderly patients with frequent comorbidities, without compromising local control. Currently, some protocols wants to get further proposing singlefraction HIBT with promising results (46,47).
In a time of cost saving for patients and health care systems, Shah et al. (48) showed in a cost-e cacy study that compared with WBI using three dimensional conformal RT and intensity-modulated RT, every APBI techniques allow for 1000 treated patients, cost savings between $0.7 and $6 million and between $5 and $14.9 million, respectively. Lanni et al. (49) con rmed that APBI using brachytherapy techniques was less costly than conventional WBI with a standard boost.
The limitations of the present study are mainly represented by its retrospective status, the small number of patients and (fortunately) the very few numbers of oncological events that did not allow performing an accurate statistical analysis for prognostic factors.

Conclusion
Long-term follow-up con rms that HIBT is safe and effective in an elderly patient cohort of early breast cancer. APBI using HIBT represents a smart alternative between no post-operative irradiation (endocrine therapy alone) and WBI. Our results suggest that selected elderly women presenting with high-risk breast cancer could also be considered for APBI.
In the frame of aging population with an increased breast cancer incidence, healthcare providers, insurers, and administration have to be aware of this issue, to provide to elderly women with early breast cancer, the best therapeutic option combining optimal local control and good quality of life in a cost-effective way. A statement on ethics approval and consent was provided by the Breast Cancer Research Board of the Antoine Lacassagne Cancer Center.

Consent for publication
Consent for publication was obtained from the patients.
Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests   Superimposed overall, speci c, local-free and metastatic-free survival curves showing the impact of competing factors for overall survival in the elderly.