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Accelerated partial breast irradiation in elderly breast cancer patients

Breast-conserving surgery with adjuvant whole-breast irradiation has become the standard treatment for early breast cancer (EBC) patients. Partial breast irradiation, which targets only the postoperative cavity, has been established as an alternative to whole-breast therapy in selected patients. The treatment of elderly breast cancer patients differs from the therapeutic approach in younger ones, as elderly patients are prone to geriatric frailty and comorbid conditions, the incidence and severity of which increase with age. A review of the evidence, process, techniques, and results of accelerated partial breast irradiation (APBI) in elderly EBC patients, seems to indicate that APBI is an advisable postoperative approach in properly selected elderly EBC patients, combining advantages of a radical approach that minimizes the risk of undertreatment with efficient reduction of redundant irradiated volume, treatment toxicity, overall treatment time, staff workload, radiation technique workflow, patient transportation, and the potential for non-compliance. There is no “one size fits all” technique of APBI, the best technique always depending on willing patients, individual anatomy, performance status, patient frailty and comorbid conditions, and tumour location.


Introduction
Early breast cancer (EBC) is a frequent disease in women with a constantly increasing incidence in all age categories (1). Due to the increase in life expectancy, EBC has a higher prevalence in women aged 65 and older (2). Management of the treatment of EBC has become an important concern in developed countries. Breast-conserving surgery (BCS) with adjuvant whole-breast irradiation (WBI) and adjuvant hormonal treatment has been the standard treatment of EBC for decades. The use of WBI following BCS significantly decreases 10-year locoregional recurrence rates in all patients and 15-year mortality in some of them (3).
Despite the undoubted advantages of WBI in terms of improved relapse rates and eventually survival, this approach presents several important drawbacks. First, WBI requires an extended treatment time (3 to 7 weeks), which places a heavy burden on patients and also increases staff and radiation technique workloads. Secondly, WBI may be overtreatment given that the vast majority of local relapses (>85%) that occur after BCS (with or without WBI) occur in or close to the primary tumour bed (4). As a result, irradiating the entire breast may needlessly put patients at risk of developing clinically-significant side effects. For these reasons, partial breast irradiation (PBI), which targets only the postoperative cavity, has been established as an alternative to WBI in selected patients (5)(6)(7).
To date, the largest prospective randomized trial of external beam PBI is the multicentric IMPORT-LOW trial, which Review Article Accelerated partial breast irradiation in elderly breast cancer patients has demonstrated that PBI of 40 Gy in 15 daily fractions is not inferior to the same schedule of WBI in terms of local control and toxicity (8). Results of this trial favour this treatment as an easy technique of simple field reduction implementable in all radiotherapy centres that already provide breast radiotherapy. However, compared to standard 3-week WBI, there is no reduction of the treatment duration with this approach.
In accelerated partial breast irradiation (APBI), the total dose of radiation is given over 1 week or a shorter period of time to the part of the breast with the highest risk of microscopic disease. Accelerated radiotherapy uses fewer fractions of radiation to a smaller target volume, with a higher dose per single fraction, and with usually more than one fraction per day. Altogether, APBI aims to improve treatment tolerability and toxicity by limiting the treated volume and overall treatment time, without compromising clinical outcomes.
This paper is a review concerning evidence, process, techniques, and results of ABPI in elderly EBC patients.

Radiation therapy in the elderly
The treatment of elderly breast cancer patients differs from the therapeutic approach in younger ones. Radiation therapy can be highly effective and well tolerated in elderly patients (9), and age alone is not a limiting factor for adjuvant radiotherapy in breast carcinoma. However, elderly patients are prone to geriatric frailty and comorbid conditions, the incidence and severity of which increases with age. Weak underlying functional reserve and limited life expectancy of older patients can both limit the expected long-term benefits of standard adjuvant treatment (10). The radiation oncologist must be mindful of the potential to overestimate the functional reserve of the elderly and overtreat such patients, with the risk of unnecessary treatment morbidity and non-cancer related death. Moreover, compliance to a long course of WBI is often suboptimal, especially for patients living further away from a radiation centre (11).
In the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis, the absolute reduction rate of local recurrence (LR) with WBI in patients aged 60 years or older with low/intermediate-grade, hormone receptor-positive cancer was very small (5-10% reduction in 10-year risk of recurrence) (3). Consequently, several trials have demonstrated that omission of adjuvant WBI in elderly patients does not result in survival deterioration, albeit with statistically significant increase of local recurrence (12)(13)(14). To date, there has been no absolute age limit beyond which adjuvant irradiation does not improve local control in EBC. Therefore, there may also be a potential risk of undertreating older women because of an underestimation of life expectancy in patients of advanced age but with few significant comorbid conditions (15).
A systematic review with meta-analysis of 8653 women treated by APBI in eight randomized trials found that patients treated with APBI had a higher rate of local recurrence versus WBI, but without any differences in survival or other clinical outcomes (23). Later, a Cochrane review of partial breast irradiation for early breast cancer (24) found no clear evidence of a difference between PBI/APBI and WBI in terms of cause-specific survival, distant metastasis-free survival, relapse-free survival, loco-regional recurrence-free survival, or mastectomy rates. Finally, recent meta-analysis of 9 randomized trials and 8,720 patients showed lower 5-year non-breast cancer and overall mortality in patients treated with (A)PBI compared to whole breast irradiation. These findings suggest that APBI may avoid deaths from other causes in EBC patients. Since APBI trials included EBC patients with advanced age ( Table 2), the need to avoid any harmful effects of treatment may be vital especially in the elderly and should be discussed with patients appropriately.
Several medical societies, notably the American Society for Radiation Oncology (ASTRO), the Groupe Européen de Curiethérapie -European Society for Radiotherapy and Oncology (GEC-ESTRO), and the American Brachytherapy Society (ABS), have provided recommendations aimed at patient selection for APBI (5)(6)(7). Detailed guidelines concerning the appropriate target definition and quality assurance are also available, especially for MIB APBI technique (25,26). Likewise, long-term outcomes are well documented for MIB (21,22), but less so for other APBI techniques. Finally, the long-term risk of secondary cancer is reduced 2-to 4-fold in MIB with the lowest mean lung dose, compared to other APBI techniques (27).
In the light of such observations, APBI seems to be an advisable postoperative approach in properly selected elderly EBC patients, with its combined advantages of a radical approach that minimizes the risk of undertreatment, and efficient reduction of redundant irradiated volume, treatment toxicity, overall treatment time, staff workload, radiation technique workflow, patient transportation, and potential for non-compliance. APBI has become a standard of care in patients with low-risk EBC, but there is no "one size fits all" technique of APBI. The best technique always depends on willing patients, anatomy, performance status, frailty, comorbid conditions, tumour laterality, and location.

APBI in elderly EBC patients
Although the use of APBI is well described predominantly in women aged 50 years or more, there are several manuscripts concerning the feasibility and results of APBI directly in elderly women with breast cancer, aged 65 years or older.
GERICO-03 prospective phase II trial assessed the feasibility, reproducibility, and impact of APBI on functional status in elderly women aged 70 years or older. Fortysix patients with EBC (T1-2 <30 mm, pN0, median age 74 years) underwent high-dose rate (HDR) brachytherapy with a delivered dose of 34 Gy in 10 fractions over 5 days. The treatment was assessed as feasible and reproducible, with no significant impact on functional dependence, when the Activities of Daily Living and Instrumental Activities of Daily Living scores remained unchanged 6 and 12 months According to the analysis, APBI and WBI resulted in similar recurrencefree and overall survival rates in the cohort of elderly EBC patients, even after adjustment for the more favourable characteristics of the patients in the former group (29).
In Florence, a monocentric randomized phase III trial was performed comparing APBI using 5 times 6 Gy nonconsecutive daily fractions of IMRT vs. WBI (20). In 2015, a subgroup analysis from this trial was published concerning elderly patients aged 70 or older. A total of 117 patients aged 70 years or more (median 74.4 years, range 70.1-85.3 years) were analysed (58 in the WBI arm, 59 in the APBI arm). At a median follow-up of 5-years, the IBTR rate was 1.9% in both groups. The APBI group presented significantly better results in terms of acute skin toxicity, which could translate in a consistent improvement of overall quality of life and elderly patients' compliance (30).
In 2012, a nomogram was published to predict the benefit of postoperative breast irradiation for older patients with breast cancer after BCS (31). Based on this model, Sumodhee et al. investigated the position of APBI in the cohort of elderly EBC patients, compared to WBI or endocrine therapy alone. In 79 elderly patients with APBI (median age 77 years, range 66-89 years), the 10-year mastectomy-free survival (MFS) rate after 10 years was 97.4%, compared to nomogram-calculated MFS rate  96.3% with adjuvant WBI, or 92.7% without adjuvant radiotherapy (32). This study supports the position of APBI as a compromise between WBI and omission of radiotherapy in elderly EBC patients.

Intraoperative/perioperative APBI in elderly patients
APBI is generally performed several weeks after surgery to avoid possible wound-healing complications and only after complete results of the pathology examination are available. As mentioned before, only selected patients with strict pathological findings are suitable for APBI and these conditions are not available at the time of surgery. However, perioperative APBI techniques have some undeniable advantages. The main advantage of intraoperative irradiation (IORT) is that it allows the radiation oncologist to visualize the surgical cavity directly before irradiation, and also allows for the rapid completion of both surgery and radiotherapy in 1 day. However, the risk of consecutive adverse histopathological findings after IORT that may disqualify the patient from already accomplished APBI is not negligible.
In the TARGIT study, of the 1,140 patients allocated to targeted IORT in the prepathological stratum, 219 (19%) ultimately received both IORT and WBI because postoperative evaluation revealed high-risk characteristics in that subset of patients (33). In the ELIOT trial, 651 patients treated with electron IORT had significantly higher risk of ipsilateral breast tumour recurrence (IBTR) after 5 years compared to WBI (4.4% vs. 0.4%). Nonetheless, the risk of IBTR after IORT in this trial would be 1.9% if only good candidates for APBI according to GEC-ESTRO recommendations were irradiated intraoperatively (16).
Another perioperative approach is open-cavity MIB or industrial applicator implantation, when one can see without difficulty the cavity that needs to be implanted as well as the distribution and spacing (Figure 4). Moreover, the patient is protected from repeated anaesthesia or invasive procedure at the same time. The APBI itself starts only after definitive completion of the postoperative histopathological report. Therefore, in the case of intra-operative implant, the catheters must stay in place for at least 10 to 15 days (6-8 days to obtain the full postoperative pathological report plus 4 to 5 more days for the treatment itself, plus one more weekend in some cases). This time may be a potential risk for patient discomfort or local infection. In the situation of intra-operative implant, when APBI is not possible due to pathological findings with regard to the GEC-ESTRO recommendations, it is possible to remove catheters and continue with the external beam WBI or systemic therapy. It is also possible to use the implant for the interstitial cavity boost, with consequent WBI. In the study conducted by Cambeiro et al. (34), intraoperative MIB implant for postoperative APBI in low risk EBC was investigated. APBI was performed in 88 from 137 initial candidates (64.2%), in 34 patients (24.8%) the implant was used as the boost to EBRT, and in 15 cases (11%) brachytherapy was not performed. Likewise, the Czech monocentric prospective study evaluated the feasibility of using perioperative MIB (starting 6 days postoperatively) in highly selected EBC patients aged 60 years or more. From 125 patients intended for APBI with perioperative MIB implantation, only 12 patients (9.6%) did not undergo APBI due to unsuitable final histopathological findings (35). Based on the low rate of adverse histological findings in carefully selected elderly patients, APBI with perioperatively implanted MIB seems to be a reasonable approach.

Future perspectives
Further acceleration of adjuvant radiotherapy in EBC is under investigation, both for external beam APBI or brachytherapy. Results from a phase I/II trial for hypofractionated APBI using a 2-day dose schedule was recently published (36). A total of 45 patients (median age 66 years) were treated with balloon-based intracavitary brachytherapy 4 times 7 Gy, twice daily on 2 consecutive days. After 6 years, there was no IBTR recorded, and the chronic toxicities were acceptable according to the authors. In addition, for elderly EBC patients, the feasibility and early clinical outcomes of a single fraction of post-operative MIB were evaluated in a prospective phase I/II trial (37). In 26 patients (aged 70 years or older, median 77 years) after lumpectomy, intraoperative catheter implant was performed for post-operative APBI in a single fraction of 16 Gy.
The results of these trials are encouraging, but need longer follow-up and confirmation on a larger cohort of patients.

Conclusions
APBI seems to be an advisable postoperative approach in properly selected elderly EBC patients, combining advantages of a radical approach that minimizes the risk of undertreatment, with efficient reduction of redundant irradiated volume, treatment toxicity, overall treatment time, staff workload, radiation technique workflow, patient transportation, and potential for non-compliance. Moreover, APBI seems to be an ideal compromise between WBI and the omission of any radiotherapy at all in elderly EBC patients. To date, APBI is considered a standard postoperative treatment in low-risk EBC patients with suitable pathological characteristics. There are currently multiple techniques to deliver APBI, with best evidence favouring multicatheter interstitial brachytherapy. However, there is no "one size fits all" technique of APBI, with the best technique always depending on willing patients, anatomy, performance status, frailty, comorbid conditions, tumor laterality, and location. With ongoing trials, we anticipate further shortening of the treatment time in elderly patients with ultra-hypofractionated or single dose APBI schedules. Unfortunately, accessibility of APBI and specific cost analyses vary across the world and across regions of particular continents and countries. by the Guest Editors (Vincent Vinh-Hung and Nam P Nguyen) for the series "Radiotherapy for Breast Cancer in Advanced Age" published in Translational Cancer Research. The article has undergone external peer review.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi. org/10.21037/tcr.2019.07.03). The series "Radiotherapy for Breast Cancer in Advanced Age" was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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