Retrospective analysis of intra-operative radiotherapy (IORT) in early breast cancer—an Australian institution experience

Introduction

Breast-conserving surgery (BCS) with adjuvant whole-breast external beam radiotherapy (EBRT) for early breast cancer is the current standard of care; decreasing local recurrence and mortality rates (1,2). However, the 3–6 weeks adjuvant radiotherapy course has psychological impacts with decreased quality of life, and limited access for rural patients due to treatment duration. Adverse toxicity has also shown to decrease patient compliance (3,4).

Partial breast irradiation (PBI) is an approach that has gained interest for low-risk breast cancers where recurrences are most likely close to the tumour bed. Given the reduced volume of irradiated tissue, this strategy can be delivered in less fractions. One PBI technique is intra-operative radiotherapy (IORT), consisting of a single intra-operative dose of irradiation-targeted tumour cavity treatment, and is an elegant PBI technique that mitigates the above issues observed in EBRT patients (1-4). The ELIOT and TARGIT-A randomised control trials have been instrumental in the advance for IORT; offering a tangible option for low-risk early breast cancer patients (5,6). The literature has also observed that IORT has minimal side effects, in comparison to EBRT (3-7).

This approach was made clinically applicable in Vaidya’s risk-adapted multi-centre randomised controlled trial where IORT was supplemented by EBRT in post-operative histopathology patients with higher risk factors. This landmark study demonstrated a non-inferiority margin of less than 2.5% with 5-year local recurrence rates and long-term survival outcomes (8). With the subsequent publication of American Society for Radiation Oncology (ASTRO) guidelines (9), our study adopted a similar risk-adapted approach, aiming to assess IORT feasibility and efficacy through our single-institution prospective data registry. We report on our recurrence rate, complications, toxicity, and survival. We present this article in accordance with the STROBE reporting checklist (available at https://abs.amegroups.com/article/view/10.21037/abs-24-28/rc).

Methods

This study’s data were identified from an ethics-approved electronic registry of 101 patients who underwent breast cancer surgery with IORT from January 2017 to December 2021 at the Monash Cancer Centre. The data included patient demographics, type of surgery, tumour characteristics, complications, recurrence, and survival status. All data were de-identified prior to analysis, with ethics sought from our institution’s research support services. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). In accordance with the National Clinical Trials Governance Framework, the study was approved by the institutional ethics board of Monash Health (No. RES-24-0000-350Q). Individual consent for this retrospective analysis was waived.

As demonstrated in Figure 1, eligible patients included those with a pre-operative tissue diagnosis of breast cancer, and minimum age of 40 years. This comprised ductal carcinoma in situ (DCIS), invasive ductal and lobular carcinoma, as well as mucinous and tubular carcinomas. Based on pre-operative imaging of ultrasound, mammogram and some with magnetic resonance imaging (MRI) (tumour sizes were required to be less than 45 mm). Patients had clinically and radiologically negative axillary lymph nodes. Patients were excluded if they had multi-centric disease, previous radiotherapy, contra-indications to radiotherapy or tumours in a location not suitable for the technique as assessed by the surgical team (tumours too close to the skin surface).

Figure 1 IORT with Xoft Axxent eBx delivery system—low-energy radiation delivery with a balloon applicator that temporarily placed in the tumour cavity. Ultrasound evaluation and protective shield are used to ensure adequate skin distance and decrease surrounding tissue toxicity. IORT, intra-operative radiotherapy; eBx, electronic brachytherapy.

Post multidisciplinary pre-operative counselling and informed consent, patients then underwent wide local excision (WLE) ± sentinel lymph node biopsy (SLNB), followed by IORT. Intra-operatively, all patients had a prophylactic dose of cephazolin on induction. SLNB, in core-biopsy confirmed invasive carcinoma patients, was performed first. WLE of the tumour was performed and lead shield insertion depending on cardiac and chest wall proximity.

Once the tumour is removed, the surgeon assesses the fill volume to the tumour cavity with a foley catheter. Under ultrasound guidance, the balloon applicator size is selected to fit firmly within the tumour cavity, with a 1cm distance from balloon to skin. It is then secured by the surgeon with sutures. With the Xoft Axxent electronic brachytherapy (eBx) system (Xoft, Inc., San Jose, CA, USA), 20 Gray (Gy) was administered to the brachytherapy balloon surface with 50-kV X-ray radiation as illustrated in Figure 2.

Figure 2 Flowchart of risk-adapted approach.

The time duration is determined by a library of plans and an algorithm, which is determined by a set of variables which include the balloon size, room temperature, and atmospheric pressure. These variables are entered by a physicist in theatre prior to delivery which determines the time. After approximately 10–15 minutes of IORT, the retention sutures, and eBX balloon were removed. Post washout and haemostasis, the cavity was closed primarily or with oncoplastic techniques.

All patients were subsequently discussed at the breast oncology multidisciplinary team (MDT) meeting, with adjuvant risk-adapted treatment plans. The negative margin rate was defined as no tumour on ink for invasive tumours, and 2 mm margin for DCIS lesions. Patients with positive margins were recommended for re-excision. EBRT was recommended for high-risk pathology—tumours with positive margins, node positivity, presence of lymphovascular invasion, or higher grade or larger tumour size than previously thought.

To reduce surveillance bias, all patients had planned follow-ups at 1 week, 1 month, 6 months, and 12 months. Subsequent yearly reviews were conducted where all patients underwent mammogram and ultrasound. Toxicities were assessed at each review by the same clinician to avoid bias; with early defined as within 3 months, and late defined as beyond 3 months. Other clinicopathological variables such as locoregional recurrence, distant metastasis, and mortality were assessed up to the most recent follow-up, in January 2024.

Statistical analysis

In terms of statistical methods, Fisher’s exact test was used to assess the relation of the two categorical variables of recurrence and non-recurrence from our IORT group, to the IORT groups of the ELIOT and TARGIT-A trials. No subgroup or sensitivity analysis was performed due to the low recurrence rate and small sample size which would likely lead to statistically insignificant results.

Results

The number of cases during the study period determined the sample size; with the cohort of 101 patient characteristics illustrated in Table 1. The mean age was 66±8.46 years, with 75 (74.26%) in the category of more than 60-year-old and only 2 (1.98%) in the less than 45-year-old category. Five (4.95%) patients had bilateral or multifocal tumours, comprising the analysis of 106 tumours. Tumour size ranged from 5 to 45 mm with a mean of 15.11±7.70 mm.

Majority were low-risk breast cancers—>95% were oestrogen receptor (ER)/progesterone receptor (PR) positive, whilst 1 (1.10%) invasive carcinoma was a Bloom-Richardson-Elston grade of 3 (G3). Fifteen (14.15%) patients were tumour-in-situ stage, 77 (72.63%) T1 stage, and 14 (13.21%) T2 stage. The most common phenotype was invasive ductal carcinoma (IDC) with 81 (76.42%) tumours. In Figure 2, 10 (9.90%) patients underwent additional EBRT post IORT, with 6 (5.94%) being node positive. The four other patients were due to positive surgical margin, or large tumour size 32–37 mm.

As per MDT recommendations, two of the node positive patients had adjuvant chemotherapy, whilst two declined. Thirteen (12.26%) patients had positive margins and underwent re-excision within a month, with successful margins. Of note, one re-excision underwent simultaneous axillary lymph node dissection (ALND), whilst two other node positive patients declined ALND.

With the 48-month median follow-up, we identified 3 (2.97%) local recurrences, 1 (0.99%) locoregional recurrence, and 1 (0.99%) distant recurrence. Their clinicopathological characteristics and subsequent management are depicted in Table 2. Four (80%) patients recurred before the 5-year mark, and one at 6 years. Only one patient was in the less than 45-year-old category at time of enrolment. There were 3 invasive tumour recurrences and one DCIS recurrence; with 1 invasive tumour presenting with nodal metastasis. Three were ipsilateral breast tumour recurrence (IBTR) and one was contralateral.

The lone distant recurrence had nodal, pleural and bone metastases at 2-year surveillance. Despite right pleurodesis for metastatic effusion, fulvestrant, and targeted therapy—she was palliated and passed 12 months after recurrence. She was the sole breast cancer-related death. The cohort had a 98.02% overall survival; with the other death identified as a 77-year-old with non-survivable cardiac arrest post 5-year follow-up. Sixteen (15.84%) patients were either lost to follow-up or requested to be discharged to their general practitioner or surgeon’s private rooms. However, only two patients had very short follow-up; one at 6 months and the latter at 12 months. The remaining 14 had 36- to 48-month follow-up prior to non-participation; hence the generalisability of results should not be significantly impacted.

Figure 3 and Table 3 depict the frequency of complications and toxicities graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Thirteen (12.9%) patients had acute complications—defined as occurring within 1 month of IORT. The most prevalent acute complication was grade 2—5 (4.95%) infections occurred. Skin toxicity such as grade 1 erythema was not consistently graded, hence it is difficult to ascertain severity and patient impact. However, 2 (1.98%) patients were identified with severe erythema post IORT (grade 2 toxicity). For other grade 2 toxicities, 3 (2.97%) patients required more than 3 drainages of acute seromas. Grade 3 toxicity was minimal, with 3 (2.97%) returns to theatre; 1 for evacuation of haematoma and 2 for debridement of skin necrosis.

Figure 3 Acute and chronic toxicity events.

Sixteen (15.8%) patients developed chronic complications—defined as persistent at 6 months post IORT. All were grade 1 toxicity—with seroma the most prevalent, followed by fibrosis (11.88% and 2.97% respectively). Chronic hyperpigmentation was observed in 1 (0.99%) patient, leading to excellent cosmetic outcomes for the cohort post IORT.

Discussion

Since the National Comprehensive Cancer Network (NCCN) 1990s recommendation, conventional BCS in early-stage breast cancer involves WLE ± SLNB with adjuvant EBRT (1,2). This entailed 3–6 weeks whole-breast moderate hypofractionated radiotherapy that may include a ‘boost dose’ to the tumour bed (1,2). However, this came at a cost with side effects of radiation-induced toxicity such as skin damage, patient non-compliance, and daily therapy affecting quality of life. Rarer effects of EBRT include cardiac injury, osteitis, pneumonitis, second malignancy, and brachial injury (3,4,6).

Hence PBI techniques were conceived, with this study focusing on IORT—a uniform single radiation dose administered intra-operatively to the tumour bed. The efficacy theory was due to studies reporting 80-85% of breast cancer recurrence at or near the original site (5,6). Potential benefits of IORT are decreased surrounding tissue irradiation, no delay between surgery and radiotherapy, and decreased radiation-induced cardiopulmonary toxicity with a shield placement (7-11). These outcomes potentially translate to an increased survival rate (8-11). IORT also eliminates geographic miss as adjuvant EBRT may not target the displaced tumour bed well; an increasingly common issue in the era of oncoplastic breast surgery (12,13). It also avoids mastectomy in rural patients without access to a radiotherapy facility, or unable to undergo weeks of daily radiation (12).

However, IORT is still debated due to lack of long-term recurrence rates and variations of IORT techniques leading to inability to extrapolate clinical significance (2). Another issue is lack of histopathology on final tumour sizes, margins and nodal status pre-radiotherapy; which are known predictors of local recurrence (1,2). This was partially addressed in Kostova-Lefterova’s Xoft Axxent treatment protocol where 12/20 patients had a rapid frozen examination to evaluate resection margins within an hour (14).

In the early 2000s, the TARGIT-A and ELIOT randomised trials compared IORT with standard treatment of EBRT (4-8). Both trials employed brachytherapy (low-energy X-ray) techniques; however, TARGIT-A utilised 50-kV X-ray (intrabeam) whilst ELIOT employed an electron beam linear accelerator which delivered 3–12 MeV (4-8). Both patient populations were similar to ours with early breast cancer albeit only included patients aged 40 and 48–75 years respectively; and tumour diameter of up to 3.5 and 2.5 cm respectively (4-8).

Our study drew comparison to TARGIT-A, in the use of the Xoft system. This has the same kV X-ray dose to that of TARGIT-A’s intrabeam device (4,5). However, whilst TARGIT-A had a risk adapted protocol, ELIOT did not (4-8). It had a 1:1 randomisation and that led to a hazard ratio of 10 for local recurrence (4,5). Hence our approach with the widely used Xoft brachytherapy system and risk adapted protocol is more applicable for other breast cancer services worldwide.

They helped identify high-risk features such as aggressive tumour biology, positive margins, or positive lymph nodes. Henceforth, a stricter patient selection criterion was performed for subsequent trials (4-8). This was also endorsed by recent 2023 ASTRO guidelines, deeming IORT an acceptable PBI technique. Conditional recommendations included grade 3, ER negative, and size 2–3 cm (9). Unlike these two trials, our cohort included a pre-operative negative nodal status.

The main difference in inclusion criteria was the histopathological inclusion of only oestrogen-positive IDC in TARGIT-A (7), whilst we included DCIS and all types of invasive cancer. Hormone receptor negative patients were also included in our criteria, although majority of the cohort was positive (Table 1). Some studies also excluded invasive lobular carcinoma (ILC), citing its multifocal/multicentric nature a poor prognostic factor (9). However, in the ELIOT trial, ILC was not a contraindication for IORT (4,5). Seven (6.60%) of our cohort had ILC with no recurrence; suggesting no difference in outcomes for various phenotypes.

Our single institution prospective registry observed a low 4.95% recurrence rate in the median 48-month follow-up, and 99.0% disease-specific survival rate with one patient death 12 months post regional and distal recurrence. The single non-breast cancer-related mortality was in a cardiac arrest patient post 5-year follow-up. This compares favourably with a systematic review of 17 studies using the Xoft Axxent system reporting a recurrence rate of 1–5.8% at a median follow-up of 22.75 months (14). This is also similar to ELIOT and TARGIT-A trials’ 5-year follow-up of 4.2% in 651 IORT patients and 2.11% in 1,140 IORT patients respectively (4-8). TARGIT-A also observed a higher overall survival in the TARGIT arm; attributed to higher rates of cardiopulmonary deaths in the EBRT arm (7,8) whilst ELIOT demonstrated no overall survival difference (4,5).

With our limited sample size, Fisher’s exact test was utilised to compare the locoregional recurrence in our group to that of the two trials. There was no significant difference between our locoregional recurrence of 3.96% and the ELIOT trial of 4.2%, P>0.99, 95% confidence interval: 0.35–4.21. Comparing our study and the TARGIT-A trial of 2.11%, P=0.28, 95% confidence interval: 0.17–2.11. Hence the expected proportions of recurrence between our study and the two trials were not substantially different. The limitation of this analysis is the different durations of follow-up with our study at 48 months and the two trials at 60 months.

Regarding the cohort’s local recurrences as per Tables 2,3 were managed with WLE and SLNB, with the one contralateral recurrence also undergoing IORT. The one ipsilateral locoregional recurrence underwent neoadjuvant chemotherapy with dose-dense doxorubicin and cyclophosphamide (ddAC)-paclitaxel before left mastectomy and ALND. All four patients underwent EBRT as per MDT recommendations.

Two of the IBTR recurrences may be attributed to patient non-compliance—the first, listed in Table 2, ceased anastrozole (due to adverse drug reaction) for a 16 mm tumour. The second, declined adjuvant chemotherapy for a high Ki67 15 mm tumour. Both were G2 hormone receptor positive IDC. We believe additional EBRT also contributed to the cohort’s low recurrence rate; 9.90% of IORT patients were deemed high risk and underwent EBRT. Two hundred and thirty-nine (15%) of the TARGIT arm also received 50 Gy EBRT, with the IORT dose considered a boost (6).

Compared to the four locoregional recurrences, the distant recurrence patient had high-risk features of a large, high-grade, node-positive tumour—45 mm G3 IDC with positive margin and high Ki67 20% with extra-nodal extension. She recurred despite adjuvant chemotherapy, EBRT, and re-excision of supero-medial margins with ALND. Twenty-one percent of the ELIOT trial IORT arm were N1 nodal status (1–3 positive lymph nodes) (4,5), whilst the TARGIT-A trial IORT arm had 15% patients (6-8). However, despite her very high risk, the patient did not develop local recurrence. Thus, IORT with adjuvant EBRT was very favourable despite the high risk.

In Strnad’s trial (11), 6% of IORT patients had pure DCIS, compared to our study of 14.15%, with zero recurrence. 50% of the TARGIT-A trial patients also had concurrent DCIS identified on final histopathology (6-8). The 2023 ASTRO recommendation for IORT in low-risk DCIS with features of low to intermediate grade, age >39 years, and size <2.1 cm was crucial in our selection criteria. In terms of their conditional recommendation for high grade or size 2.1–3 cm, 9.43% of our cohort with high-grade DCIS were included to fulfil a gap in the literature (9). Our excellent local control results in pre-invasive breast cancer are promising. However, with this small sample size and ASTRO expert opinion-based recommendations, further studies are needed (9).

Compared to other studies (15-17), similar skin toxicities were observed in our cohort—0.99% haematoma evacuation, 2.97% seromas that were drained more than 3 times, 4.95% infections, and 1.98% necrosis requiring debridement. With 1.98% patients with severe erythema and 0.99% hyperpigmentation, the overall acute complication rate of 12.9% and 15.8% chronic complication outcomes are promising (Table 3). In the IORT arm of the TARGIT-A trial, 1% had haematomas, 2.1% had seromas requiring drainage more than 3 times, 1.8% infections, 2.8% necrosis (6-8). The TARGIT trial had similar wound complications but grade 3–4 skin complications were significantly reduced in the IORT arm (P=0.029) (6-8). The ELIOT trial IORT patients had less skin damage (P=0.0002) albeit no difference in other complications such as fibrosis or pain. It also demonstrated less pulmonary fibrosis albeit higher rates of fat necrosis (4,5).

In addition to IORT, the 2023 ASTRO PBI guidelines discussed an adjuvant 5-fraction technique (9). The University of Florence trial with intensity-modulated radiation therapy (IMRT) of 30 Gy in 5 once-daily fractions showed no significant difference in the 10-year IBTR between accelerated PBI (APBI) and whole-breast irradiation (WBI) of 3.7% and 2.5% (18). There was similar overall and breast cancer-specific survival of 97.8% and 96.7% respectively (18). The UK IMPORT LOW trial also demonstrated non-inferiority of adjuvant partial-breast and reduced-dose radiotherapy compared with EBRT (19). The 5-year estimated cumulative incidence of local relapse was 1.1% in the control whole-breast group, 0.2% in the reduced dose group, and 0.5% in the partial-breast group (19). However, compared to IORT, these PBI techniques still require a longer interval of 5–15 adjuvant radiotherapy sessions, and a risk of a geographic miss. It is less feasible too with more adjuvant resources required.

Another phase III trial, FAST-Forward, had 3 arms—1-week WBI (26 or 27 Gy in 5 fractions) and 3-week WBI (40 Gy in 15 fractions) (20). This demonstrated noninferiority with 5-year estimated cumulative incidence of IBTR 1.7% for 27 Gy, 1.4% for 26 Gy, and 2.1% for 40 Gy (20). There was similar late normal tissue toxicity for the 26 Gy arm but worse late normal tissue toxicity for the 27 Gy arm (20). This steep dose-response relationship is concerning, with further research regarding the modification of radiotherapy dose and fractionation required (20). Hence although some advances have been made with shorter adjuvant regimes, IORT is still a viable PBI option, in terms of patient access and outcomes.

To our knowledge, there are no published phase III studies using Xoft Axxent eBx IORT, with a 2021 systematic review reporting no randomized controlled trials (RCTs) and discussing non-randomized studies (14). Our study’s limitations include a lack of a control group, short median follow-up of 48 months, and 15.84% loss to follow-up patients. This could underestimate our locoregional and distant recurrence rates; and thus, long-term oncologic outcomes. There is also a potential selection bias given the non-randomisation nature of the study. Resource intensity such as increased theatre time and complexity of physics in the delivery of IORT are also barriers to its economic feasibility.

Hence this analysis demonstrates that the risk adapted protocol is effective independent of the IORT device or type of rays (Xoft, intrabeam, or intra-operative electrons). This is with the caveat that EBRT is included in the management algorithm as a rescue strategy. To our knowledge, this is one of the first analysis illustrating this issue.

Other strengths of this study are its prospective nature and reported low recurrence and toxicity rates, comparing favourably with other IORT studies and PBI techniques. The generalisability of our study is based on a broad eligibility criterion with all cancer phenotypes, including pre-invasive; as well as a wide age range and diverse multi-ethnicity population. Other distinguishing features include Australian setting with applicability to the local population, and risk-adapted protocol, MRI utility to confirm unifocality, and Xoft machine where most published studies are intrabeam. These key points add to the body of literature and will inform future studies.

Conclusions

Hence the non-inferiority of IORT in local recurrence-free survival, distal disease-free survival, overall survival, and breast cancer mortality is promising (7,8). Our oncologic outcomes with 4.95% locoregional/distant recurrence rate and 99.0% breast cancer-specific survival at median 48-month follow-up were similar to the literature, reiterating the efficacy of IORT in BCS. The complications observed in our study were small and had minor clinical significance. IORT needs to be further evaluated as a management pathway to avoid acute and chronic toxicity, improve quality of life with short treatment duration and easier access; thus, avoiding mastectomy with improved cosmetic outcomes. For IORT to be clinically applicable, careful multidisciplinary patient selection, unified IORT techniques and strict prospective surveillance is crucial. Further long-term outcomes from our cohort will help delineate this modality role in the field of early breast cancer.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://abs.amegroups.com/article/view/10.21037/abs-24-28/rc

Data Sharing Statement: Available at https://abs.amegroups.com/article/view/10.21037/abs-24-28/dss

Peer Review File: Available at https://abs.amegroups.com/article/view/10.21037/abs-24-28/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://abs.amegroups.com/article/view/10.21037/abs-24-28/coif). The authors have no 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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics board of Monash Health (No. RES-24-0000-350Q) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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