Effect of intraoperative radiotherapy for patients with low-risk early-stage breast cancer

Introduction: External Beam Radiation Therapy (EBRT), a type of whole breast radiation therapy, has been widely used in patients with early-stage breast cancer, however it is associated with longer treatment periods and higher toxicity. Intraoperative Radiotherapy (IORT) has emerged as an alternative, reducing treatment times, however, there is uncertainty about its effectiveness and safety. Objective: To assess the effects of IORT on low-risk early-stage breast cancer in comparison to EBRT. Methods: We searched in Epistemonikos, a database of systematic reviews, to identify the available evidence evaluating the benefi t of IORT on these patients. We extracted data of primary studies from relevant systematic reviews. Data were reanalyzed and a meta-analysis, using evidence of randomized trials, was conducted. Results are reported trough a summary of fi ndings table using the GRADE approach. Results and conclusions: We identifi ed eight systematic reviews including seven primary studies overall, of which two were randomized trials. We concluded that IORT slightly reduces adverse events and probably increases the local recurrence rate in comparison with EBRT. Review Article Effect of intraoperative radiotherapy for patients with low-risk early-stage breast cancer Diego Carreño1*, Camila Quirland1, Pedro Ferrer2, Luz María González3 and Badir Chahuán4 1Health Technology Assessment Unit, Department of Cancer Research, Arturo López Pérez Foundation, Santiago, Chile 2Institute of Nutrition and Food Technology, University of Chile, Santiago, Chile 3Oncological Institute, Arturo López Pérez Foundation, Santiago, Chile 4Reconstructive and Oncological Breast Surgery Unit, Oncological Institute, Arturo López Pérez Foundation, Santiago, Chile Received: 15 January, 2021 Accepted: 04 February, 2021 Published: 05 February, 2021 *Corresponding author: Diego Carreño, Health Technology Assessment Unit, Department of Cancer Research, Arturo López Pérez Foundation, Santiago, Chile, E-mail:


Introduction
Breast cancer is the most common cancer and the second cause of cancer death among women in the Americas. Every year more than 462,000 new cases and almost 100,000 deaths from breast cancer occur in the region. In women from Latin America and the Caribbean, this health problem accounts for 27% of new cases and 16% of cancer deaths. Its incidence in the Americas is expected to increase by 2030, with an estimation of 572,000 new cases and 130,000 deaths [1]. In Chile, breast cancer is the most prevalent in women, accounting for 54,227 new cases and 28,584 deaths in 2020. In 75-year-old women or younger, the risk of developing this disease and their mortality is of 16% and 8%, respectively [2].
The breast-conserving therapy combined with postoperative radiotherapy is an equivalent treatment strategy to mastectomy for patients with early-stage breast cancer. External beam radiation therapy (EBRT), a type of whole breast radiation therapy, has become a gold standard as adjuvant therapy after breast-conserving surgery, reducing the risk of local recurrence and improving survival. The results of this intervention are associated with dosedependence, higher incidence of cardiotoxicity and lung cancer, which increases over time after exposure [3].
Citation: Carreño  As an alternative to whole breast radiation therapy, the clinical practice includes the accelerated partial breast irradiation, a localized form of radiation concentrated on the tumor bed, site where most recurrence occur, which reduces the exposure to radiation from nearby organs and minimizes late adverse events [4,5].
Intraoperative radiotherapy (IORT) is one of the validated techniques of accelerated partial breast irradiation, whose greatest advantage over EBRT is that it limits the treatment to one session, which is applied to the tumor bed during surgery [4].
Despite the above, there is still uncertainty about the superiority and safety of the use of IORT over EBRT. Hence, the aim of this review is to assess the comparative effects of IORT over EBRT.

Methods
We searched in Epistemonikos, a database harboring documents from multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies evaluating the effects of IORT in patients with low-risk earlystage breast cancer in comparison to EBRT [6]. The resulting summary of the body of evidence is presented as an evidence matrix [7]. The FRISBEE methodology was used to extract, review, and analyze the available evidence [8]. The outcomes included in the summary of fi ndings table are those considered critical for decision-making, according to the opinion of the authors, and in general they are in agreement with the systematic reviews identifi ed. Data of relevant outcomes were extracted from the identifi ed reviews, including local recurrence, mortality, grade 3-4 adverse events related to skin radiotherapy toxicity, complications associated with the intervention, health-related quality of life, and physician reported cosmesis (breast appearance). When the available evidence came from more than one primary study, data were reanalyzed using meta-analysis. Results are reported through a summary of fi ndings table following the GRADE approach.
All further analysis and the reported results are based on the extracted data from the randomized trails, since they represent the body of evidence with the highest level of certainty. Additionally, observational studies did not provide any additional relevant information.
The randomized trials, named TARGIT-A and ELIOT, included patients aged 45 years or older, all of them were women with early-stage breast cancer, harboring tumors of a size of 2.5 cm or less, and that were suitable for breastconserving surgery. Respect to TNM classifi cation, the largest proportion was T1c and T1ab, and N0 and N1, respectively. In

Discussion
The principal aim of the present study was to evaluate the effect of IORT on low-risk earlystage breast cancer in comparison to EBRT. Following the GRADE approach, our results show that the risk of local recurrence in patients could probably be three times higher in patients undergoing IORT than EBRT. The benefi t in mortality is uncertain and could probably lead to a decrease for both intraoperative and external radiotherapy. Adverse events associated with radiotherapy decrease slightly in patients undergoing IORT compared to those treated with EBRT. In the same way, IORT may slightly decrease complications associated with radiation therapy and the achievement of cosmesis compared to EBRT. Additionally, IORT probably increases quality of life in comparison with external radiotherapy.
The results obtained apply to patients with initial breast cancer, postmenopausal, with tumor of 2.0 cm or smaller, a favorable molecular histological subtype (luminal A), and suitable for breast-conserving surgery. Although some studies Table 1: Summary of fi ndings using the GRADE approach. Outcomes are reported in order of importance in the decision-making process.

IORT for patients with low-risk early-stage breast cancer Patients
Patients with low-risk early-stage breast cancer *The risk WITH EBRT is based on the risk in the control group of the trials. The risk WITH IORT (and its margin of error) is calculated from relative effect (and its margin of error). **Adverse events such as radiation therapy grade 3 or 4 toxicity to the skin, e.g., erythema, dryness, hyperpigmentation, and pruritus. ***Complications such as hematoma needing surgical evacuation, seroma needing more than three aspirations, infection needing intravenous antibiotics or surgical intervention, and skin breakdown or delayed wound healing. 1 Based on the assessment of risk of bias reported in three systematic reviews, we decided not downgrade certainty level [5], [10], [12].

About the certainty of the evidence (GRADE)* 
High: This research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different † is low. ◯ Moderate: This research provides a good indication of the likely effect. The likelihood that the effect will be substantially different † is moderate ◯◯ Low: This research provides some indication of the likely effect. However, the likelihood that it will be substantially different † is high. ◯◯◯ Very Low: This research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different † is very high. *This concept is also called 'quality of the evidence' or 'confi dence in effect estimates'. † Substantially different = a large enough difference that it might affect a decision.
Citation: Carreño  included patients from other molecular subtypes, the results in terms of reported local recurrence for them are considerably higher for the intervention, therefore, the use of IORT in this context is not recommended [14].
In addition to the clinical benefi ts, IORT is associated with lower costs [12]. This could be due to a shorter time of treatment, which implies a reduction in the cost of professional fees and the period of medical rest (less time for medical leave of absence), an early return to work, and a decrease in years old, respectively. According to these recommendations, some studies have shown favorable results, even when they include patients aged 40 years and older, however, further analysis and follow-up of these studies is required to extend the indication to this population [23].

Conclusion
Our results revealed that IORT does not show an absolute superiority when compared to EBRT, in terms of the outcomes reported in this article. Thus, although IORT is associated with clinical benefi ts by reducing the incidence of grade 3-4 toxicity to the skin, it does not reduce the risk of local recurrences in these patients in comparison to EBRT. Further research is needed to elucidate which alternative constitute the best option for the treatment of these patients and to clarify the subgroups of patients who may benefi t the most with one alternative or the other.