Hype or hope? A review of challenges in balancing tumor control and treatment toxicity in breast cancer from the perspective of the radiation oncologist

The aim of this article is to discuss the challenges and new strategies in managing breast cancer patients, with a specific focus on radiation oncology and the importance of balancing oncologic outcomes with quality of life and post-treatment morbidity. A comprehensive literature review was conducted to identify advances in the management of breast cancer, exploring de-escalation strategies, hypofractionation schemes, predictors and tools for reducing toxicity (radiation-induced lymphocyte apoptosis, deep inspiration breath-hold, adaptive radiotherapy), enhancer treatments (hyperthermia, immunotherapy) and innovative diagnostic modalities (PET-MRI, omics). Balancing oncologic outcomes with quality of life and post-treatment morbidity is crucial in the era of personalized medicine. Radiotherapy plays a critical role in the management of breast cancer patients. Large randomized trials are necessary to generalize some practices and cost remains the main obstacle for many innovations that are already applicable (AU)

Hype or hope? A review of challenges in balancing tumor control and treatment toxicity in breast cancer from the perspective of the radiation oncologist.

The aim of this article is to discuss the challenges and new strategies in managing breast cancer patients, with a specific focus on radiation oncology and the importance of balancing oncologic outcomes with quality of life and post-treatment morbidity. A comprehensive literature review was conducted to identify advances in the management of breast cancer, exploring de-escalation strategies, hypofractionation schemes, predictors and tools for reducing toxicity (radiation-induced lymphocyte apoptosis, deep inspiration breath-hold, adaptive radiotherapy), enhancer treatments (hyperthermia, immunotherapy) and innovative diagnostic modalities (PET-MRI, omics). Balancing oncologic outcomes with quality of life and post-treatment morbidity is crucial in the era of personalized medicine. Radiotherapy plays a critical role in the management of breast cancer patients. Large randomized trials are necessary to generalize some practices and cost remains the main obstacle for many innovations that are already applicable.

Recommendations of the Spanish brachytherapy group of the Spanish Society of Radiation Oncology and the Spanish Society of Medical Physics for interstitial high-dose-rate brachytherapy for gynaecologic malignancies

The present document includes consensus-based recommendations from the Brachytherapy Group (GEB) of the Spanish Society of Radiation Oncology (SEOR) and the Spanish Society of Medical Physics (SEFM) for interstitial high-dose-rate (HDR) brachytherapy (BT) for gynaecologic malignancies. A nine-item survey—which included questions on experience with interstitial BT; indications and technique; applicator type; magnetic resonance imaging (MRI)-based planning; dose; fractionation schedule; and treatment planning—was sent to all radiation oncology departments (n = 174) in Spain in 2021. Responses were received from 36 centres (50% of all centres [n = 72] with a BT unit). The consensus-based recommendations presented here are based on a review of the available literature, professional experience among the group of experts, and in-person discussions held during the annual meeting of these two societies. We describe the results of the survey and the following: indications; contraindications; patient selection; description of applicators; role of imaging in planning; contouring; dose prescription; dosimetric reconstruction; optimisation; and dose indications for cancers of the cervix, vagina, and vulva. The various clinical scenarios in which interstitial BT is used in the treatment of gynaecological tumours are described in detail, including cervix intracavitary/interstitial hybrid HDR-BT; cervix perineal templates/freehand implants; primary vaginal malignancies/vaginal recurrences; and vulvar interstitial implants (AU)

Accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy compared with whole-breast irradiation with boost for early breast cancer: 10-year results of a GEC-ESTRO randomised, phase 3, non-inferiority trial.

BACKGROUND: Several randomised, phase 3 trials have investigated the value of different techniques of accelerated partial breast irradiation (APBI) for patients with early breast cancer after breast-conserving surgery compared with whole-breast irradiation. In a phase 3 randomised trial, we evaluated whether APBI using multicatheter brachytherapy is non-inferior compared with whole-breast irradiation. Here, we present the 10-year follow-up results. METHODS: We did a randomised, phase 3, non-inferiority trial at 16 hospitals and medical centres in Austria, Czech Republic, Germany, Hungary, Poland, Spain, and Switzerland. Patients aged 40 years or older with early invasive breast cancer or ductal carcinoma in situ treated with breast-conserving surgery were centrally randomly assigned (1:1) to receive either whole-breast irradiation or APBI using multicatheter brachytherapy. Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with a supplemental boost of 10 Gy to the tumour bed, and APBI was delivered as 30·1 Gy (seven fractions) and 32·0 Gy (eight fractions) of high-dose-rate brachytherapy in 5 days or as 50 Gy of pulsed-dose-rate brachytherapy over 5 treatment days. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was ipsilateral local recurrence, analysed in the as-treated population; the non-inferiority margin for the recurrence rate difference (defined for 5-year results) was 3 percentage points. The trial is registered with ClinicalTrials.gov, NCT00402519; the trial is complete. FINDINGS: Between April 20, 2004, and July 30, 2009, 1328 female patients were randomly assigned to whole breast irradiation (n=673) or APBI (n=655), of whom 551 in the whole-breast irradiation group and 633 in the APBI group were eligible for analysis. At a median follow-up of 10·36 years (IQR 9·12-11·28), the 10-year local recurrence rates were 1·58% (95% CI 0·37 to 2·8) in the whole-breast irradiation group and 3·51% (1·99 to 5·03) in the APBI group. The difference in 10-year rates between the groups was 1·93% (95% CI -0·018 to 3·87; p=0·074). Adverse events were mostly grade 1 and 2, in 234 (60%) of 393 participants in the whole-breast irradiation group and 314 (67%) of 470 participants in the APBI group, at 7·5-year or 10-year follow-up, or both. Patients in the APBI group had a significantly lower incidence of treatment-related grade 3 late side-effects than those in the whole-breast irradiation group (17 [4%] of 393 for whole-breast irradiation vs seven [1%] of 470 for APBI; p=0·021; at 7·5-year or 10-year follow-up, or both). At 10 years, the most common type of grade 3 adverse event in both treatment groups was fibrosis (six [2%] of 313 patients for whole-breast irradiation and three [1%] of 375 patients for APBI, p=0·56). No grade 4 adverse events or treatment-related deaths have been observed. INTERPRETATION: Postoperative APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is a valuable alternative to whole-breast irradiation in terms of treatment efficacy and is associated with fewer late side-effects. FUNDING: German Cancer Aid, Germany.

Recommendations of the Spanish brachytherapy group of the Spanish Society of Radiation Oncology and the Spanish Society of Medical Physics for interstitial high-dose-rate brachytherapy for gynaecologic malignancies.

The present document includes consensus-based recommendations from the Brachytherapy Group (GEB) of the Spanish Society of Radiation Oncology (SEOR) and the Spanish Society of Medical Physics (SEFM) for interstitial high-dose-rate (HDR) brachytherapy (BT) for gynaecologic malignancies. A nine-item survey-which included questions on experience with interstitial BT; indications and technique; applicator type; magnetic resonance imaging (MRI)-based planning; dose; fractionation schedule; and treatment planning-was sent to all radiation oncology departments (n = 174) in Spain in 2021. Responses were received from 36 centres (50% of all centres [n = 72] with a BT unit). The consensus-based recommendations presented here are based on a review of the available literature, professional experience among the group of experts, and in-person discussions held during the annual meeting of these two societies. We describe the results of the survey and the following: indications; contraindications; patient selection; description of applicators; role of imaging in planning; contouring; dose prescription; dosimetric reconstruction; optimisation; and dose indications for cancers of the cervix, vagina, and vulva. The various clinical scenarios in which interstitial BT is used in the treatment of gynaecological tumours are described in detail, including cervix intracavitary/interstitial hybrid HDR-BT; cervix perineal templates/freehand implants; primary vaginal malignancies/vaginal recurrences; and vulvar interstitial implants.

The Role of Interstitial Brachytherapy for Breast Cancer Treatment: An Overview of Indications, Applications, and Technical Notes.

Breast cancer represents the second leading cause of cancer-related death in the female population, despite continuing advances in treatment options that have significantly accelerated in recent years. Conservative treatments have radically changed the concept of healing, also focusing on the psychological aspect of oncological treatments. In this scenario, radiotherapy plays a key role. Brachytherapy is an extremely versatile radiation technique that can be used in various settings for breast cancer treatment. Although it is invasive, technically complex, and requires a long learning curve, the dosimetric advantages and sparing of organs at risk are unequivocal. Literature data support muticatheter interstitial brachytherapy as the only method with strong scientific evidence to perform partial breast irradiation and reirradiation after previous conservative surgery and external beam radiotherapy, with longer follow-up than new, emerging radiation techniques, whose effectiveness is proven by over 20 years of experience. The aim of our work is to provide a comprehensive view of the use of interstitial brachytherapy to perform breast lumpectomy boost, breast-conserving accelerated partial breast irradiation, and salvage reirradiation for ipsilateral breast recurrence, with particular focus on the implant description, limits, and advantages of the technique.

Very accelerated partial breast irradiation Phase I-II multicenter trial (VAPBI): Feasibility and early results.

PURPOSE: This is a multicenter Phase I-II trial endorsed by the GEC-ESTRO Breast Working Group, to analyze if very accelerated partial breast irradiation (VAPBI) with multicatheter interstitial brachytherapy is feasible and safe compared with the standard APBI treatment in 4-5 days for early stage breast carcinomas. METHODS AND MATERIALS: We have included 81 patients with pT1-2 pN0 invasive carcinomas after breast-conserving surgery. Between August 2017 and July 2019, 33 women received high-dose-rate brachytherapy, four fractions of 6.25 Gy in 2-3 days, and 48 patients received three fractions of 7.45 Gy in 2 days. Thirty-six patients were implanted perioperatively and 45 postoperatively. Mean age was 68 (51-90). Free surgical margins were of 2 mm or greater. RESULTS: Acute effects were 11% dermatitis, 18.5% hematoma, 3.7% infection, and 14.8% pain. At a median followup of 20 months (range 8-35), no relapse has occurred. Pigmentation changes in the entrance and exit of tubes were visible in 16%, but 1 year later, few cases remained. Patients developed G1-2 induration or fibrosis in 18.5% and 2.5%, respectively. No patient developed telangiectasia. The cosmetic outcome was good/excellent in 97.5% and fair in 2.5%. CONCLUSIONS: VAPBI with multicatheter interstitial brachytherapy using four fractions of 6.25 Gy or three fractions of 7.45 Gy in two or 3 days is feasible. No excess has been observed in acute effects. At a mean followup of 20 months, late side effects seem to be similar to standard fractionation. VAPBI in two to 3 days is beneficial for the patients and reduces the workload of the brachytherapy units.

Consensus statement from the Spanish Brachytherapy Group (GEB) on accelerated partial breast irradiation using multicatheter interstitial brachytherapy.

AIM: To establish consensus guidelines for a safe clinical practice of accelerated partial breast irradiation (APBI) interstitial multicatheter brachytherapy (BT). BACKGROUND: APBI with interstitial multicatheter BT has proved to be effective in the treatment of early stage breast cancer. This paradigm shift in the approach to early breast cancer conservative treatment, along with the existing controversies on the clinical practice of APBI, prompted the Spanish Brachytherapy Group (GEB) of the Spanish Societies of Radiation Oncology (SEOR) and Medical Physics (SEFM) to address BT APBI in a consensus meeting. MATERIALS AND METHODS: Prior to the meeting, a survey with 27 questions on indication, inclusion criteria, BT modality, implant technique, image guidance and simulation, CTV and OAR definition, dose prescription and fractionation, dose calculation, implant quality metrics and OAR dose constrains was distributed. Items not reaching a level of agreement of 70% were discussed and voted during the meeting. RESULTS: 26 Institutions completed the survey, 60% of them perform APBI procedures. The analysis of the survey showed consensus reached on approximately half the questions. An expert panel discussed the remaining items; thereafter, a voting established the definite consensus. CONCLUSIONS: This document summarizes the consensus guidelines agreed during the meeting of the Spanish Brachytherapy Group SEOR-SEFM. Institutions with BT facilities available should offer interstitial BT APBI as a treatment option to patients fulfilling the inclusion criteria. Institutions willing to implement interstitial BT APBI are encouraged to follow the consensus guidelines established herein.

Changes of CD68, CD163, and PD-L1 tumor expression during high-dose-rate and pulsed-dose-rate brachytherapy for cervical cancer.

PURPOSE: We hypothesized that radiation doses delivered with high-dose-rate (HDR) and pulsed-dose-rate (PDR) brachytherapy in patients with cervical cancer could trigger immune stimulation by modulating immune cells in the tumor microenvironment. The objective was to determine CD68, CD163, and PD-L1 expression in biopsies from patients with cervical cancer and to compare the effects of HDR vs. PDR brachytherapy on the expression of these proteins. METHODS AND MATERIALS: Nineteen consecutive women (mean age, 55.9 years) with histologically proven cervical cancer scheduled for brachytherapy after standard external beam irradiation therapy combined with platinum-based chemotherapy were included in a prospective study. Core tissue biopsies were obtained before radiochemotherapy (biopsy #1), after completion of radiochemotherapy and before brachytherapy (biopsy #2), and 2 weeks after completion of brachytherapy (biopsy #3). HDR or PDR brachytherapy was delivered according to availability of equipment. CD68, CD163, and PD-L1 immunohistochemical expression was estimated using a quantitative method. Conditional logistic regression models were used to assess the relationship between gene expression and time of biopsy for each brachytherapy technique. RESULTS: In relation to CD68 and CD163, statistically significant relationships between gene expression and biopsy tissue samples were not found in any of the brachytherapy techniques, although there was trend toward downexpression of CD68 and CD163 in biopsies #2 and #3 in the HDR brachytherapy cohort only. There was a significant increase in PD-L1 expression in biopsy #3 also in the HDR cohort as compared with the PDR cohort. CONCLUSIONS: Decreased CD68 and CD163 expression did not reach statistical significance, but this trend may have clinical translational potential. Overexpression of PD-L1 in tissue biopsies taken at 14 days in the HDR brachytherapy cohort may tentatively suggest that this time period would be an adequate interval for blockade of the PD-1/PD-L1 axis.

ESTRO-ACROP guideline: Interstitial multi-catheter breast brachytherapy as Accelerated Partial Breast Irradiation alone or as boost - GEC-ESTRO Breast Cancer Working Group practical recommendations.

PURPOSE: This consensus statement from the Breast Cancer Working Group of Groupe Européen de Curiethérapie of European Society for Radiotherapy and Oncology (GEC-ESTRO) aims at generating practical guidelines for multi-catheter image-guided brachytherapy in the conservative management of breast cancer patients used for either Accelerated Partial Breast Irradiation (APBI) or for a breast boost. METHODS: Recent advances in techniques of multi-catheter brachytherapy were summarized and all the relevant literature was reviewed by a panel of experts. Panel members of the GEC-ESTRO experts participated in a series of conferences, supplemented their clinical experience, were surveyed to determine their current practices and patterns, performed a literature review, and formulated recommendations for implementing APBI with multi-catheter brachytherapy, focusing on treatment planning issues, catheter insertion, dosimetry and quality assurance. This document was reviewed and approved by the full panel, the GEC-ESTRO executive board and by the ACROP (Advisory Committee on Radiation Oncology Practice). RESULTS: Three-dimensional (3D) treatment planning, catheter insertion techniques, dosimetry and methods of quality assurance for APBI and boost with multi-catheter image-guided brachytherapy after breast conserving surgery are described. Detailed recommendations for daily practice including dose constraints are given. CONCLUSIONS: Recent standards and guidelines for the use of APBI with different multi-catheter image-guided brachytherapy techniques have been defined. Different techniques are used to insert the catheters. Guidelines are mandatory to assure precise catheter insertion for coverage of the target volume and to guarantee high-quality dosimetry. The same rules apply for brachytherapy based boost irradiation for breast cancer after whole breast irradiation as well as for partial breast re-irradiation.

La irradiación parcial acelerada de la mama: un nuevo paradigma en el tratamiento del carcinoma precoz de mama / Accelerated partial breast irradiation: a new paradigm in the treatment of early breast carcinoma

Objetivo. La recaída local en el carcinoma de mama precoz puede quedar limitada a la zona próxima al tumor, por lo que puede no ser necesario irradiar la mama entera (WBI), que es, actualmente, el tratamiento conservador estándar. Métodos. Se ha revisado la literatura buscando los trabajos aleatorizados de las distintas modalidades de irradiación parcial acelerada para una puesta al día. Resultados. La irradiación intraoperatoria en sesión única ha dado resultados inadecuados con electrones (estudio ELIOT) por una selección inapropiada de los pacientes. El estudio TARGIT con Rx de 50kV en sesión única añadiendo WBI cuando se demuestran factores de riesgo resulta eficaz cuando se administra durante la primera cirugía conservadora, y no en un segundo tiempo. Los sistemas intracavitarios con balón o similar dan buenos resultados a corto plazo, pero se debe tratar de usar múltiples canales para reducir las complicaciones. Las técnicas de irradiación parcial con radioterapia externa 3D pueden aumentar ligeramente las complicaciones locales, no así la radioterapia de intensidad modulada, y en ambos casos resultan eficaces, pero debe esperarse más tiempo y un mayor número de pacientes para confirmarse. La braquiterapia intersticial con multicatéter se ha demostrado igual de eficaz que la WBI y con menos complicaciones. Conclusiones. Hay pacientes con cáncer de mama de bajo riesgo que no requieren WBI. La irradiación parcial acelerada es equivalente, especialmente con técnica intersticial multicatéter, y probablemente con otras técnicas que requieren más seguimiento, con menor dosis de irradiación a pulmón y corazón, por lo que debe ofrecerse como alternativa a la WBI en casos seleccionados (AU)

Objective. Local relapse in early breast carcinoma may be limited to the area around the tumour. Consequently, whole breast irradiation (WBI), which is currently the standard conservative treatment, may not be required. Methods. We reviewed the literature through a search for randomized trials of the different types of accelerated partial breast irradiation in order to provide an update. Results. Intraoperative irradiation with electrons in a single session (ELIOT study) provided suboptimal results due to improper patient selection. The TARGIT trial reported that 50kV x-rays in a single session, with the addition of WBI in patients with risk factors, was effective when administered during the first conservative surgery, rather than in a second intervention. Intracavitary balloon or similar systems offer good short-term results but attempts should be made to use multiple channels to reduce complications. Partial irradiation techniques with 3D-external beam radiation therapy, except for intensity-modulated radiotherapy, may slightly increase local complications. Both are effective, but this finding requires confirmation in studies with a longer follow-up and more patients. Multicatheter interstitial brachytherapy has been demonstrated to be as effective as WBI and has fewer complications. Conclusions. Some patients with low-risk breast cancer do not require WBI. Accelerated partial breast irradiation is equivalent, especially with the multicatheter interstitial technique, and probably with other techniques requiring more follow-up, and delivers a lower radiation dose to the lung and heart. Accelerated partial breast irradiation should be offered as an alternative to WBI in selected patients (AU)

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.

BACKGROUND: In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. METHODS: We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1.44% (95% CI 0.51-2.38) with APBI and 0.92% (0.12-1.73) with whole-breast irradiation (difference 0.52%, 95% CI -0.72 to 1.75; p=0.42). No grade 4 late side-effects were reported. The 5-year risk of grade 2-3 late side-effects to the skin was 3.2% with APBI versus 5.7% with whole-breast irradiation (p=0.08), and 5-year risk of grade 2-3 subcutaneous tissue late side-effects was 7.6% versus 6.3% (p=0.53). The risk of severe (grade 3) fibrosis at 5 years was 0.2% with whole-breast irradiation and 0% with APBI (p=0.46). INTERPRETATION: The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. FUNDING: German Cancer Aid.

Boost radiotherapy in young women with ductal carcinoma in situ: a multicentre, retrospective study of the Rare Cancer Network.

BACKGROUND: Outcome data in young women with ductal carcinoma in situ (DCIS) are rare. The benefits of boost radiotherapy in this group are also unknown. We aimed to assess the effect of boost radiotherapy in young patients with DCIS. METHODS: We included 373 women from 18 institutions who met the following inclusion criteria: having tumour status Tis and nodal status (N)0, age 45 years or younger at diagnosis, and having had breast-conserving surgery. 57 (15%) patients had no radiotherapy after surgery, 166 (45%) had radiotherapy without boost (median dose 50 Gy [range 40-60]), and 150 (40%) had radiotherapy with boost (60 Gy [53-76]). The primary outcome was local relapse-free survival. FINDINGS: Median follow-up was 72 months (range 1-281). 55 (15%) patients had local relapse. Local relapse-free survival at 10 years was 46% (95% CI 24-67) for patients given no radiotherapy, 72% (61-83) for those given radiotherapy without boost, and 86% (78-93) for those given radiotherapy and boost (difference between all three groups, p<0.0001). Age, margin status, and radiotherapy dose were significant predictors of local relapse-free survival. Compared with patients who had no radiotherapy, those who had radiotherapy had a decreased risk of local relapse (without boost, hazard ratio 0.33 [95% CI 0.16-0.71], p=0.004; with boost, 0.15 [0.06-0.36], p<0.0001). INTERPRETATION: In the absence of randomised trials, boost radiotherapy should be considered in addition to surgery for breast-conserving treatment for DCIS.