Clinical outcomes and timing on the combination of focal radiation therapy and immunotherapy for the treatment of brain metastases.

Introduction: Radiotherapy is one of the standard treatments for brain metastases (BM). Over the past years, the introduction of immunotherapy as routine treatment for solid tumors has forced investigators to review and evaluate how it would interact with radiation. Radiation and Immunotherapy have shown a synergic effect activating the host's immune system and enhancing treatment response. The combinatory effect on BM is currently under investigation. Methods: Data published on Pubmed to determine toxicity, survival, treatment characteristics and timing on the combination of radiotherapy and immunotherapy for the treatment of BM has been reviewed. Results: Mostly retrospective reviews report an improvement of intracranial progression free survival (iPFS) when combining radioimmunotherapy for BM patients. Two systematic reviews and meta-analysis and one phase II prospective trial also report a benefit on iPFS without an increase of toxicity. Among the published literature, the definition of concurrency is heterogeneous, being one month or even narrowed intervals correlated to better clinical outcomes. Toxicity due to concurrent radioimmunotherapy, specifically symptomatic radionecrosis, is also directly analyzed and reported to be low, similar to the toxicity rates secondary to stereotactic radiosurgery alone. Conclusion: Radiation combined with immunotherapy has shown in predominantly retrospective reviews a synergic effect on the treatment of BM. The concurrent combination of radioimmunotherapy is a feasible therapeutic strategy and seems to improve clinical outcomes, especially iPFS, when delivered within <30 days. Larger prospective and randomized studies are needed to establish reliable outcomes, best delivery strategies and toxicity profile.

Axillary lymph node dissection versus radiotherapy in breast cancer with positive sentinel nodes after neoadjuvant therapy (ADARNAT trial).

Introduction: Breast cancer surgery currently focuses on de-escalating treatment without compromising patient survival. Axillary radiotherapy (ART) now replaces axillary lymph node dissection (ALND) in patients with limited sentinel lymph node (SLN) involvement during the primary surgery, and this has significantly reduced the incidence of lymphedema without worsening the prognosis. However, patients treated with neoadjuvant systemic treatment (NST) cannot benefit from this option despite the low incidence of residual disease in the armpit in most cases. Data regarding the use of radiotherapy instead of ALND in this population are lacking. This study will assess whether ART is non-inferior to ALND in terms of recurrence and overall survival in patients with positive SLN after NST, including whether it reduces surgery-related adverse effects. Methods and analyses: This multicenter, randomized, open-label, phase 3 trial will enroll 1660 patients with breast cancer and positive SLNs following NST in approximately 50 Spanish centers over 3 years. Patients will be stratified by NST regimen and nodal involvement (isolated tumoral cells or micrometastasis versus macrometastasis) and randomly assigned 1:1 to ART without ALND (study arm) or ALND alone (control arm). Level 3 and supraclavicular radiotherapy will be added in both arms. The primary outcome is the 5-year axillary recurrence determined by clinical and radiological examination. The secondary outcomes include lymphedema or arm dysfunction, quality of life based (EORTC QLQ-C30 and QLQ-BR23 questionnaires), disease-free survival, and overall survival. Discussion: This study aims to provide data to confirm the efficacy and safety of ART over ALND in patients with a positive SLN after NST, together with the impact on morbidity. Ethics and dissemination: The Research Ethics Committee of Bellvitge University Hospital approved this trial (Protocol Record PR148/21, version 3, 1/2/2022) and all patients must provide written informed consent. The involvement of around 50 centers across Spain will facilitate the dissemination of our results. Trial registration: ClinicalTrials.gov, identifier number NCT04889924.

Ten-year experience of bone SBRT in breast cancer: analysis of predictive factors of effectiveness

Purpose Data on the benefit of stereotactic body radiation therapy (SBRT) in patients with breast cancer (BC) and bone metastases remain limited. The purpose of this study is to report our 10-year experience of bone SBRT, analyzing toxicity and prognostic factors for local control (LC); progression-free survival, and overall survival (OS). Methods/patients We analyzed all spine and non-spine bone SBRT performed in patients with BC during the 2012–2022 period at our institution. Treatments carried out with ablative intent in stereotactic conditions with dose/fraction ≥ 5 Gy in 5 or fewer sessions were considered. Demographic, treatment, and toxicity data were recorded according to CTCAEv4. Risk factors were assessed through univariate and multivariate analysis by Cox regression. Results 60 bone SBRT treatments were performed during the study period. 75% were spine SBRT and 25% were non-spine SBRT (median BED4Gy was 80 Gy4). The median age was 52.5 years (34–79). The median tumor volume was 2.9 cm3 (0.5–39.4). The median follow-up was 32.4 months (1.2–101.7). 1 and 2 years LC were 92.9 and 86.6%, respectively. 1 and 2 years OS were 100 and 90.6%, respectively. Multivariate analysis (MVA) associated volume of the treated lesion ≥ 13 cm3 with worse LC (p = 0.046; HR 12.1, 95%CI = 1.1–140.3). In addition, deferring SBRT > 3 months after lesion diagnosis to prioritize systemic treatment showed a significant benefit, improving the 2 years LC up to 96.8% vs. 67.5% for SBRT performed before this period (p = 0.031; HR 0.1, 95%CI = 0.01–0.8). Hormonal receptors, the total number of metastases, and CA15-3 value were significantly associated with OS in MVA. During follow-up, three non-spine fractures (5%) were observed. Conclusions According to our data, bone SBRT is a safe and effective technique for BC. Upfront systemic treatment before SBRT offers a benefit in LC. Therefore, SBRT should be considered after prior systemic treatment in this population (AU)

Management of the axilla in postmenopausal patients with cN0 hormone receptor-positive/HER2-negative breast cancer treated with neoadjuvant endocrine therapy and its prognostic impact.

PURPOSE: To evaluate the differences in nodal positivity if the sentinel lymph node biopsy (SLNB) is performed before or after neoadjuvant endocrine therapy (NET) in breast cancer patients, and its impact on prognosis. METHODS: A retrospective cohort study was performed in a single center including 91 postmenopausal cases with clinically node-negative and hormone receptor-positive/HER2-negative (HR + /HER2-) breast cancer, treated with NET and SLNB. SLNB was done pre-NET until 2014, and post-NET thereafter. Axillary lymph node dissection (ALND) was indicated only in SLNB macrometastasis, although in selected elderly patients, it was omitted. Kaplan-Meier survival curves were estimated in relation to the status of the axilla, and the differences assessed using the log-rank test. RESULTS: Between December 2006 and March 2022, SLNB was performed pre-NET in 14 cases and post-NET in 77. Both groups were similar in baseline tumor and patient characteristics. SLNB positivity was similar regardless of whether SLNB was performed before (5/14, 35.7%) or after NET (27/77, 37%), with 2/14 SLN macrometastases in the pre-NET cohort and 17/77 in the post-NET cohort. Only three patients (18.7%) with SLN macrometastasis had > 3 positive nodes following ALND. The 5-year overall survival and distant disease-free survival were 92.4% and 94.8%, respectively, with no significant differences according to SLNB status (p 0.5 and 0.8, respectively). CONCLUSION: SLN positivity did not differ according to its timing (before or after NET). Therefore, NET has no effect on lymph node clearance. Furthermore, the prognosis is good regardless of the axillary involvement. Therefore, factors other than axillary involvement may affect the prognosis in these patients.

Ten-year experience of bone SBRT in breast cancer: analysis of predictive factors of effectiveness.

PURPOSE: Data on the benefit of stereotactic body radiation therapy (SBRT) in patients with breast cancer (BC) and bone metastases remain limited. The purpose of this study is to report our 10-year experience of bone SBRT, analyzing toxicity and prognostic factors for local control (LC); progression-free survival, and overall survival (OS). METHODS/PATIENTS: We analyzed all spine and non-spine bone SBRT performed in patients with BC during the 2012-2022 period at our institution. Treatments carried out with ablative intent in stereotactic conditions with dose/fraction ≥ 5 Gy in 5 or fewer sessions were considered. Demographic, treatment, and toxicity data were recorded according to CTCAEv4. Risk factors were assessed through univariate and multivariate analysis by Cox regression. RESULTS: 60 bone SBRT treatments were performed during the study period. 75% were spine SBRT and 25% were non-spine SBRT (median BED4Gy was 80 Gy4). The median age was 52.5 years (34-79). The median tumor volume was 2.9 cm3 (0.5-39.4). The median follow-up was 32.4 months (1.2-101.7). 1 and 2 years LC were 92.9 and 86.6%, respectively. 1 and 2 years OS were 100 and 90.6%, respectively. Multivariate analysis (MVA) associated volume of the treated lesion ≥ 13 cm3 with worse LC (p = 0.046; HR 12.1, 95%CI = 1.1-140.3). In addition, deferring SBRT > 3 months after lesion diagnosis to prioritize systemic treatment showed a significant benefit, improving the 2 years LC up to 96.8% vs. 67.5% for SBRT performed before this period (p = 0.031; HR 0.1, 95%CI = 0.01-0.8). Hormonal receptors, the total number of metastases, and CA15-3 value were significantly associated with OS in MVA. During follow-up, three non-spine fractures (5%) were observed. CONCLUSIONS: According to our data, bone SBRT is a safe and effective technique for BC. Upfront systemic treatment before SBRT offers a benefit in LC. Therefore, SBRT should be considered after prior systemic treatment in this population.

Effectiveness and safety of intraoperative radiotherapy (IORT) with low-energy X-rays (INTRABEAM) for accelerated partial breast irradiation (APBI)

PurposeTo evaluate treatment outcomes in patients with early-stage breast cancer (ESBC) treated with targeted intraoperative radiation therapy (IORT) administered as accelerated partial breast irradiation (APBI).MethodsBetween December 2014 and May 2019, 50 patients diagnosed with ESBC were treated with a 50 kilovoltage (kV) X-ray source with a single dose of 20 Gy using the Intrabeam® radiotherapy delivery system. All patients were followed prospectively to assess local control (LC), disease-free survival (DFS), cancer-specific survival (CSS), overall survival (OS), radiation-induced toxicity, and cosmetic outcomes. We also evaluated the prognostic implications of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR).ResultsMedian follow-up was 53 months. Mean patient age was 70 years. The mean duration of radiation delivery was 22.25 min. Two patients developed a recurrence. One death was recorded. Elevated pretreatment NLR levels were a significant risk factor for mortality (p = 0.0026). The most common treatment-related toxicities were breast induration (30%) and seroma (18%). Five-year LC, DFS, CSS, and OS rates were 97.1%, 93.9%, 100%, and 94.4%, respectively. Cosmesis was excellent or good in most cases (94%).ConclusionThese findings confirm the effectiveness of a single dose of 20 Gy of IORT with the Intrabeam device as APBI. The toxicity profile was good with excellent cosmesis. These results provide further support for the clinical use of APBI in well-selected patients. (AU)

Effectiveness and safety of intraoperative radiotherapy (IORT) with low-energy X-rays (INTRABEAM®) for accelerated partial breast irradiation (APBI).

PURPOSE: To evaluate treatment outcomes in patients with early-stage breast cancer (ESBC) treated with targeted intraoperative radiation therapy (IORT) administered as accelerated partial breast irradiation (APBI). METHODS: Between December 2014 and May 2019, 50 patients diagnosed with ESBC were treated with a 50 kilovoltage (kV) X-ray source with a single dose of 20 Gy using the Intrabeam® radiotherapy delivery system. All patients were followed prospectively to assess local control (LC), disease-free survival (DFS), cancer-specific survival (CSS), overall survival (OS), radiation-induced toxicity, and cosmetic outcomes. We also evaluated the prognostic implications of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). RESULTS: Median follow-up was 53 months. Mean patient age was 70 years. The mean duration of radiation delivery was 22.25 min. Two patients developed a recurrence. One death was recorded. Elevated pretreatment NLR levels were a significant risk factor for mortality (p = 0.0026). The most common treatment-related toxicities were breast induration (30%) and seroma (18%). Five-year LC, DFS, CSS, and OS rates were 97.1%, 93.9%, 100%, and 94.4%, respectively. Cosmesis was excellent or good in most cases (94%). CONCLUSION: These findings confirm the effectiveness of a single dose of 20 Gy of IORT with the Intrabeam device as APBI. The toxicity profile was good with excellent cosmesis. These results provide further support for the clinical use of APBI in well-selected patients.

The effect of omitting axillary dissection and the impact of radiotherapy on patients with breast cancer sentinel node macrometastases: a cohort study following the ACOSOG Z0011 and AMAROS trials.

PURPOSE: To report the outcomes of implementing the ACOSOG Z0011 and AMAROS trials relevant to clinical practice, and to define target groups in whom to avoid or recommend axillary radiotherapy (ART). We also aimed to analyse the reduction in morbidity when axillary lymph node dissection (ALND) was omitted. METHODS: A retrospective cohort study of T1-T2 patients with macrometastases at sentinel lymph node (SLN) who were treated between 2011 and 2020. Breast surgery included either lumpectomy or mastectomy. Patients with ≤ 2 positive SLN were divided into two cohorts by whether they received ART or not. Survival outcomes and morbidity were analysed by Kaplan-Meyer curves and Cox-regression, respectively. RESULTS: 260 pN1a patients were included and ALND was avoided in 167 (64.2%). According the Z0011 results, 72 (43.1%) received no further ART; and based on AMAROS criteria 95 (56.9%) received ART. Median follow-up was 54 months. The 5-year overall survival was 96.8% in the non-RT cohort and 93.4% in the RT cohort (p = 0.19), while the respective 5-year disease-free survivals were 100% and 92.3% (p = 1.06). Lymphedema developed in 3.6% of patients after SLNB versus 43% after ALND (OR 20.25; 95%CI 8.13-50.43). Decreased upper-extremity range of motion appeared in 8.4% of patients after SLNB versus 31.2% after ALND (OR 4.95; 95%CI 2.45-9.98%). CONCLUSIONS: Our study confirms that omitting ALND is safe and has high survival rates in patients with T1-T2 tumours and ≤ 2 positive SLNs. Adding ART could be a treatment option for patients who present other risk factors. Avoiding ALND with or without ART was associated with significantly less arm morbidity.

Five-year results of accelerated partial breast irradiation: A single-institution retrospective review of 289 cases.

PURPOSE: The purpose of the study was to describe our institutional experience with accelerated partial breast irradiation (APBI) using multicatheter brachytherapy with high-dose-rate. We report 5-year survival outcomes, cosmesis, and treatment-related toxicity. METHODS AND MATERIALS: This included a retrospective review of patients who underwent breast-conserving surgery followed by APBI at our institution from 2004 to 2017. RESULTS: A total of 289 patients were evaluated. Median followup was 72 months. Median age was 70 years. APBI was the only primary treatment in 86.2% of cases with early-stage breast cancer and a second conservative treatment in 13.8%. The implant was performed postoperatively in 213 patients (73.7%) and intraoperatively in 76 (26.3%). The most common radiation schemes were 10 fractions of 3.4 Gy and eight fractions of 4 Gy. Elderly or frail patients (10%) received a single 16 Gy dose. Of the 289 patients, 215 met Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology criteria for APBI; in this group, late side effects included Grade 2 (G2) fibrosis (14.8%), skin discoloration at the catheter points (8.8%), and telangiectasia (0.5%). The cosmetic result was considered excellent or good in 88.3% of cases. Five-year local control, disease-free, cancer-specific, and overall survival rates were 98.9%, 96.7%, 99.1%, and 95.6%, respectively. CONCLUSIONS: Local control and survival outcomes at 5 years of followup in this group of well-selected patients were excellent, with low rates of treatment-related toxicity. These findings confirm the safety and effectiveness of APBI, even in elderly and frail patients. These results provide further support for the clinical use of APBI in suitable patients.

Can we avoid axillary lymph node dissection in N2 breast cancer patients with chemo-sensitive tumours such as HER2 and TNBC?

PURPOSE: To find a group of cN2 patients or patients with high axillary burden who become ypN0 after neoadjuvant chemotherapy (NACT) and who may benefit from avoiding a lymphadenectomy. METHODS: A retrospective observational cohort study was conducted with 221 clinically staged N2 patients or patients with at least 3 suspicious lymph nodes found by ultrasound at diagnosis. The predictive factors for ypN0 analysed were age, MRI-determined tumour size, histological subtype, the Nottingham histologic grade, surrogate molecular subtype, ki-67 and vascular invasion when present. Clinical and radiological responses after NACT were also evaluated. Univariate and multivariate analyses by logistic regression were performed. Distant disease-free survival (DDFS) was calculated in relation to the status of the axillary lymph nodes after NACT. RESULTS: After NACT, 89 patients (40.3%) had axillary pathologic complete response (pCR) (ypN0) and 132 (59.7%) had residual axillary disease (ypN+). Molecular surrogate subtype, Ki-67 expression, and the clinical and radiological responses to NACT were the only independent factors associated with ypN0. Axillary pCR was observed more often in HER2-positive and triple-negative tumours than in luminal ones (OR 7.5 and 3.6, respectively). DDFS was 88.7% (95% CI 80.7-96.7%) for ypN0 and 56.2% (95% CI 32.1-80.3%) for ypN+ (p = 0.09). CONCLUSIONS: In HER2-positive and triple-negative breast cancer patients staged as cN2 or with high axillary burden before NACT, a sentinel lymph node biopsy after NACT could be recommended if there is a clinical and radiological response.

Changes in peripheral immune cells after intraoperative radiation therapy in low-risk breast cancer.

A detailed understanding of the interactions and the best dose-fractionation scheme of radiation to maximize antitumor immunity have not been fully established. In this study, the effect on the host immune system of a single dose of 20 Gy through intraoperative radiation therapy (IORT) on the surgical bed in low-risk breast cancer patients undergoing conserving breast cancer has been assessed. Peripheral blood samples from 13 patients were collected preoperatively and at 48 h and 3 and 10 weeks after the administration of radiation. We performed a flow cytometry analysis for lymphocyte subpopulations, natural killer cells (NK), regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs). We observed that the subpopulation of NK CD56+high CD16+ increased significantly at 3 weeks after IORT (0.30-0.42%, P < 0.001), while no changes were found in immunosuppressive profile, CD4+CD25+Foxp3+Helios+ Treg cells, granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (Mo-MDSCs). A single dose of IORT may be an effective approach to improve antitumor immunity based on the increase in NK cells and the non-stimulation of immunosuppressive cells involved in immune escape. These findings support future combinations of IORT with immunotherapy, if they are confirmed in a large cohort of breast cancer patients.

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.

Second breast-conserving therapy with interstitial brachytherapy (APBI) as a salvage treatment in ipsilateral breast tumor recurrence: a retrospective study of 40 patients.

PURPOSE: Breast-conserving treatment (BCT) have emerged as an alternative to mastectomy in patients with ipsilateral breast tumor recurrence (IBTR). We evaluated survival outcomes and treatment-related toxicity in a series of 40 patients with IBTR, who underwent tumorectomy plus interstitial brachytherapy (APBI) as a salvage treatment. MATERIAL AND METHODS: Retrospective analysis included 40 patients diagnosed with IBTR and treated with intraoperative (26 patients) or post-operative (14 patients) multicatheter brachytherapy for APBI at our institution between June 2002 and October 2017. We assessed cosmesis, toxicity, overall survival (OS), and cancer-specific survival (CSS). RESULTS: Tumorectomy was performed in all cases, including intraoperative tumor margin assessment and sentinel node biopsy. Median age was 65 years (range, 41-92). The total prescribed dose was 32 Gy (8 fractions) in 19 patients and 34 Gy (10 fractions) in 20 patients. One elderly patient (age 92) received a single fraction of 16 Gy. Median follow-up was 61.5 months (range, 6-153). A median of 14 tubes were inserted. Mean treated V100 was 115 cc. Two patients developed a second relapse at 3 and 5 years after salvage treatment: one patient underwent salvage mastectomy and remains alive 10 years after brachytherapy, and the second one developed both local relapse and bone metastasis. The disease is stable at present. Five-year OS and CSS rates were 85.3% and 97.5%, respectively. Two patients died from cancer-related causes. Acute and late toxicity rates were low; seven patients developed acute infectious mastitis. Late fibrosis > grade 3 and late mastitis were observed in 14 and 6 cases, respectively. CONCLUSIONS: Second BCT with APBI as a salvage treatment in ipsilateral breast recurrence achieves good local disease control, with a satisfactory toxicity profile compared to mastectomy. This approach seems to be safe and effective, although more data from randomized trials are needed.

Advantages of intraoperative implant for interstitial brachytherapy for accelerated partial breast irradiation either frail patients with early-stage disease or in locally recurrent breast cancer.

PURPOSE: To describe the intraoperative multicatheter implantation technique for accelerated partial breast irradiation (APBI) delivered with high-dose-rate brachytherapy (HDR-BT). Secondarily, to evaluate outcomes and toxicity in a series of 83 patients treated with this technique at our institution. MATERIAL AND METHODS: Retrospective analysis of a series of patients treated with HDR-BT APBI after intraoperative multicatheter interstitial implant between November 2006 and June 2017 at our institution. We assessed cosmesis, toxicity, overall survival (OS), and disease-free survival (DFS). RESULTS: Eighty-three patients were included: 59 patients (71.1%) with primary early-stage breast cancer and 24 (28.9%) with locally recurrent breast cancer. Tumorectomy was performed in all cases, with intraoperative tumor margin assessment and sentinel node biopsy. Median age was 82 years (range, 44-92). The total prescribed dose was 32 Gy (8 treatment fractions) in 60 patients (72.3%), and 34 Gy (10 fractions) in 23 patients (27.7%). Median follow-up was 40 months (range, 1-136 months). Three-year OS and DFS in the recurrent and primary cancer groups were 87% vs. 89%, and 96 % vs. 97.8%, respectively. Five patients died from non-cancer related causes. No local relapses were observed. Rates of acute and late toxicity were low in both groups. The cosmesis was good or excellent in most of patients treated for primary disease; in patients who underwent salvage brachytherapy for local recurrence, cosmesis was good in 49 patients and fair in 6. CONCLUSIONS: This technique, although time-consuming, achieves good local disease control with a satisfactory toxicity profile in both early-stage and local recurrent breast cancer patients. It may be especially suitable for frail patients.