DEGRO guideline for personalized radiotherapy of brain metastases and leptomeningeal carcinomatosis in patients with breast cancer.

PURPOSE: The aim of this review was to evaluate the existing evidence for radiotherapy for brain metastases in breast cancer patients and provide recommendations for the use of radiotherapy for brain metastases and leptomeningeal carcinomatosis. MATERIALS AND METHODS: For the current review, a PubMed search was conducted including articles from 01/1985 to 05/2023. The search was performed using the following terms: (brain metastases OR leptomeningeal carcinomatosis) AND (breast cancer OR breast) AND (radiotherapy OR ablative radiotherapy OR radiosurgery OR stereotactic OR radiation). CONCLUSION AND RECOMMENDATIONS: Despite the fact that the biological subtype of breast cancer influences both the occurrence and relapse patterns of breast cancer brain metastases (BCBM), for most scenarios, no specific recommendations regarding radiotherapy can be made based on the existing evidence. For a limited number of BCBM (1-4), stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT) is generally recommended irrespective of molecular subtype and concurrent/planned systemic therapy. In patients with 5-10 oligo-brain metastases, these techniques can also be conditionally recommended. For multiple, especially symptomatic BCBM, whole-brain radiotherapy (WBRT), if possible with hippocampal sparing, is recommended. In cases of multiple asymptomatic BCBM (≥ 5), if SRS/SRT is not feasible or in disseminated brain metastases (> 10), postponing WBRT with early reassessment and reevaluation of local treatment options (8-12 weeks) may be discussed if a HER2/Neu-targeting systemic therapy with significant response rates in the central nervous system (CNS) is being used. In symptomatic leptomeningeal carcinomatosis, local radiotherapy (WBRT or local spinal irradiation) should be performed in addition to systemic therapy. In patients with disseminated leptomeningeal carcinomatosis in good clinical condition and with only limited or stable extra-CNS disease, craniospinal irradiation (CSI) may be considered. Data regarding the toxicity of combining systemic therapies with cranial and spinal radiotherapy are sparse. Therefore, no clear recommendations can be given, and each case should be discussed individually in an interdisciplinary setting.

Oligometastasis in breast cancer-current status and treatment options from a radiation oncology perspective.

Evidence from a few small randomized trials and retrospective cohorts mostly including various tumor entities indicates a prolongation of disease free survival (DFS) and overall survival (OS) from local ablative therapies in oligometastatic disease (OMD). However, it is still unclear which patients benefit most from this approach. We give an overview of the several aspects of stereotactic body radiotherapy (SBRT) in extracranial OMD in breast cancer from a radiation oncology perspective. A PubMed search referring to this was conducted. An attempt was made to relate the therapeutic efficacy of SBRT to various prognostic factors. Data from approximately 500 breast cancer patients treated with SBRT for OMD in mostly in small cohort studies have been published, consistently indicating high local tumor control rates and favorable progression-free (PFS) and overall survival (OS). Predictors for a good prognosis after SBRT are favorable biological subtype (hormone receptor positive, HER2 negative), solitary metastasis, bone-only metastasis, and long metastasis-free interval. However, definitive proof that SBRT in OMD breast cancer prolongs DFS or OS is lacking, since, with the exception of one small randomized trial (n = 22 in the SBRT arm), none of the cohort studies had an adequate control group. Further studies are needed to prove the benefit of SBRT in OMD breast cancer and to define adequate selection criteria. Currently, the use of local ablative SBRT should always be discussed in a multidisciplinary tumor board.

IOERT versus external beam electrons for boost radiotherapy in stage I/II breast cancer: 10-year results of a phase III randomized study.

BACKGROUND: Intraoperative radiotherapy with electrons (IOERT) boost could be not inferior to external beam radiotherapy (EBRT) boost in terms of local control and tissue tolerance. The aim of the study is to present the long-term follow-up results on local control, esthetic evaluation, and toxicity of a prospective study on early-stage breast cancer patients treated with breast-conserving surgery with an IOERT boost of 10 Gy (experimental group) versus 5 × 2 Gy EBRT boost (standard arm). Both arms received whole-breast irradiation (WBI) with 50 Gy (2 Gy single dose). METHODS: A single-institution phase III randomized study to compare IOERT versus EBRT boost in early-stage breast cancer was conducted as a non-inferiority trial. Primary endpoints were the evaluation of in-breast true recurrences (IBTR) and out-field local recurrences (LR) as well as toxicity and cosmetic results. Secondary endpoints were overall survival (OS), disease-free survival (DFS), and patient's grade of satisfaction with cosmetic outcomes. RESULTS: Between 1999 and 2004, 245 patients were randomized: 133 for IOERT and 112 for EBRT. The median follow-up was 12 years (range 10-16 years). The cumulative risk of IBTR at 5-10 years was 0.8% and 4.3% after IOERT, compared to 4.2% and 5.3% after EBRT boost (p = 0.709). The cumulative risk of out-field LR at 5-10 years was 4.7% and 7.9% for IOERT versus 5.2% and 10.3% for EBRT (p = 0.762). All of the IOERT arm recurrences were observed at > 100 months' follow-up, whereas the mean time to recurrence in the EBRT group was earlier (55.2 months) (p < 0.05). No late complications associated with IOERT were observed. The overall cosmetic results were scored as good or excellent in physician and patient evaluations for both IOERT and EBRT. There were significantly better scores for IOERT at all time points in physician and patient evaluations with the greatest difference at the end of EBRT (p = 0.006 objective and p = 0.0004 subjective) and most narrow difference at 12 months after the end of EBRT (p = 0.08 objective and p = 0.04 subjective analysis). CONCLUSION: A 10-Gy IOERT boost during breast-conserving surgery provides high local control rates without significant morbidity. Although not significantly superior to external beam boosts, the median time to local recurrences after IOERT is prolonged by more than 4 years.

Nonmetastatic pancreatic cancer : Improved survival with chemoradiotherapy > 40 Gy after systemic treatment.

PURPOSE: The role of radiotherapy (RT) for nonmetastatic pancreatic cancer is still a matter of debate since randomized control trials have shown inconsistent results. The current retrospective single-institution study includes both resected and unresected patients with nonmetastasized pancreatic cancer. The aim is to analyze overall survival (OS) after irradiation combined with induction chemotherapy. PATIENTS AND METHODS: Of the 73 patients with nonmetastatic pancreatic cancer eligible for the present analysis, 42 (58%) patients had adjuvant chemoradiotherapy (CRT), while 31 (42%) received CRT as primary treatment. In all, 65 (89%) had chemotherapy at any time before, during, or after RT, and 39 (53%) received concomitant CRT. The median total dose was 50 Gy (range 12-77 Gy), while 61 (84%) patients received >40 Gy. RESULTS: With a median follow-up of 22 months (range 1.2-179.8 months), 14 (19%) are still alive and 59 (81%) of the patients have died, whereby 51 (70%) were cancer-related deaths. Median OS and the 2­year survival rate were 22.9 months (1.2-179.8 months) and 44%, respectively. In addition, 61 (84%) patients treated with >40 Gy had a survival advantage (median OS 23.7 vs. 17.3 months, p = 0.026), as had patients with 4 months minimum of systemic treatment (median OS 27.5 vs. 14.3 months, p = 0.0004). CONCLUSION: CRT with total doses >40 Gy after induction chemotherapy leads to improved OS in patients with nonmetastatic pancreatic cancer.

Survival and local control rates of triple-negative breast cancer patients treated with boost-IOERT during breast-conserving surgery.

AIM: The purpose of this work was to retrospectively evaluate survival and local control rates of triple-negative breast cancer subtypes classified as five marker negative (5NP) and core basal (CB), respectively, after breast-conserving surgery and intraoperative boost radiotherapy with electrons (IOERT) followed by whole breast irradiation. METHODS AND MATERIALS: A total of 71 patients with triple-negative breast cancer were enrolled, who were treated with lumpectomy, axillary lymph node dissection, and IOERT with 9.6 Gy (median Dmax) followed by normofractionated whole breast irradiation to median total doses of 54 Gy. Chemotherapy was applied in a neoadjuvant (12 %), adjuvant (75 %), or combinational setting (7 %). RESULTS: After a median follow-up of 97 months (range 4-170 months), 5 in-breast recurrences were detected (7.0 %). For all patients, 8-year actuarial rates for local control, metastases-free survival, disease-specific survival, and overall survival amounted to 89, 75, 80, and 69 %, respectively. All local recurrences occurred in grade 3 (G3) tumors irrespective of their specific immunohistochemical phenotype; thus, the local control rate for grades 1/2 (G1/2) was 100 % for both 5NP and CB, while for G3 it was 88 % for 5NP and 90 % for CB (p = 0.65 and 0.82, respectively, n.s.). For disease-specific survival, only the difference of the best-prognosis group 5-NP/G3 vs. the worst-prognosis cohort CB/G1/2 was statistically significant: 90 % vs. 54 % (p = 0.03). CONCLUSION: Boost-IOERT provides acceptable long-term in-breast control in triple negative breast cancer. The best subgroup in terms of disease-specific survival was represented by 5NP in combination with tumor grading G3.

KPS/LDH index: a simple tool for identifying patients with metastatic melanoma who are unlikely to benefit from palliative whole brain radiotherapy.

PURPOSE: Low Karnofsky performance status (KPS) and elevated lactate dehydrogenases (LDHs) as a surrogate marker for tumor load and cell turnover may depict patients with a very short life expectancy. To validate this finding and compare it to other indices, namely, the recursive partitioning analysis (RPA) and diagnosis-specific graded prognostic assessment (DS-GPA), a multicenter analysis was undertaken. METHODS: A retrospective analysis of 234 metastatic melanoma patients uniformly treated with palliative whole brain radiotherapy (WBRT) was done. Univariate and multivariate analyses were used to determine the impact of patient-, tumor-, and treatment-related parameters on overall survival (OS). RESULTS: KPS and LDH emerged as independent factors predicting OS. By combining KPS and LDH values (KPS/LDH index), groups of patients with statistically significant differences in median OS (days; 95 % CI) after onset of WBRT were identified: group 1 (KPS ≥ 70/normal LDH) 234 (96-372), group 2 (KPS ≥ 70/elevated LDH) 112 (69-155), group 3 (KPS <70/normal LDH) 43 (12-74), and group 4 (KPS <70/elevated LDH) 29 (17-41). Between all four groups, statistically significant differences were observed. The RPA and DS-GPA indices failed to distinguish significantly between good and moderate prognosis and were inferior in predicting a very unfavorable prognosis. CONCLUSIONS: The parameters KPS and LDH independently impacted on OS. The combination of both (KPS/LDH index) identified patients with a very short life expectancy, who might be better served by recommending best supportive care instead of WBRT. The KPS/LDH index is simple and effective in terms of time and cost as compared to other prognostic indices.

miR-16-5p Is a Stably-Expressed Housekeeping MicroRNA in Breast Cancer Tissues from Primary Tumors and from Metastatic Sites.

For quantitative microRNA analyses in formalin-fixed paraffin-embedded (FFPE) tissue, expression levels have to be normalized to endogenous controls. To investigate the most stably-expressed microRNAs in breast cancer and its surrounding tissue, we used tumor samples from primary tumors and from metastatic sites. MiRNA profiling using TaqMan(®) Array Human MicroRNA Cards, enabling quantification of 754 unique human miRNAs, was performed in FFPE specimens from 58 patients with metastatic breast cancer. Forty-two (72%) samples were collected from primary tumors and 16 (28%) from metastases. In a cross-platform analysis of a validation cohort of 32 FFPE samples from patients with early breast cancer genome-wide microRNA expression analysis using SurePrintG3 miRNA (8 × 60 K)(®) microarrays from Agilent(®) was performed. Eleven microRNAs could be detected in all samples analyzed. Based on NormFinder and geNorm stability values and the high correlation (rho ≥ 0.8) with the median of all measured microRNAs, miR-16-5p, miR-29a-3p, miR-126-3p, and miR-222-3p are suitable single gene housekeeper candidates. In the cross-platform validation, 29 human microRNAs were strongly expressed (mean log2-intensity > 10) and 21 of these microRNAs including miR-16-5p and miR-29a-3p were also stably expressed (CV < 5%). Thus, miR-16-5p and miR-29a-3p are both strong housekeeper candidates. Their Normfinder stability values calculated across the primary tumor and metastases subgroup indicate that miR-29a-3p can be considered as the strongest housekeeper in a cohort with mainly samples from primary tumors, whereas miR-16-5p might perform better in a metastatic sample enriched cohort.

IOERT as anticipated tumor bed boost during breast-conserving surgery after neoadjuvant chemotherapy in locally advanced breast cancer--results of a case series after 5-year follow-up.

To evaluate retrospectively rates of local (LCR) and locoregional tumor control (LRCR) in patients with locally advanced breast cancer (LABC) who were treated with preoperative chemotherapy (primary systemic treatment, PST) followed by breast-conserving surgery (BCS) and either intraoperative radiotherapy with electrons (IOERT) preceding whole-breast irradiation (WBI) (Group 1) or with WBI followed by an external tumor bed boost (electrons or photons) instead of IOERT (Group 2). From 2002 to 2007, 83 patients with clinical Stage II or III breast cancer were enrolled in Group 1 and 26 in Group 2. All patients received PST followed by BCS and axillary lymph node dissection. IOERT boosts were applied by single doses of 9 Gy (90% reference isodose) versus external boosts of 12 Gy (median dose range, 6-16) in 2 Gy/fraction (ICRU). WBI in both groups was performed up to total doses of 51-57 Gy (1.7-1.8 Gy/fraction). The respective median follow-up times for Groups 1 and 2 amount 59 months (range, 3-115) and 67.5 months (range, 13-120). Corresponding 6-year rates for LCR, LRCR, metastasis-free survival, disease-specific survival and overall survival were 98.5, 97.2, 84.7, 89.2 and 86.4% for Group 1 and 88.1, 88.1, 74, 92 and 92% for Group 2, respectively, without any statistical significances. IOERT as boost modality during BCS in LABC after PST shows a trend to be superior in terms of LCR and LRCR in comparison with conventional boosts.

Standardization of pathologic evaluation and reporting of postneoadjuvant specimens in clinical trials of breast cancer: recommendations from an international working group.

Neoadjuvant systemic therapy is being used increasingly in the treatment of early-stage breast cancer. Response, in the form of pathological complete response, is a validated and evaluable surrogate end point of survival after neoadjuvant therapy. Thus, pathological complete response has become a primary end point for clinical trials. However, there is a current lack of uniformity in the definition of pathological complete response. A review of standard operating procedures used by 28 major neoadjuvant breast cancer trials and/or 25 sites involved in such trials identified marked variability in specimen handling and histologic reporting. An international working group was convened to develop practical recommendations for the pathologic assessment of residual disease in neoadjuvant clinical trials of breast cancer and information expected from pathology reports. Systematic sampling of areas identified by informed mapping of the specimen and close correlation with radiological findings is preferable to overly exhaustive sampling, and permits taking tissue samples for translational research. Controversial areas are discussed, including measurement of lesion size, reporting of lymphovascular space invasion and the presence of isolated tumor cells in lymph nodes after neoadjuvant therapy, and retesting of markers after treatment. If there has been a pathological complete response, this must be clearly stated, and the presence/absence of residual ductal carcinoma in situ must be described. When there is residual invasive carcinoma, a comment must be made as to the presence/absence of chemotherapy effect in the breast and lymph nodes. The Residual Cancer Burden is the preferred method for quantifying residual disease in neoadjuvant clinical trials in breast cancer; other methods can be included per trial protocols and regional preference. Posttreatment tumor staging using the Tumor-Node-Metastasis system should be included. These recommendations for standardized pathological evaluation and reporting of neoadjuvant breast cancer specimens should improve prognostication for individual patients and allow comparison of treatment outcomes within and across clinical trials.

DART-bid: dose-differentiated accelerated radiation therapy, 1.8 Gy twice daily: high local control in early stage (I/II) non-small-cell lung cancer.

BACKGROUND: While surgery is considered standard of care for early stage (I/II), non-small-cell lung cancer (NSCLC), radiotherapy is a widely accepted alternative for medically unfit patients or those who refuse surgery. International guidelines recommend several treatment options, comprising stereotactic body radiation therapy (SBRT) for small tumors, conventional radiotherapy ≥ 60 Gy for larger sized especially centrally located lesions or continuous hyperfractionated accelerated RT (CHART). This study presents clinical outcome and toxicity for patients treated with a dose-differentiated accelerated schedule using 1.8 Gy bid (DART-bid). PATIENTS AND METHODS: Between April 2002 and December 2010, 54 patients (median age 71 years, median Karnofsky performance score 70%) were treated for early stage NSCLC. Total doses were applied according to tumor diameter: 73.8 Gy for < 2.5 cm, 79.2 Gy for 2.5-4.5 cm, 84.6 Gy for 4.5-6 cm, 90 Gy for > 6 cm. RESULTS: The median follow-up was 28.5 months (range 2-108 months); actuarial local control (LC) at 2 and 3 years was 88%, while regional control was 100%. There were 10 patients (19%) who died of the tumor, and 18 patients (33%) died due to cardiovascular or pulmonary causes. A total of 11 patients (20%) died intercurrently without evidence of progression or treatment-related toxicity at the last follow-up, while 15 patients (28%) are alive. Acute esophagitis ≤ grade 2 occurred in 7 cases, 2 patients developed grade 2 chronic pulmonary fibrosis. CONCLUSION: DART-bid yields high LC without significant toxicity. For centrally located and/or large (> 5 cm) early stage tumors, where SBRT is not feasible, this method might serve as radiotherapeutic alternative to present treatment recommendations, with the need of confirmation in larger cohorts.

Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials. Part 2--TARGIT.

BACKGROUND: Two randomized intraoperative radiation therapy trials for early-stage breast cancer were recently published. The ELIOT Trial used electrons (IOERT), and the TARGIT-A Trial Update used 50-kV X-rays (IORT). These studies were compared for similarities and differences. The results were analyzed and used to determine which patients might be suitable for single-dose treatment. METHODS: The primary sources of data were the ELIOT Trial and TARGIT-A Trial, as well as a comprehensive analysis of the peer-reviewed literature of accelerated partial breast irradiation (APBI) using 50-kV X-rays or electrons. Studies published or presented prior to March 2014 were analyzed for efficacy, patient restrictions, complications, and outcome. RESULTS: With a median follow-up of 5.8 years, the 5-year recurrence rates for ELIOT versus EBRT patients were 4.4 and 0.4 %, respectively, p = 0.0001. A low-risk ELIOT group was identified with a 5-year recurrence rate of 1.5 %. With a median follow-up of 29 months, the 5-year recurrence rates for the TARGIT-A versus EBRT patients were 3.3 and 1.3 %, respectively, p = 0.042. CONCLUSIONS: With 5.8 years of median follow-up, IOERT appears to have a subset of low risk women for whom IOERT is acceptable. With 29 months of median follow-up the results of IORT with 50-kV devices are promising, but longer follow-up data are required. At the current time, single-fraction IOERT or IORT patients should be treated under strict institutional protocols.

Intraoperative radiation therapy: a critical analysis of the ELIOT and TARGIT trials. Part 1--ELIOT.

INTRODUCTION: Two randomized intraoperative radiation therapy trials for early-stage breast cancer were recently published. The ELIOT Trial used electrons (IOERT), and the TARGIT-A Trial Update used 50-kV X-rays (IORT). These studies were compared for similarities and differences. The results were analyzed and used to determine which patients might be suitable for single-dose treatment. METHOD: The primary sources of data were the ELIOT Trial and TARGIT-A Trial, as well as a comprehensive analysis of the peer-reviewed literature of accelerated partial breast irradiation (APBI) using 50-kV X-rays or electrons. Studies published or presented prior to March 2014 were analyzed for efficacy, patient restrictions, complications, and outcome. RESULTS: With a median follow-up of 5.8 years, the 5-year recurrence rates for ELIOT versus external beam radiation therapy (EBRT) patients were 4.4 % and 0.4 %, respectively, p = .0001. A low-risk ELIOT group was identified with a 5-year recurrence rate of 1.5 %. With a median follow-up of 29 months, the 5-year recurrence rates for the TARGIT-A versus EBRT patients were 3.3 % and 1.3 %, respectively, p = .042. CONCLUSION: With 5.8 years of median follow-up, IOERT appears to have a subset of low-risk women for whom IOERT is acceptable. With 29 months of median follow-up the results of IORT with 50-kV devices are promising, but longer follow-up data are required. At the current time, single-fraction IOERT or IORT patients should be treated under strict institutional protocols.

Hypofractionated stereotactic radiotherapy of acoustic neuroma: volume changes and hearing results after 89-month median follow-up.

PURPOSE: The goal of this work was to evaluate toxicity and local control following hypofractionated stereotactic radiation treatment with special focus on changes in tumor volume and hearing capacity. PATIENTS AND METHODS: In all, 29 patients with unilateral acoustic neuroma were treated between 2001 and 2007 within a prospective radiation protocol (7 × 4 Gy ICRU dose). Median tumor volume was 0.9 ml. Follow-up started at 6 months and was repeated annually with MRI volumetry and audiometry. Hearing preservation was defined as preservation of Class A/B hearing according to the guidelines of the American Academy of Otolaryngology (1995). RESULTS: No patient had any intervention after a median imaging follow-up of 89.5 months, one patient showed radiological progression. Transient increase of tumor volume developed in 17/29 patients, whereas 22/29 patients (75.9%) presented with a volume reduction at last follow-up. A total of 21 patients were eligible for hearing evaluation. Mean pure tone average (PTA) deteriorated from 39.3 to 65.9 dB and mean speech discrimination score (SDS) dropped from 74.3 to 38.1%. The 5-year actuarial Class A/B hearing preservation rate was 50.0 ± 14.4%. CONCLUSION: Radiation increases only minimally, if at all, the hearing deterioration which emerges by observation alone. Presbyacusis is not responsible for this deterioration. Transient tumor enlargement is common. Today radiation of small- and medium-sized acoustic neuroma can be performed with different highly conformal techniques as fractionated treatment or single low-dose radiosurgery with equal results regarding tumor control, hearing preservation, and side effects. Hypofractionation is more comfortable for the patient than conventional regimens and represents a serious alternative to frameless radiosurgery.

Chemo-Radio-Immunotherapy for NSCLC III: ESR/ATS Thresholds for DLCO Correlate with Radiation Dosimetry and Pneumonitis Rate.

INTRODUCTION: Durvalumab following chemoradiotherapy (CRT) for non-small cell lung cancer stage III has become the standard of care (SoC) in the past few years. With this regimen, 5-year overall survival (OS) has risen to 43%. Therefore, adequate pulmonary function (PF) after treatment is paramount in long-term survivors. In this respect, carbon monoxide diffusing capacity (DLCO), which represents the alveolar compartment, seems to be a suitable measure for residual lung capacity. The aim of the current analysis was to correlate DLCO with pneumonitis and radiation dose. PATIENTS AND METHODS: One hundred and twelve patients with histologically confirmed NSCLC III treated between 2015/10 and 2022/03 were eligible for this study. Patients received two cycles of platinum-based induction chemotherapy followed by high-dose radiotherapy (RT). As of 2017/09, durvalumab maintenance therapy was administered for one year. The clinical endpoints were based on the thresholds jointly published by the European Respiratory Society (ERS) and the American Thoracic Society (ATS). Pre-treatment DLCO of 60% was correlated to the incidence of pneumonitis, whereas the post-treatment DLCO decline of 10% was related to radiation dose. RESULTS: Patients with a pre-treatment DLCO < 60% had a higher probability of pneumonitis (n = 98; r = 0.175; p-value 0.042), which could be reproduced in the subgroup of patients who did not receive durvalumab (n = 40; r = 0.288; p-value 0.036). In these individuals, the decline in DLCO ≥ 10% depended significantly on the size of the lung volume receiving between 45% and 65% (V65-45%) of the total radiation dose (r = 0.354; p-value = 0.020) and V20 Total Lung (r = 0.466; corrected p-value = 0.042). CONCLUSIONS: The current analysis revealed that DLCO is a predictor for clinically relevant pneumonitis and a monitoring tool for post-treatment lung function as it correlates with radiation dose. This underlines the importance of peri-treatment lung function testing.