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.

First clinical application of image-guided intraoperative electron radiation therapy with real time intraoperative dose calculation in recurrent rectal cancer: technical procedure.

Intraoperative radiation therapy (IORT) is a radiation technique applying a single fraction with a high dose during surgery. We report the first abdomino-pelvic application of an image-guided intraoperative electron radiation therapy with intraoperative real time dose calculation based on the individual intraoperative patient anatomy. A patient suffering from locoregionally recurrent rectal cancer after treatment with neoadjuvant re-chemoradiation was chosen for this approach. After surgical removal of the recurrence, an adequate IORT applicator was placed as usual. A novel mobile imaging device (ImagingRing, MedPhoton) was positioned around the patient covering the region to be treated with the IORT-applicator in place. It allowed the acquisition of three-dimensional intraoperative cone-beam computed tomography images suitable for dose calculation using an automated scaling (heuristic object and head scatter as well as hardening corrections) of Hounsfield units. After image acquisition confirmed the correct applicator position, the images were transferred to our treatment planning system for intraoperative dose calculation. Treatment could be accomplished using the calculated dose distribution. We herein describe the details of the procedure including necessary adjustments in the typically used IORT equipment and work flow. We further discuss the pros and cons of this new approach generally overcoming a decade long limitation of IORT procedures as well as future perspectives regarding IORT treatments.

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.

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.

Carbon Monoxide Diffusing Capacity (DLCO) Correlates with CT Morphology after Chemo-Radio-Immunotherapy for Non-Small Cell Lung Cancer Stage III.

Introduction: Curatively intended chemo-radio-immunotherapy for non-small cell lung cancer (NSCLC) stage III may lead to post-therapeutic pulmonary function (PF) impairment. We hypothesized that the decrease in global PF corresponds to the increase in tissue density in follow-up CTs. Hence, the study aim was to correlate the dynamics in radiographic alterations to carbon monoxide diffusing capacity (DLCO) and FEV1, which may contribute to a better understanding of radiation-induced lung disease. Methods: Eighty-five patients with NSCLC III were included. All of them received two cycles of platinum-based induction chemotherapy followed by high dose radiation. Thereafter, durvalumab was administered for one year in 63/85 patients (74%). Pulmonary function tests (PFTs) were performed three months and six months after completion of radiotherapy (RT) and compared to baseline. At the same time points, patients underwent diagnostic CT (dCT). These dCTs were matched to the planning CT (pCT) using RayStation® Model Based Segmentation and deformable image registration. Differential volumes defined by specific isodoses were generated to correlate them with the PFTs. Results: In general, significant correlations between PFTs and differential volumes were found in the mid-dose range, especially for the volume of the lungs receiving between 65% and 45% of the dose prescribed (V65−45%) and DLCO (p<0.01). This volume range predicted DLCO after RT (p-value 0.03) as well. In multivariate analysis, DLCO (p-value 0.040) and FEV1 (p-value 0.014) predicted pneumonitis. Conclusions: The current analysis revealed a strong relation between the dynamics of DLCO and CT morphology changes in the mid-dose range, which convincingly indicates the importance of routinely used PFTs in the context of a curative treatment approach.

Long-Term Results of the TARGIT-A Trial: More Questions than Answers.

Background: During the last decade, partial breast irradiation (PBI) has gained traction as a relevant treatment option for patients with early-stage low-risk breast cancer after breast-conserving surgery. The TARGIT-A prospective randomized trial compared a "risk-adapted" intraoperative radiotherapy (IORT) approach with 50-kv X-rays (INTRABEAM®) as the PBI followed by optional whole-breast irradiation (WBI) and conventional adjuvant WBI in terms of observed 5-year in-breast recurrence rates. Recently, long-term data were published. Since the first publication of the TARGIT-A trial, a broad debate has been emerged regarding several uncertainties and limitations associated with data analysis and interpretation. Our main objective was to summarize the data, with an emphasis on the updated report and the resulting implications. Summary: From our point of view, the previously unresolved questions still remain and more have been added, especially with regard to the study design, a change in the primary outcome measure, the significant number of patients lost to follow-up, and the lack of a subgroup analysis according to risk factors and treatment specifications. Key Message: Taking into account the abovementioned limitations of the recently published long-term results of the TARGIT-A trial, the German Society of Radiation Oncology (DEGRO) Breast Cancer Expert Panel adheres to its recently published recommendations on PBI: "the 50-kV system (INTRABEAM) cannot be recommended for routine adjuvant PBI treatment after breast-conserving surgery."

Hypofractionated Whole Breast Irradiation and Boost-IOERT in Early Stage Breast Cancer (HIOB): First Clinical Results of a Prospective Multicenter Trial (NCT01343459).

Background and purpose: To investigate intraoperative electron radiation therapy (IOERT) as a tumor bed boost during breast conserving surgery (BCS) followed by hypofractionated whole breast irradiation (HWBI) on age-correlated in-breast recurrence (IBR) rates in patients with low- to high-risk invasive breast cancer. Material and methods: BCS and IOERT (11.1 Gy) preceded a HWBI (40.5 Gy) in 15 fractions. Five-year IBR-rates were compared by a sequential ratio test (SQRT) with best evidences in three age groups (35−40 y and 41−50 y: 3.6%, >50 y: 2%) in a prospective single arm design. Null hypothesis (H0) was defined to undershoot these benchmarks for proof of superiority. Results: Of 1445 enrolled patients, 326 met exclusion criteria, leaving 1119 as eligible for analysis. After a median follow-up of 50 months (range 0.7−104), we detected two local recurrences, both in the age group >50 y. With no observed IBR, superiority was demonstrated for the patient groups 41−50 and >50 y, respectively. For the youngest group (35−40 y), no appropriate statistical evaluation was yet possible due to insufficient recruitment. Conclusions: In terms of five-year IBR-rates, Boost-IOERT followed by HWBI has been demonstrated to be superior in patients older than 50 and in the age group 41−50 when compared to best published evidence until 2010.

High Dose Thoracic Re-Irradiation and Chemo-Immunotherapy for Centrally Recurrent NSCLC.

INTRODUCTION: Thoracic re-irradiation for recurrent lung cancer dates back four decades, when the first small series on 29 patients receiving palliative doses was published. With 5-year overall survival rates of 57% in PDL-1 positive patients after primary chemo-radio-immunotherapy, the number of patients who experience loco-regional relapse will increase in the near future. In this context, centrally recurring lung tumors pose a major treatment challenge. Hence, the aim of the current review is to compile the available evidence on curatively intended thoracic re-irradiation for this special clinical situation. METHODS: A systematic literature search according to the PRISMA guidelines was performed. A study was included when the following criteria were met: (1) 66% of the patients had NSCLC, (2) a total dose of 50 Gy in the second course and/or a biologically effective dose of at least 100 Gy in both treatment courses was administered, (3) re-irradiation was administered with modern radiation techniques, (4) 50% or more of the patients had a centrally located relapse, (5) the minimum cohort size was 30 patients. RESULTS: Of the initial 227 studies, 11 were analyzed, 1 of which was prospective. Median overall survival (OS) was 18.1 months (range 9.3-25.1), median progression free survival (PFS) was nine months (range 4.5-16), and median loco-regional control (LRC) was 12.1 months (range 6.5-20). Treatment-related mortality rates ranged from 2% to 14%. The total dose at re-irradiation correlated with both LRC (p-value = 0.012) and OS (p-value = 0.007) with a close relation between these two clinical endpoints (p-value = 0.006). The occurrence of acute toxicity grade 1 to 4 depended on the PTV size at re-irradiation (p-value = 0.033). CONCLUSION: The evidence regarding curative re-irradiation for centrally recurrent NSCLC is primarily based on scarce retrospective data, which are characterized by a high degree of heterogeneity. The OS in this clinically challenging situation is expected to be around 1.5 years after re-treatment. Patients with a good performance score, younger age, small tumors, and a longer interval to recurrence potentially benefit most from re-irradiation. In this context, prospective trials are warranted to achieve substantial advances in the field.

Hsa-miR-3651 could serve as a novel predictor for in-breast recurrence via FRMD3.

BACKGROUND: MicroRNAs are small non-coding RNAs with pivotal regulatory functions in multiple cellular processes. Their significance as molecular predictors for breast cancer was demonstrated in the past 15 years. The aim of this study was to elucidate the role of hsa-miR-3651 for predicting of local control (LC) in early breast cancer. RESULTS: By means of high-throughput technology, hsa-miR-3651 was found to be differentially expressed between patients who experienced local relapse compared to those without (N = 23; p = 0.0035). This result could be validated in an independent cohort of 87 patients using RT-qPCR (p < 0.0005). In a second analysis step with a chip-based microarray containing 70,523 probes of potential target molecules, FERM domain protein 3 (FRMD3) was found to be the most down-regulated protein (N = 21; p = 0.0016). Computational analysis employing different prediction algorithms revealed FRMD3 as a likely downstream target of hsa-miR-3651 with an 8mer binding site between the two molecules. This could be validated in an independent patient set (N = 20, p = 0.134). CONCLUSION: The current study revealed that hsa-miR-3651 is a predictor of LC in early breast cancer via its putative target protein FRMD3. Since microRNAs interfere in multiple pathways, the results of this hypothesis generating study may contribute to the development of tailored therapies for breast cancer in the future.

Re-Irradiation for Locally Recurrent Lung Cancer: A Single Center Retrospective Analysis.

The treatment of locally recurrent lung cancer is a major challenge for radiation-oncologists, especially with data on high-dose reirradiation being limited to small retrospective studies. The aim of the present study is to assess overall survival (OS) for patients with locally recurrent lung cancer after high-dose thoracic reirradiation. Thirty-nine patients who were re-irradiated for lung cancer relapse between October 2013 and February 2019 were eligible for the current retrospective analysis. All patients were re-irradiated with curative intent for in-field tumor recurrence. The diagnostic work-up included a mandatory 18F-FDG-PET-CT scan and-if possible-histological verification. The ECOG was ≤2, and the interval between initial and second radiation was at least nine months. Thirty patients (77%) had non-small cell lung cancer (NSCLC), eight (20%) had small cell lung cancer (SCLC), and in one patient (3%) histological confirmation could not be obtained. More than half of the patients (20/39, 51%) received re-treatment with dose differentiated accelerated re-irradiation (DART) at a median interval of 20.5 months (range: 6-145.3 months) after the initial radiation course. A cumulative EQD2 of 131 Gy (range: 77-211 Gy) in a median PTV of 46 mL (range: 4-541 mL) was delivered. Patients with SCLC had a 3 mL larger median re-irradiation volume (48 mL, range: 9-541) compared to NSCLC patients (45 mL, range: 4-239). The median cumulative EQD2 delivered in SCLC patients was 84 Gy (range: 77-193 Gy), while NSCLC patients received a median cumulative EQD2 of 135 Gy (range: 98-211 Gy). The median OS was 18.4 months (range: 0.6-64 months), with tumor volume being the only predictor (p < 0.000; HR 1.007; 95%-CI: 1.003-1.012). In terms of toxicity, 17.9% acute and 2.6% late side effects were observed, with a toxicity grade >3 occurring in only one patient. Thoracic high dose reirradiation plays a significant role in prolonging survival, especially in patients with small tumor volume at recurrence.

State of the art in breast intraoperative electron radiation therapy after intraoperative ultrasound introduction.

BACKGROUND: Breast intraoperative electron radiation therapy (B-IOERT) can be used in clinical practice both as elective irradiation (partial breast irradiation - APBI) in low risk breast cancer patients, and as an anticipated boost. The procedure generally includes the use of a shielding disk between the residual breast and the pectoralis fascia for the protection of the tissues underneath the target volume. The aim of the study was to evaluate the role of intraoperative ultrasound (IOUS) in improving the quality of B-IOERT. PATIENTS AND METHODS: B-IOERT was introduced in Trieste in 2012 and its technique was improved in 2014 with IOUS. Both, needle and IOUS were used to measure target thickness and the latter was used even to check the correct position of the shielding disk. The primary endpoint of the study was the evaluation of the effectiveness of IOUS in reducing the risk of a disk misalignment related to B-IOERT and the secondary endpoint was the analysis of acute and late toxicity, by comparing two groups of patients treated with IOERT as a boost, either measured with IOUS and needle (Group 1) or with needle alone (Group 2). Acute and late toxicity were evaluated by validated scoring systems. RESULTS: From the institutional patients who were treated between June 2012 and October 2019, 109 were eligible for this study (corresponding to 110 cases, as one patients underwent bilateral conservative surgery and bilateral B-IOERT). Of these, 38 were allocated to group 1 and 72 to group 2. The target thickness measured with the IOUS probe and with the needle were similar (mean difference of 0.1 mm, p = 0.38). The percentage of patients in which the shield was perfectly aligned after IOUS introduction increased from 23% to more than 70%. Moreover, patients treated after IOUS guidance had less acute toxicity (36.8% vs. 48.6%, p = 0.33) from radiation therapy, which reached no statistical significance. Late toxicity turned out to be similar regardless of the use of IOUS guidance: 39.5% vs. 37.5% (p = 0.99). CONCLUSIONS: IOUS showed to be accurate in measuring the target depth and decrease the misalignment between collimator and disk. Furthermore there was an absolute decrease in acute toxicity, even though not statistically significant, in the group of women who underwent B-IOERT with IOUS guidance.

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.

Impact of reirradiation, chemotherapy, and immunotherapy on survival of patients with recurrent lung cancer: A single-center retrospective analysis.

BACKGROUND: Given the limited curative treatment options for recurrent lung cancer patients, the aim of our retrospective study was to investigate whether these patients would benefit in terms of overall survival (OS) by adding immunotherapy to high-dose reirradiation. MATERIALS AND METHODS: Between 2013 and 2019, 47 consecutive patients with in-field tumor recurrence underwent high-dose thoracic reirradiation at our institute. Twenty patients (43%) received high-dose reirradiation only, while 27/47 (57%) additionally had systemic therapy (immunotherapy and/or chemotherapy). With the exception of one patent, the interval between first and second radiation was at least 9 months. All patients had an Eastern cooperative oncology group ≤2. The diagnostic work-up included a mandatory fluorodeoxyglucose-positron emission tomography-computed tomography scan and histological verification. The primary endpoint was OS after completion of the second course of irradiation. RESULTS: In the whole cohort of 47 patients, the median overall survival (mOS) after reirradiation was 18.9 months (95% confidence interval [CI] 16.5-21.3 months), while in the subgroup of 27 patients who received additional systemic treatment after reirradiation, mOS amounted to 21.8 months (95% CI 17.8-25.8 months). Within this group the comparison between reirradiation combined with either immunotherapy (n = 21) or chemotherapy (n = 6) revealed a difference in OS, which was in favor of the first (log-rank p value = 0.063). Three patients (11%) experienced acute side effects and one (4%) showed a late hemorrhage grade 3. CONCLUSION: Patients who received immunotherapy and reirradiation lived longer than those who did not receive immunotherapy.