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PURPOSE/OBJECTIVE: Currently, there are few prospective data on the tolerability of combining targeted therapies (TT) with radiation therapy (RT). The objective of this prospective study was to assess the feasibility and toxicity of pairing RT with concurrent TT in cancer patients. The aim was to enhance the existing evidence base for the simultaneous administration of targeted substances together with radiotherapy. METHODS: Prospective study enrollment was conducted at a single institution between March 1, 2020, and December 31, 2021, for all patients diagnosed with histologically confirmed cancer who underwent external beam radiotherapy in combination with targeted therapy. The study, known as the "targeted RT study," was registered in the German Clinical Trials Register under DRKS00026193. Systematic documentation of the toxicity profiles of different targeted therapies was performed, and the assessment of acute toxicity followed the guidelines of the National Cancer Institute Common Terminology Criteria for Adverse Events Version v5.0. RESULTS: A total of 334 patients underwent 683 radiation therapy series. During the course of RT, 51 different TT substances were concurrently administered. External beam radiotherapy was employed for various anatomical sites. The combination of RT and concurrent TT administration was generally well tolerated, with no instances of severe acute toxicity observed. The most commonly reported toxicity was fatigue, ranging from mild to moderate Common Terminology Criteria for Adverse Events (CTCAE) °I-°III. Other frequently observed toxicities included dermatitis, dyspnea, dysphagia, and dry cough. No toxicity greater than moderate severity was recorded at any point. In only 32 patients (4.7% of evaluated RT series), the concurrent substance administration was discontinued due to side effects. However, these side effects did not exceed mild severity according to CTCAE, suggesting that discontinuation was a precautionary measure. Only one patient receiving Imatinib treatment experienced a severe CTCAE °III side effect, leading to discontinuation of the concurrent substance due to the sudden occurrence of melaena during RT. CONCLUSION: In conclusion, the current study did not demonstrate a significant increase or additional toxicity when combining radiotherapy and concurrent targeted therapy. However, additional research is required to explore the specific toxicity profiles of the various substances that can be utilized in this context. TRIAL REGISTRATION NUMBER: DRKS00026193. Date of registration 12/27/2022 (retrospectively registered).

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The standard treatment for locally advanced cervical cancer typically includes concomitant chemoradiation, a regimen known to induce severe hematologic toxicity (HT). Particularly, pelvic bone marrow dose exposure has been identified as a contributing factor to this hematologic toxicity. Chemotherapy further increases bone marrow suppression, often necessitating treatment interruptions or dose reductions. A systematic search for original articles published between 1 January 2006 and 7 January 2024 that reported on chemoradiotherapy for locally advanced cervical cancer and hematologic toxicities was conducted. Twenty-four articles comprising 1539 patients were included in the final analysis. HT of grade 2 and higher was observed across all studies and frequently exceeded 50%. When correlating active pelvic bone marrow and HT, significant correlations were found for volumes between 10 and 45 Gy and HT of grade 3 and higher. Several dose recommendations for pelvic bone and pelvic bone marrow sparing to reduce HT were established, including V10 < 90-95%, V20 < 65-86.6% and V40 < 22.8-40%. Applying dose constraints to the pelvic bone/bone marrow is a promising approach for reducing HT, and thus reliable implementation of therapy. However, prospective randomized controlled trials are needed to define precise dose constraints and optimize clinical strategies.

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We aimed to evaluate the standard of care of adjuvant radiotherapy (RT) after breast-conserving surgery (BCS) in elderly female patients (≥65 years) treated outside of clinical trials and to identify potential factors related to the omission of RT and the interaction with endocrine therapy (ET). All women treated with BCS at two major breast centers between 1998 and 2014 were evaluated. Data were provided by the Tumor Registry Munich. Survival analyses were conducted using the Kaplan-Meier method. Prognostic factors were identified using multivariate Cox regression analysis. The median follow-up was 88.4 months. Adjuvant RT was performed in 82% (2599/3171) of patients. Irradiated patients were younger (70.9 vs. 76.5 years, p < 0.001) and were more likely to receive additional chemotherapy (p < 0.001) and ET (p = 0.014). Non-irradiated patients more often had non-invasive DCIS tumors (pTis: 20.3% vs. 6.8%, p < 0.001) and did not undergo axillary surgery (no axillary surgery: 50.5% vs. 9.5%, p < 0.001). Adjuvant RT was associated with improved locoregional tumor control after BCS in invasive tumors (10-year local recurrence-free survival (LRFS): 94.0% vs. 75.1%, p < 0.001, 10-year lymph node recurrence-free survival (LNRFS): 98.1% vs. 93.1%, p < 0.001). Multivariate analysis confirmed significant benefits for local control with postoperative RT. Furthermore, RT led to increased locoregional control even in patients who received ET (10-year LRFS 94.8% with ET + RT vs. 78.1% with ET alone, p < 0.001 and 10-year LNRFS: 98.2% vs. 95.0%, p = 0.003). Similarly, RT alone had significantly better locoregional control rates compared to ET alone (10-year LRFS 92.6% with RT alone vs. 78.1% with ET alone, p < 0.001 and 10-year LNRFS: 98.0% vs. 95.0%, p = 0.014). The present work confirms the efficacy of postoperative RT for breast carcinoma in elderly patients (≥65 years) treated in a modern clinical setting outside of clinical trials, even in patients who receive ET.

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BACKGROUND: We describe and evaluate a deep network algorithm which automatically contours organs at risk in the thorax and pelvis on computed tomography (CT) images for radiation treatment planning. METHODS: The algorithm identifies the region of interest (ROI) automatically by detecting anatomical landmarks around the specific organs using a deep reinforcement learning technique. The segmentation is restricted to this ROI and performed by a deep image-to-image network (DI2IN) based on a convolutional encoder-decoder architecture combined with multi-level feature concatenation. The algorithm is commercially available in the medical products "syngo.via RT Image Suite VB50" and "AI-Rad Companion Organs RT VA20" (Siemens Healthineers). For evaluation, thoracic CT images of 237 patients and pelvic CT images of 102 patients were manually contoured following the Radiation Therapy Oncology Group (RTOG) guidelines and compared to the DI2IN results using metrics for volume, overlap and distance, e.g., Dice Similarity Coefficient (DSC) and Hausdorff Distance (HD95). The contours were also compared visually slice by slice. RESULTS: We observed high correlations between automatic and manual contours. The best results were obtained for the lungs (DSC 0.97, HD95 2.7 mm/2.9 mm for left/right lung), followed by heart (DSC 0.92, HD95 4.4 mm), bladder (DSC 0.88, HD95 6.7 mm) and rectum (DSC 0.79, HD95 10.8 mm). Visual inspection showed excellent agreements with some exceptions for heart and rectum. CONCLUSIONS: The DI2IN algorithm automatically generated contours for organs at risk close to those by a human expert, making the contouring step in radiation treatment planning simpler and faster. Few cases still required manual corrections, mainly for heart and rectum.

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BACKGROUND: Patients with left-sided breast cancer have an increased risk of cardiovascular disease (CVD) after radiotherapy (RT). While the awareness of cardiac toxicity has increased enormously over the last decade, the role of individual baseline cardiac risks has not yet been systematically investigated. Aim of the present study was to evaluate the impact of baseline CVD risks on radiation-induced cardiac toxicity. METHODS: Two hundred ten patients with left-sided breast cancer treated in the prospective Save-Heart Study using a deep inspiration breath-hold (DIBH) technique were analysed regarding baseline risk factors for CVD. Three frequently used prediction tools (Procam, Framingham and Reynolds score) were applied to evaluate the individual CVD risk profiles. Moreover, 10-year CVD excess absolute risks (EAR) were estimated using the individual mean heart dose (MHD) of treatment plans in free breathing (FB) and DIBH. RESULTS: The individual baseline CVD risk factors had a strong impact on the 10-year cumulative CVD risk. The mean baseline risks of the non-diabetic cohort (n = 200) ranged from 3.11 to 3.58%, depending on the risk estimation tool. A large number of the non-diabetic patients had a very low 10-year CVD baseline risk of ≤1%; nevertheless, 8-9% of patients reached ≥10% baseline 10-year CVD risk. In contrast, diabetic patients (n = 10) had significantly higher baseline CVD risks (range: 11.76-24.23%). The mean 10-year cumulative risk (Framingham score) following RT was 3.73% using the DIBH-technique (MHD:1.42Gy) and 3.94% in FB (MHD:2.33Gy), after adding a 10-year-EAR of + 0.34%(DIBH) and + 0.55%(FB) to the baseline risks, respectively. Smoking status was one of the most important and modifiable baseline risk factors. After DIBH-RT, the 182 non-smoking patients had a mean 10-year cumulative risk of 3.55% (3.20% baseline risk, 0.35% EAR) as compared to 6.07% (5.60% baseline risk, 0.47% EAR) for the 28 smokers. CONCLUSION: In the present study, all CVD prediction tools showed comparable results and could easily be integrated into daily clinical practice. A systematic evaluation and screening helps to identify high-risk patients who may benefit from primary prevention. This could result in an even higher benefit than from heart-sparing irradiation techniques alone.

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PURPOSE: Aim of the present analysis was to evaluate the movement and dose variability of the different lymph node levels of node-positive breast cancer patients during adjuvant radiotherapy (RT) with regional nodal irradiation (RNI) in deep-inspiration breath hold (DIBH). METHODS: Thirty-five consecutive node-positive breast cancer patients treated from October 2016 to February 2018 receiving postoperative RT of the breast or chest wall including RNI of the supra-/infraclavicular lymph node levels (corresponding to levels IV, III, Rotter LN (interpectoral), and some parts of level II) were analyzed. To evaluate the lymph node level movement, a center of volume (COV) was obtained for each lymph node level for free-breathing (FB) and DIBH plans. Geometric shifts and dose differences between FB and DIBH were analyzed. RESULTS: A significant movement of the COV in anterior (y) and cranial (z) dimensions was observed for lymph node levels I-II and Rotter lymph nodes (p < 0.001) due to DIBH. Only minor changes in the lateral dimension (x axis) were observed, without reaching significance for levels III, IV, and internal mammary. There was a significant difference in the mean dose of level I (DIBH vs. FB: 38.2 Gy/41.3 Gy, p < 0.001) and level II (DIBH vs. FB: 45.9 Gy/47.2 Gy, p < 0.001), while there was no significant difference in level III (p = 0.298), level IV (p = 0.476), or internal mammary nodes (p = 0.471). CONCLUSION: A significant movement of the axillary lymph node levels was observed during DIBH in anterior and cranial directions for node-positive breast cancer patients in comparison to FB. The movement leads to a significant dose reduction in level I and level II.

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PURPOSE: Aim of the current comparative modelling study was to estimate the individual radiation-induced risk for death of ischaemic heart disease (IHD) under free breathing (FB) and deep inspiration breath-hold (DIBH) in a real-world population. MATERIALS AND METHODS: Eighty-nine patients with left-sided early breast cancer were enrolled in the prospective SAVE-HEART study. For each patient three-dimensional conformal treatment plans were created in FB and DIBH and corresponding radiation-induced risks of IHD mortality were estimated based on expected survival, individual IHD risk factors and the relative radiation-induced risk. RESULTS: With the use of DIBH, mean heart doses were reduced by 35% (interquartile range: 23-46%) as compared to FB. Mean expected years of life lost (YLL) due to radiation-induced IHD mortality were 0.11 years in FB, and 0.07 years in DIBH. YLL were remarkably independent of age at treatment in patients with a favourable tumour prognosis. DIBH led to more pronounced reductions in YLL in patients with high baseline risk (0.08 years for upper vs 0.02 years for lower quartile), with favourable tumour prognosis (0.05 years for patients without vs 0.02 years for those with lymph-node involvement), and in patients with high mean heart doses in FB (0.09 years for doses >3 Gy vs 0.02 years for doses <1.5 Gy). CONCLUSION: Ideally, the DIBH technique should be offered to all patients with left-sided breast cancer. However, highest benefits are expected for patients with a favourable tumour prognosis, high mean heart dose or high baseline IHD risk, independent of their age.

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