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Simple Summary: In the present work, we analyzed long-term outcomes of patients with synchronous oligometastatic (OMD) non-small cell lung cancer (NSCLC) with locally advanced tumors in comparison to patients treated for stage III NSCLC. All patients with oligometastatic NSCLC had to have a histopathologically confirmed diagnosis and were screened for driver mutations using next-generation sequencing. Patients with tumors showing EGFR, ALK or ROS1 gene alterations were excluded, and the PD-L1 tumor proportion score was determined. 18FDG-PET/CT and cranial MRI or CT were performed in all patients. All patients were treated with definitive or neoadjuvant radiochemotherapy plus surgery in addition to systemic therapy. Overall survival of OMD patients at five years was similar to that of stage III patients: 28.3% versus 34.9%. Baseline severe comorbidity, ECOG performance status, sex and pretreatment serum CRP level were the most important prognostic factors for the survival of OMD patients. Cumulative incidence of distant metastases was the highest competing risk for OMD patients, approaching 50% at 4 years. A multidisciplinary approach, including thoracic radiotherapy or a trimodality treatment, metastases-directed local therapy and contemporary systemic therapy, can lead to very good long-term survival of patients with oligometastatic and locally advanced non-small cell lung cancer, especially in patients without severe comorbidities and with good performance status. Background: In patients with oligometastatic NSCLC, a cT3–cT4 primary tumor or an cN2/cN3 lymph node status was reported to be associated with unfavorable outcome. The aim of this study was to assess the importance of definitive or neoadjuvant thoracic radiochemotherapy for long-term outcome of these patients in order to find more appropriate treatment schedules. Methods: Analysis of the West Cancer Centre (WTZ) institutional database from 08/2016 to 08/2020 was performed. Patients with primary synchronous OMD, all without actionable driver mutations, who received definitive thoracic radiochemotherapy (RCT) or neoadjuvant RCT followed by surgery (trimodality treatment) were included. Survival outcome is compared with stage III NSCLC. Results: Altogether, 272 patients received concurrent radiochemotherapy. Of those, 220 presented with stage III (158 with definitive RCT, 62 with trimodality approach). A total of 52 patients had OMD patients with cT3/cT4 or cN2/cN3 tumors. Overall survival (OS) at five years for OMD patients was 28.3% (95%-CI: 16.4–41.5%), which was not significantly different from OS of patients with stage III NSCLC treated with definitive or neoadjuvant RCT (34.9% (95%-CI: 27.4–42.8%)). However, the PFS of OMD patients at five years or last follow-up was significantly worse than that of stage III patients (13.0% vs. 24.3%, p = 0.0048). The latter was due to a higher cumulative incidence of distant metastases in OMD patients (50.2% vs. 20.4% at 48 months, p < 0.0001) in comparison to stage III patients. A cross-validated classifier that included severe comorbidity, ECOG performance status, gender and pre-treatment serum CRP level as the most important factors in the univariable analysis, was able to divide the OMD patient group into two equally sized groups with a four-year survival rate of 49.4% in the good prognosis group and 9.9% in the poor prognosis group (p = 0.0021). Laboratory chemistry and clinical parameters, in addition to imaging and high-precision therapies, can help to predict and improve prognosis. Conclusions: A multimodality treatment approach and local metastases-directed therapy in addition to chemoimmunotherapy can lead to good long-term survival in patients with cT3/cT4 or cN2/cN3 OMD NSCLC without severe comorbidities and in good performance status and is therefore recommended. [ABSTRACT FROM AUTHOR]

Simple Summary: The effects of reduced prescription doses on normal tissue toxicity in the treatment of non-Hodgkin lymphomas of the neck/thorax region remain unclear. Acute side effects, which already occur at low organ doses, can only be described to a limited extent by the models given in the literature. Nonetheless, the knowledge about these dose–response relationships is particularly important to predict an acute response in normal tissue adequately. Considering a robust normal tissue toxicity model, dose prescriptions and treatment plans can be optimized to increase the treatment quality and, thus, the outcome for the patient. This biophysical study aimed to determine fitting parameters for the Lyman–Kutcher–Burman (LKB) dose–response model for normal tissue complication probability (NTCP) calculations of acute side effects and to investigate the impact of reduced radiation doses on the probability of their occurrence in supradiaphragmatic non-Hodgkin lymphoma (NHL) irradiation. A cohort of 114 patients with NHL in the cervicothoracic region, treated between 2015 and 2021 at the University Hospitals of Münster, Hamburg, and Essen, with involved site radiation therapy (ISRT), were included. Among them, 68 patients with aggressive NHL (a-NHL) received consolidative radiation therapy with 24–54 Gy following (R-)CHOP chemotherapy. Additionally, 46 patients with indolent NHL (i-NHL) underwent radiotherapy with 22.5–45.0 Gy. Two treatment plans were prospectively created for each patient (a-NHL: 30.0/40.0 Gy; i-NHL: 24.0/30.0 Gy). NTCP were then calculated using the optimized LKB model. The adapted dose–response models properly predicted the patient's probability of developing acute side effects when receiving doses ≤ 50 Gy. In addition, it was shown that reduced radiation doses can influence the NTCP of acute side effects depending on the aggressiveness of NHL significantly. This study provided a foundation to prospectively assess the probability of adverse side effects among today's reduced radiation doses in the treatment of NHL. [ABSTRACT FROM AUTHOR]

Simple Summary: Online adaptive radiotherapy (oART) can potentially reduce the required planning target volume (PTV) margins for clinical target volume (CTV) coverage. To achieve this advantage, it is crucial that intrafractional CTV deformation during adaptation remains smaller than deformation from fraction to fraction. In this study, we analyzed the dosimetric effects of intrafractional CTV deformations using a time-dependent CTV deformation model based on cone beam CT data generated before and after adaptation. Data were obtained from nine patients undergoing online adaptive definitive focal radiochemotherapy as part of a clinical registry. In half of the treatment series, a significant time dependence in the required margin to maintain an effective uniform dose within the CTV was observed. Extending the adaptation time beyond 10 min by an additional 5 min necessitated a 1.9 ± 0.24 mm increase in the margin. This underscores the importance of minimizing adaptation time as it significantly influences the precision of oART. Interfraction anatomic deformations decrease the precision of radiotherapy, which can be improved by online adaptive radiation therapy (oART). However, oART takes time, allowing intrafractional deformations. In this study on focal radiotherapy for bladder cancer, we analyzed the time effect of oART on the equivalent uniform dose in the CTV (EUDCTV) per fraction and for the accumulated dose distribution over a treatment series as measure of effectiveness. A time-dependent digital CTV model was built from deformable image registration (DIR) between pre- and post-adaptation imaging. The model was highly dose fraction-specific. Planning target volume (PTV) margins were varied by shrinking the clinical PTV to obtain the margin-specific CTV. The EUDCTV per fraction decreased by—4.4 ± 0.9% of prescribed dose per min in treatment series with a steeper than average time dependency of EUDCTV. The EUDCTV for DIR-based accumulated dose distributions over a treatment series was significantly dependent on adaptation time and PTV margin (p < 0.0001, Chi2 test for each variable). Increasing adaptation times larger than 10 min by five minutes requires a 1.9 ± 0.24 mm additional margin to maintain EUDCTV for a treatment series. Adaptation time is an important determinant of the precision of oART for one half of the bladder cancer patients, and it should be aimed at to be minimized. [ABSTRACT FROM AUTHOR]

Simple Summary: This scientific research characterizes the recurrence pattern of patients with glioblastoma after trimodality treatment, neurosurgery and radiation therapy, either intensity modulated radiation therapy (IMRT) or volumetric intensity modulated arc therapy (VMAT), as well as concurrent chemotherapy in a clinical setting based on daily image-guided radiation therapy (IGRT) at the West German Cancer Center. This study underlines the importance of reconsideration of clinical target volume margins in the clinical routine. Larger radiation therapy margins may decrease the proportion of out-field recurrences, but an effect on overall survival is highly questionable. Background: While prognosis of glioblastoma after trimodality treatment is well examined, recurrence pattern with respect to the delivered dose distribution is less well described. Therefore, here we examine the gain of additional margins around the resection cavity and gross-residual-tumor. Methods: All recurrent glioblastomas initially treated with radiochemotherapy after neurosurgery were included. The percentage overlap of the recurrence with the gross tumor volume (GTV) expanded by varying margins (10 mm to 20 mm) and with the 95% and 90% isodose was measured. Competing-risks analysis was performed in dependence on recurrence pattern. Results: Expanding the margins from 10 mm to 15 mm, to 20 mm, to the 95%- and 90% isodose of the delivered dose distribution with a median margin of 27 mm did moderately increase the proportion of relative in-field recurrence volume from 64% to 68%, 70%, 88% and 88% (p < 0.0001). Overall survival of patients with in-and out-field recurrence was similar (p = 0.7053). The only prognostic factor significantly associated with out-field recurrence was multifocality of recurrence (p = 0.0037). Cumulative incidences of in-field recurrences at 24 months were 60%, 22% and 11% for recurrences located within a 10 mm margin, outside a 10 mm margin but within the 95% isodose, or outside the 95% isodose (p < 0.0001). Survival from recurrence was improved after complete resection (p = 0.0069). Integrating these data into a concurrent-risk model shows that extending margins beyond 10 mm has only small effects on survival hardly detectable by clinical trials. Conclusions: Two-thirds of recurrences were observed within a 10 mm margin around the GTV. Smaller margins reduce normal brain radiation exposure allowing for more extensive salvage radiation therapy options in case of recurrence. Prospective trials using margins smaller than 20 mm around the GTV are warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this trial was to define one optimal contemporary treatment procedure for large intraocular melanoma. Radiosurgery is a highly effective treatment in cancer. In this trial, all consecutive patients with large intraocular melanoma treated with multimodality treatment, comprising 4D image-guided volumetric modulated arc radiosurgery procedure followed by resection, were evaluated. In the short-term follow-up there was no clinical toxicity due to external beam radiation therapy, and no local tumor recurrence. In 98% of the cases, the eye bulb could be maintained with partial residual visual acuity in the mean follow-up of 18 months. The outcome estimates one optimal treatment procedure for high-risk, large intraocular melanoma, with excellent results in the first follow-up. The main objective of this prospective observational study was the characterization of the feasibility and early outcome of image-guided (IG) volumetric modulated arc (VMAT) radiosurgery (SRS) followed by resection for patients with large intraocular melanoma. Our study included consecutive patients with unfavorable-risk melanoma, enrolled in an ophthalmic oncology center. IG-VMAT-SRS was applied by high-resolution 4D image guidance and monitoring. Current stereotactic technique parameters were evaluated for comparison. Side effects and eye function, based on a 5-point CTC assessment score, were quantified. In patients with tumors located more than 0.7–1 mm apart from the optic nerve, partial to complete volume-sparing of the optic nerve head could be achieved. In 95.5% of this subgroup, the vitality of the optic nerve and vision could be preserved by the multimodality-treatment approach (mean follow-up: 18 months (7.5–36 months)). The advanced technology of stereotactic radiotherapy demonstrated the achievability of steep dose gradients around the high-dose volume, with 4D-IG-VMAT dose application. These results enforce IG-VMAT-SRS followed by resection as one of the major therapeutic options for patients with large intraocular melanoma. The combination of 4D-IG high-precision SRS and resection provides an effective treatment for large intraocular melanoma, with few side effects, and enables an eye bulb and even vision preserving modus operandi. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of the present retrospective study was to develop a new scoring system for prognosis of patients undergoing surgery for breast cancer brain metastasis. Our institutional cohort (n = 95) was analyzed with regard to independent predictors of short (<6 months) and long (≥3 years) survival. Breast-preserving surgery, presence of multiple brain metastases, and age ≥ 65 years at brain cancer diagnosis were associated with short survival. In turn, positive HER2 receptor status in brain metastasis, time interval ≥ 3 years between breast cancer and brain metastasis diagnosis and KPS ≥ 90% were the long survival predictors. The scores based on the above-mentioned independent predictors showed good diagnostic accuracy for the prediction of short (AUC = 0.773) and long (AUC = 0.775) survival. After external validation, the presented scores might become useful tools to support the interdisciplinary decision for the selection of treatment strategy in individuals with breast cancer brain metastases. Background: Brain metastases requiring surgical treatment determine the prognosis of patients with breast cancer. We aimed to develop the scores for the prediction of short (<6 months) and long (≥3 years) survival after BCBM surgery. Methods: Female patients with BCBM surgery between 2008 and 2019 were included. The new scores were constructed upon independent predictors for short and long postoperative survival. Results: In the final cohort (n = 95), 18 (18.9%) and 22 (23.2%) patients experienced short and long postoperative survival, respectively. Breast-preserving surgery, presence of multiple brain metastases and age ≥ 65 years at breast cancer diagnosis were identified as independent predictors of short postoperative survival. In turn, positive HER2 receptor status in brain metastases, time interval ≥ 3 years between breast cancer and brain metastases diagnosis and KPS ≥ 90% independently predicted long survival. The appropriate short and long survival scores showed higher diagnostic accuracy for the prediction of short (AUC = 0.773) and long (AUC = 0.775) survival than the breast Graded Prognostic Assessment score (AUC = 0.498/0.615). A cumulative survival score (total score) showed significant association with overall survival (p = 0.001). Conclusion: We identified predictors independently impacting the prognosis after BCBM surgery. After external validation, the presented scores might become useful tools for the selection of proper candidates for BCBM surgery. [ABSTRACT FROM AUTHOR]

Objective: Occurrence of brain metastases BM is associated with poor prognosis in patients with breast cancer (BC). Magnetic resonance imaging (MRI) is the standard of care in the diagnosis of BM and determines further treatment strategy. The aim of the present study was to evaluate the association between the radiographic markers of BCBM on MRI with other patients' characteristics and overall survival (OS). Methods: We included 88 female patients who underwent BCBM surgery in our institution from 2008 to 2019. Data on demographic, clinical, and histopathological characteristics of the patients and postoperative survival were collected from the electronic health records. Radiographic features of BM were assessed upon the preoperative MRI. Univariable and multivariable analyses were performed. Results: The median OS was 17 months. Of all evaluated radiographic markers of BCBM, only the presence of necrosis was independently associated with OS (14.5 vs 22.5 months, p = 0.027). In turn, intra-tumoral necrosis was more often in individuals with shorter time interval between BC and BM diagnosis (< 3 years, p = 0.035) and preoperative leukocytosis (p = 0.022). Moreover, dural affection of BM was more common in individuals with positive human epidermal growth factor receptor 2 status (p = 0.015) and supratentorial BM location (p = 0.024). Conclusion: Intra-tumoral necrosis demonstrated significant association with OS after BM surgery in patients with BC. The radiographic pattern of BM on the preoperative MRI depends on certain tumor and clinical characteristics of patients. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Persistent lymph nodes infiltration after neoadjuvant treatment remains a controversial topic in the treatment of stage III non-small-cell lung cancer (NSCLC). The aim of this study is to identify subgroups with persistent N2 disease, who could experience survival benefit from the addition of surgery. METHODS A retrospective mono-institutional study was conducted to analyse all patients with a final histopathology of NSCLC and persistent mediastinal disease after induction chemotherapy or chemoradiotherapy and surgery from January 1998 to June 2015. RESULTS A total of 145 patients (93 men, 52 women) fulfilled the inclusion criteria. The median age was 60 years (range 38–78). A total of 82 (56.5%) patients received a lobectomy, 48 (33.1%) a pneumonectomy, 11 (7.6%) a bilobectomy and 4 (2.6%) an anatomical segmentectomy; 128 (88.3%) were completely resected (R0). Operative mortality was 2.6% (4 patients), and morbidity was 35.2% (51 patients). Overall survival at 5 years was 47.3% (n  = 19) for single N2 (skip), 30.2% (n  = 16) for single N2 and N1 lymph nodes and under 5% (n  = 1) for multiple mediastinal stations disease. Overall survival at 5 years after lobectomy/bilobectomy was not statistically different than after pneumonectomy (33.5% vs 20.5%, P  = 0.082). Disease-free survival at 5 years was 30.6% (n  = 6) for ypN2a1, 23.4% (n  = 7) for ypN2a2 and under 5% (n  = 1) for ypN2b status. CONCLUSIONS Lobectomy or bilobectomy has to be taken into account as a potentially curative option with promising long-term results for patients after induction treatment and persistent single-station N2 involvement (skip or additionally N1 status). Trial registry number 14-6138-BO. [ABSTRACT FROM AUTHOR]

The optimal treatment for patients with locally advanced non-small-cell lung-cancer (NSCLC) cT4 cN0/1 cM0 is still under debate. The purpose of this study was to examine the long-term survival of cT4 cN0/1 cM0 NSCLC patients undergoing induction chemotherapy and concurrent radiochemotherapy before surgery. All consecutive patients with confirmed NSCLC (cT4 cN0/1 cM0) treated with neoadjuvant chemotherapy, concurrent radiochemotherapy (RT/CTx) (45–46 Gy) and surgical resection between 2000 and 2015 were included. According to the UICC guidelines (8th edition), T4 stage was reanalysed by an expert radiologist. The mediastinal staging was performed by systematic EBUS-TBNA or mediastinoscopy. The primary end-point was overall-survival (OS). The power to detect an increase of early tumour-associated mortality (hazard ratio > 3.5) within the first 5 years after treatment in comparison to late deaths beyond 96 months was >80%. Overall, 67 patients were treated with concurrent RT/CTx. T4 criteria were fulfilled by all patients, and multiple T4 criteria by 53 patients. Seventy percent of patients had an initial PET/CT staging. The median follow-up period was 134 months. OS rates at 2, 5, 10 and 15 years were 83.6 ± 4.5%, 65.4 ± 5.9%, 53.3 ± 6.3% and 36.6 ± 6.8%, respectively. A total of 44.8% of patients achieved a pathologic complete response. In multivariable analysis, ypT category was the most predictive factor. OS at 5 years for ypT0 (n = 31) was 80.5%, and ypT1 (n = 11) was 62.5%. Main sites of failure were brain and pulmonary metastases in seven and three patients, respectively. The intercurrent annual death rate was estimated from the survival curve beyond 96 months and was found to be 4.75% (95% CI 2.40–9.27%). No significant increased mortality was observed during the first 5 years (annual death rate: 8.31% [95% CI 5.60–12.24%], hazard-ratio = 1.72 [95% CI 0.81–3.65]). The effectiveness of this trimodality schedule is high in patients with cT4 cN0/1 cM0 NSCLC with excellent local control rates. Considering the annual death rate beyond 8 years of survival as an intercurrent death rate due to comorbidity, this treatment schedule reduces annual mortality to background even in the first 5 years after therapy. • Neoadjuvant radiochemotherapy in cT4 N0/1 NSCLC associated with ypT0-downstaging of 63%. • Patients have overall survival above 80% at 5-years after resection setting a benchmark. • Trimodal treatment reduces annual mortality to background even in 5 years post-therapy. [ABSTRACT FROM AUTHOR]

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