Anti-PD-(L)1 plus BRAF/MEK inhibitors (triplet therapy) after failure of immune checkpoint inhibition and targeted therapy in patients with advanced melanoma.

BACKGROUND: Effective treatment options are limited for patients with advanced melanoma who have progressed on immune checkpoint inhibitors (ICI) and targeted therapies (TT). Preclinical models support the combination of ICI with TT; however, clinical trials evaluating the efficacy of triplet combinations in first-line setting showed limited advantage compared to TT only. METHODS: We conducted a retrospective, multicenter study, that included patients with advanced melanoma who were treated with BRAF/MEK inhibitors in combination with an anti-PD-(L)1 antibody (triplet therapy) after failure of at least one anti-PD-(L)1-based therapy and one TT in seven major melanoma centers between February 2016 and July 2022. RESULTS: A total of 48 patients were included, of which 32 patients, 66.7% had brain metastases, 37 patients (77.1%) had three or more metastatic organs and 21 patients (43.8%) had three or more treatment lines. The median follow-up time was 31.4 months (IQR, 22.27-40.45 months). The treatment with triplet therapy resulted in an ORR of 35.4% (n = 17) and a DCR of 47.9% (n = 23). The median DOR was 5.9 months (range, 3.39-14.27 months). Patients treated with BRAF/MEK inhibitors as the last treatment line showed a slightly lower ORR (29.6%) compared to patients who received ICI or chemotherapy last (ORR: 42.9%). Grade 3-4 treatment-related adverse events occurred in 25% of patients (n = 12), with seven patients (14.6%) requiring discontinuation of treatment with both or either drug. CONCLUSIONS: Triplet therapy has shown activity in heavily pretreated patients with advanced melanoma and may represent a potential treatment regimen after failure of ICI and TT.

Long-Term Survival in Patients with Oligometastatic Non-Small Cell Lung Cancer by a Multimodality Treatment-Comparison with Stage III Disease.

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.

Adaptation Time as a Determinant of the Dosimetric Effectiveness of Online Adaptive Radiotherapy for Bladder Cancer.

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.

Impact of Modern Low Dose Involved Site Radiation Therapy on Normal Tissue Toxicity in Cervicothoracic Non-Hodgkin Lymphomas: A Biophysical Study.

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.

Fractionation versus Adaptation for Compensation of Target Volume Changes during Online Adaptive Radiotherapy for Bladder Cancer: Answers from a Prospective Registry.

Online adaptive radiotherapy (ART) allows adaptation of the dose distribution to the anatomy captured by with pre-adaptation imaging. ART is time-consuming, and thus intra-fractional deformations can occur. This prospective registry study analyzed the effects of intra-fraction deformations of clinical target volume (CTV) on the equivalent uniform dose (EUDCTV) of focal bladder cancer radiotherapy. Using margins of 5-10 mm around CTV on pre-adaptation imaging, intra-fraction CTV-deformations found in a second imaging study reduced the 10th percentile of EUDCTV values per fraction from 101.1% to 63.2% of the prescribed dose. Dose accumulation across fractions of a series was determined with deformable-image registration and worst-case dose accumulation that maximizes the correlation of cold spots. A strong fractionation effect was demonstrated-the EUDCTV was above 95% and 92.5% as determined by the two abovementioned accumulation methods, respectively, for all series of dose fractions. A comparison of both methods showed that the fractionation effect caused the EUDCTV of a series to be insensitive to EUDCTV-declines per dose fraction, and this could be explained by the small size and spatial variations of cold spots. Therefore, ART for each dose fraction is unnecessary, and selective ART for fractions with large inter-fractional deformations alone is sufficient for maintaining a high EUDCTV for a radiotherapy series.

Giant middle mediastinal lesions: when tumor size correlates with mesenchymal origin-a retrospective single-center analysis.

Background: The International Thymic Malignancy Interest Group (ITMIG) proposed an internationally accepted division of the mediastinum into three compartments based on computed tomography (CT): anterior (prevascular), middle (visceral) and posterior (paravertebral) compartment. There is no generally accepted definition for the term "giant" when applied to middle mediastinal lesions. We defined the term "giant" and described our surgical experience in treating patients with giant lesions of the middle mediastinum. Methods: CT imaging of patients operated in our center from January 2016 to August 2021 for mediastinal lesions was reviewed. Lesions were categorized to one of the ITMIG-defined compartments. Lesion size at diagnosis was measured at its largest diameter on axial CT imaging. Giant middle mediastinal lesions were defined as lesions having a size ≥90th percentile of our middle mediastinal lesion cohort. Patients with giant middle mediastinal lesions were further analyzed. Results: Thirty-six patients (23%) had lesions located in the middle mediastinal compartment. Most common diagnoses were mediastinal cysts (n=10, 28%), metastatic lesions (n=6, 17%), lymphomas (n=5, 14%), and sarcomas (n=3, 8%). Ninetieth percentile lesion size was 73 mm. As per definition, four patients had giant middle mediastinal lesions. All these four lesions were of mesenchymal origin including oesophageal leiomyoma, synovial sarcoma, leiomyosarcoma and undifferentiated round cell sarcoma. Resection was performed through posterolateral thoracotomy or sternotomy, with or without cardiopulmonary bypass. Conclusions: The term "giant" could be defined as a mass larger or equal to 73 mm. This definition selected specifically lesions with mesenchymal origin and may therefore guide diagnostic algorithm and patient management.

Location of Recurrences after Trimodality Treatment for Glioblastoma with Respect to the Delivered Radiation Dose Distribution and Its Influence on Prognosis.

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.

Comparison of Online-Onboard Adaptive Intensity-Modulated Radiation Therapy or Volumetric-Modulated Arc Radiotherapy With Image-Guided Radiotherapy for Patients With Gynecologic Tumors in Dependence on Fractionation and the Planning Target Volume Margin.

Importance: Patients with newly diagnosed locally advanced cervical carcinomas or recurrences after surgery undergoing radiochemotherapy whose tumor is unsuited for a brachytherapy boost need high-dose percutaneous radiotherapy with small margins to compensate for clinical target volume deformations and set-up errors. Cone-beam computed tomography-based online adaptive radiotherapy (ART) has the potential to reduce planning target volume (PTV) margins below 5 mm for these tumors. Objective: To compare online ART technologies with image-guided radiotherapy (IGRT) for gynecologic tumors. Design, Setting, and Participants: This comparative effectiveness study comprised all 7 consecutive patients with gynecologic tumors who were treated with ART with artificial intelligence segmentation from January to May 2022 at the West German Cancer Center. All adapted treatment plans were reviewed for the new scenario of organs at risk and target volume. Dose distributions of adapted and scheduled plans optimized on the initial planning computed tomography scan were compared. Exposure: Online ART for gynecologic tumors. Main Outcomes and Measures: Target dose coverage with ART compared with IGRT for PTV margins of 5 mm or less in terms of the generalized equivalent uniform dose (gEUD) without increasing the gEUD for the organs at risk (bladder and rectum). Results: The first 10 treatment series among 7 patients (mean [SD] age, 65.7 [16.5] years) with gynecologic tumors from a prospective observational trial performed with ART were compared with IGRT. For a clinical PTV margin of 5 mm, IGRT was associated with a median gEUD decrease in the interfractional clinical target volume of -1.5% (90% CI, -31.8% to 2.9%) for all fractions in comparison with the planned dose distribution. Online ART was associated with a decrease of -0.02% (90% CI, -3.2% to 1.5%), which was less than the decrease with IGRT (P < .001). This was not associated with an increase in the gEUD for the bladder or rectum. For a PTV margin of 0 mm, the median gEUD deviation with IGRT was -13.1% (90% CI, -47.9% to 1.6%) compared with 0.1% (90% CI, -2.3% to 6.6%) with ART (P < .001). The benefit associated with ART was larger for a PTV margin of 0 mm than of 5 mm (P = .004) due to spreading of the cold spot at the clinical target volume margin from fraction to fraction with a median SD of 2.4 cm (90% CI, 1.9-3.4 cm) for all patients. Conclusions and Relevance: This study suggests that ART is associated with an improvement in the percentage deviation of gEUD for the interfractional clinical target volume compared with IGRT. As the gain of ART depends on fractionation and PTV margin, a strategy is proposed here to switch from IGRT to ART, if the delivered gEUD distribution becomes unfavorable in comparison with the expected distribution during the course of treatment.

Experimental Examination of Conventional, Semi-Automatic, and Automatic Volumetry Tools for Segmentation of Pulmonary Nodules in a Phantom Study.

The aim of this study is to examine the precision of semi-automatic, conventional and automatic volumetry tools for pulmonary nodules in chest CT with phantom N1 LUNGMAN. The phantom is a life-size anatomical chest model with pulmonary nodules representing solid and subsolid metastases. Gross tumor volumes (GTVis) were contoured using various approaches: manually (0); as a means of semi-automated, conventional contouring with (I) adaptive-brush function; (II) flood-fill function; and (III) image-thresholding function. Furthermore, a deep-learning algorithm for automatic contouring was applied (IV). An intermodality comparison of the above-mentioned strategies for contouring GTVis was performed. For the mean GTVref (standard deviation (SD)), the interquartile range (IQR)) was 0.68 mL (0.33; 0.34-1.1). GTV segmentation was distributed as follows: (I) 0.61 mL (0.27; 0.36-0.92); (II) 0.41 mL (0.28; 0.23-0.63); (III) 0.65 mL (0.35; 0.32-0.90); and (IV) 0.61 mL (0.29; 0.33-0.95). GTVref was found to be significantly correlated with GTVis (I) p < 0.001, r = 0.989 (III) p = 0.001, r = 0.916, and (IV) p < 0.001, r = 0.986, but not with (II) p = 0.091, r = 0.595. The Sørensen-Dice indices for the semi-automatic tools were 0.74 (I), 0.57 (II) and 0.71 (III). For the semi-automatic, conventional segmentation tools evaluated, the adaptive-brush function (I) performed closest to the reference standard (0). The automatic deep learning tool (IV) showed high performance for auto-segmentation and was close to the reference standard. For high precision radiation therapy, visual control, and, where necessary, manual correction, are mandatory for all evaluated tools.

Prediction of malignant lymph nodes in NSCLC by machine-learning classifiers using EBUS-TBNA and PET/CT.

Accurate determination of lymph-node (LN) metastases is a prerequisite for high precision radiotherapy. The primary aim is to characterise the performance of PET/CT-based machine-learning classifiers to predict LN-involvement by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in stage-III NSCLC. Prediction models for LN-positivity based on [18F]FDG-PET/CT features were built using logistic regression and machine-learning models random forest (RF) and multilayer perceptron neural network (MLP) for stage-III NSCLC before radiochemotherapy. A total of 675 LN-stations were sampled in 180 patients. The logistic and RF models identified SUVmax, the short-axis LN-diameter and the echelon of the considered LN among the most important parameters for EBUS-positivity. Adjusting the sensitivity of machine-learning classifiers to that of the expert-rater of 94.5%, MLP (P = 0.0061) and RF models (P = 0.038) showed lower misclassification rates (MCR) than the standard-report, weighting false positives and false negatives equally. Increasing the sensitivity of classifiers from 94.5 to 99.3% resulted in increase of MCR from 13.3/14.5 to 29.8/34.2% for MLP/RF, respectively. PET/CT-based machine-learning classifiers can achieve a high sensitivity (94.5%) to detect EBUS-positive LNs at a low misclassification rate. As the specificity decreases rapidly above that level, a combined test of a PET/CT-based MLP/RF classifier and EBUS-TBNA is recommended for radiation target volume definition.

Feasibility, Method and Early Outcome of Image-Guided Volumetric Modulated Arc Radiosurgery Followed by Resection for AJCC Stage IIA-IIIB High-Risk Large Intraocular Melanoma.

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.

[68Ga]FAPI-PET/CT for radiation therapy planning in biliary tract, pancreatic ductal adeno-, and adenoidcystic carcinomas.

Biliary-tract-carcinomas (BTC), pancreatic-ductal-adenocarcinomas (PDAC) and adenoidcystic-carcinomas (AC) have in common that they are traditionally treated with large clinical-target-volumes (CTV). The aim of this study is to examine the impact of pretreatment-[68Ga]FAPI-PET/CT on target-volume-definition and posttreatment-[68Ga]FAPI-PET/CT-response-assessment for BTC-, PDAC- and AC-patients referred to radiation-therapy. All consecutive BTC-, PDAC-, and AC-patients who received pretreatment-[68Ga]FAPI-PET/CT±[18F]FDG-PET/CT were included from 01.01.2020 to 01.03.2022. MTV and SUVmax were separately generated based on [68Ga]FAPI- and [18F]FDG-PET/CT-images. A [68Ga]FAPI- and [18F]FDG-based-CTV was defined. Treatment-plans were compared. Treatment-response was reassessed by a second [68Ga]FAPI-PET/CT and [18F]FDG-PET/CT after treatment-completion. Intermodality comparison of lesion-to-background-ratios [SUVmax_lesion/SUVmean_background] for individual timepoints t1 and t2 revealed significant higher values for [68Ga]FAPI compared to [18F]FDG (t1, p = 0.008; t2, p = 0.005). Intermodality comparison of radiation-therapy-plans showed that [68Ga]FAPI-based planning resulted in D100% = 97.2% and V95% = 98.8% for the [18F]FDG-MTV. [18F]FDG-based-planning resulted in D100% = 35.9% and V95% = 78.1% for [68Ga]FAPI-MTV. [18F]FDG-based-planning resulted only in 2 patients in V95% > 95% for [68Ga]FAPI-MTV, and in 1 patient in D100% > 97% for [68Ga]FAPI-MTV. GTV-coverage in terms of V95% was 76.4% by [18F]FDG-based-planning and 99.5% by [68Ga]FAPI-based-planning. Pretreatment [68Ga]FAPI-PET/CT enhances radiation-treatment-planning in this particular group of patients. While perilesional and tumoral follow-up [18F]FDG-uptake behaved uniformly, perilesional and tumoral reaction may differ in follow-up [68Ga]FAPI-imaging. Complementary [68Ga]FAPI- and [18F]FDG-imaging enhance treatment-response-assessment.

Effectiveness of durvalumab consolidation in stage III non-small-cell lung cancer: focus on treatment selection and prognostic factors.

The pivotal PACIFIC trial defined durvalumab consolidation as the new standard of care in patients with stage III non-small-cell lung cancer treated with definitive radiochemotherapy. The authors characterized the durvalumab effect after induction chemotherapy according to the ESPATUE trial and definitive radiochemotherapy. All consecutive patients with stage III non-small-cell lung cancer receiving definitive radiochemotherapy between January 2017 and February 2020 were included. Primary end points were progression-free survival and overall survival. Altogether, 160 patients (75 PD-L1-positive, 62 PD-L1-negative, 23 unknown) received definitive radiochemotherapy, 146 (91%) of whom received prior induction chemotherapy. Durvalumab consolidation showed high effectiveness overall and in the good-risk group according to the PACIFIC trial (log-rank test: p < 0.005). Hazard ratios for progression-free survival and overall survival were at the lower limits of those in the PACIFIC trial. These results were robust to adjustment for potential confounders by propensity score weighting. Eastern Cooperative Oncology Group (ECOG) performance status was the most important pretreatment prognostic factor.

The PACIFIC trial is the major landmark trial for stage III non-small-cell lung cancer (NSCLC) patients treated with combined chemoradiation and defined immunotherapy as maintenance treatment and the new standard of care in patients with stage III NSCLC. Here the authors report a retrospective study comparing consecutive stage III NSCLC patients receiving induction chemotherapy and definitive chemoradiation with or without durvalumab consolidation in a high-volume lung cancer center. After induction chemotherapy, chemoradiation and immune checkpoint inhibition, a durable and remarkable tumor response can be achieved in the clinical routine. Consolidation immunotherapy with durvalumab can be confirmed as a strong innovative therapeutic option in NSCLC in almost all subgroups of patients.

Long-term survival of patients with central or > 7 cm T4 N0/1 M0 non-small-cell lung cancer treated with definitive concurrent radiochemotherapy in comparison to trimodality treatment.

ABSTARCT: BACKGROUND: To examine long-term-survival of cT4 cN0/1 cM0 non-small-cell lung carcinoma (NSCLC) patients undergoing definitive radiochemotherapy (ccRTx/CTx) in comparison to the trimodality treatment, neoadjuvant radiochemotherapy followed by surgery, at a high volume lung cancer center. METHODS: All consecutive patients with histopathologically confirmed NSCLC (cT4 cN0/1 cM0) with a curative-intent-to-treat ccRTx/CTx were included between 01.01.2001 and 01.07.2019. Mediastinal involvement was excluded by systematic EBUS-TBNA or mediastinoscopy. Following updated T4-stage-defining-criteria initial staging was reassessed by an expert-radiologist according to UICC-guidelines [8th edition]. Outcomes were compared with previously reported results from patients of the same institution with identical inclusion criteria, who had been treated with neoadjuvant radiochemotherapy and resection. Factors for treatment selection were documented. Endpoints were overall-survival (OS), progression-free-survival (PFS), and cumulative incidences of isolated loco-regional failures, distant metastases, secondary tumors as well as non-cancer deaths within the first year. RESULTS: Altogether 46 consecutive patients with histopathologically confirmed NSCLC cT4 cN0/1 cM0 [cN0 in 34 and cN1 in 12 cases] underwent ccRTx/CTx after induction chemotherapy (iCTx). Median follow-up was 133 months. OS-rates at 3-, 5-, and 7-years were 74.9%, 57.4%, and 57.4%, respectively. Absolute OS-rate of ccRTx/CTx at 5 years were within 10% of the trimodality treatment reference group (Log-Rank p = 0.184). The cumulative incidence of loco-regional relapse was higher after iCTx + ccRT/CTx (15.2% vs. 0% at 3 years, p = 0.0012, Gray's test) while non-cancer deaths in the first year were lower than in the trimodality reference group (0% vs 9.1%, p = 0.0360, Gray's test). None of the multiple recorded prognostic parameters were significantly associated with survival after iCTx + ccRT/CTx: Propensity score weighting for adjustment of prognostic factors between iCTx + ccRT/CTx and trimodality treatment did not change the results of the comparisons. CONCLUSIONS: Patients with cT4 N0/1 M0 NSCLC have comparable OS with ccRTx/CTx and trimodality treatment. Loco-regional relapses were higher and non-cancer related deaths lower with ccRTx/CTx. Definitive radiochemotherapy is an adequate alternative for patients with an increased risk of surgery-related morbidity.

Time interval between the diagnosis of breast cancer and brain metastases impacts prognosis after metastasis surgery.

PURPOSE: Breast cancer (BC) is the most frequently diagnosed tumor entity in women. Occurring at different time intervals (TI) after BC diagnosis, brain metastases (BM) are associated with poor prognosis. We aimed to identify the risk factors related to and the clinical impact of timing on overall survival (OS) after BM surgery. METHODS: We included 93 female patients who underwent BC BM surgery in our institution (2008-2019). Various clinical, radiographic, and histopathologic markers were analyzed with respect to TI and OS. RESULTS: The median TI was 45.0 months (range: 9-334.0 months). Fifteen individuals (16.1%) showed late occurrence of BM (TI ≥ 10 years), which was independently related to invasive lobular BC [adjusted odds ratio (aOR) 9.49, 95% confidence interval (CI) 1.47-61.39, p = 0.018] and adjuvant breast radiation (aOR 0.12, 95% CI 0.02-0.67, p = 0.016). Shorter TI (< 5 years, aOR 4.28, 95% CI 1.46-12.53, p = 0.008) was independently associated with postoperative survival and independently associated with the Union for International Cancer Control stage (UICC) III-IV of BC (aOR 4.82, 95% CI 1.10-21.17, p = 0.037), midline brain shift in preoperative imaging (aOR10.35, 95% CI 1.09-98.33, p = 0.042) and identic estrogen receptor status in BM (aOR 4.56, 95% CI 1.35-15.40, p = 0.015). CONCLUSIONS: Several factors seem to influence the period between BC and BM. Occurrence of BM within five years is independently associated with poorer prognosis after BM surgery. Patients with invasive lobular BC and without adjuvant breast radiation are more likely to develop BM after a long progression-free survival necessitating more prolonged cancer aftercare of these individuals.

Prognostic Factors for Leiomyosarcoma with Isolated Metastases to the Lungs: Impact of Metastasectomy.

BACKGROUND: Leiomyosarcoma (LMS) most frequently metastasizes to the lung. Metastatic LMS is considered incurable. Selected patients may benefit from pulmonary metastasectomy (PM) within multimodal therapy. This study analyzed the prognostic relevance of clinicopathologic factors in these patients. METHODS: Patients with metastatic LMS to the lung treated in our center from 2004 to 2020 were included in this single-center retrospective study. Overall survival (OS), progression-free survival (PFS), and prognostic factors were analyzed. RESULTS: The study had 64 patients (33 males, 52%) with metastatic LMS to the lung. The 5-year OS was 55% after the diagnosis of pulmonary metastases. Age older than 60 years at the primary tumor diagnosis, primary tumor larger than 70 mm, and five or more lung metastases were associated with poorer OS. Of the 64 patients, 44 underwent PM. The postoperative mortality rate was 0%. The patients selected for PM were younger and had smaller primary tumors, fewer metastases, and metastases that more often were metachronous. Metastasis grade (G1 vs. G2/3) and size (20-mm cutoff) were significant prognostic factors for OS (p = 0.05) and PFS (p = 0.028) after PM, respectively. The 44 patients who underwent PM had a survival benefit compared with the patients who were selected but did not undergo PM (n = 6) and the patients who were not selected for PM (n = 14). Three patients (7%) were alive and free of disease at the last follow-up visit respectively 5.5, 9, and 12 years after PM. CONCLUSIONS: For patients with leiomyosarcoma, PM is safe. Despite aggressive multimodal treatment, most patients will experience recurrence and eventually die of their disease. However, a small subgroup of patients could potentially be cured after PM.

Prediction of Short and Long Survival after Surgery for 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.

Radiographic markers of breast cancer brain metastases: relation to clinical characteristics and postoperative outcome.

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.