Local control and possibility of tailored salvage after hypofractionated stereotactic radiotherapy of the cavity after brain metastases resection

Source at https://doi.org/10.1002/cam4.1486.In patients undergoing surgical resection of brain metastases, the risk of local recurrence remains high. Adjuvant whole brain radiation therapy (WBRT) can reduce the risk of local relapse but fails to improve overall survival. At two tertiary care centers in Germany, a retrospective study was performed to evaluate the role of hypofractionated stereotactic radiotherapy (HFSRT) in patients with brain metastases after surgical resection. In particular, need for salvage treatment, for example, WBRT, surgery, or stereotactic radiosurgery (SRS), was evaluated. Both intracranial local (LF) and locoregional (LRF) failures were analyzed. A total of 181 patients were treated with HFSRT of the surgical cavity. In addition to the assessment of local control and distant intracranial control, we analyzed treatment modalities for tumor recurrence including surgical strategies and reirradiation. Imaging follow‐up for the evaluation of LF and LRF was available in 159 of 181 (88%) patients. A total of 100 of 159 (63%) patients showed intracranial progression after HFSRT. A total of 81 of 100 (81%) patients received salvage therapy. Fourteen of 81 patients underwent repeat surgery, and 78 of 81 patients received radiotherapy as a salvage treatment (53% WBRT). Patients with single or few metastases distant from the initial site or with WBRT in the past were retreated by HFSRT (14%) or SRS, 33%. Some patients developed up to four metachronous recurrences, which could be salvaged successfully. Eight (4%) patients experienced radionecrosis. No other severe side effects (CTCAE≥3) were observed. Postoperative HFSRT to the resection cavity resulted in a crude rate for local control of 80.5%. Salvage therapy for intracranial progression was commonly needed, typically at distant sites. Salvage therapy was performed with WBRT, SRS, and surgery or repeated HFSRT of the resection cavity depending on the tumor spread and underlying histology. Prospective studies are warranted to clarify whether or not the sequence of these therapies is important in terms of quality of life, risk of radiation necrosis, and likelihood of neurological cause of death

Heat Shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) – From Preclinical Studies to a Clinical Phase II Trial

Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups

Paving the Road for Modern Particle Therapy - What Can We Learn from the Experience Gained with Fast Neutron Therapy in Munich?

While neutron therapy was a highly topical subject in the 70s and 80s, today there are only a few remaining facilities offering fast neutron therapy (FNT). Nevertheless, up to today more than 30,000 patients were treated with neutron therapy. For some indications like salivary gland tumors and malignant melanoma, there is clinical evidence that the addition of FNT leads to superior local control compared to photon treatment alone. FNT was available in Munich from 1985 until 2000 at the Reactor Neutron Therapy (RENT) facility. Patient treatment continued at the new research reactor FRM II in 2007 under improved treatment conditions, and today it can still be offered to selected patients as an individual treatment option. As there is a growing interest in high-linear energy transfer (LET) therapy with new hadron therapy centers emerging around the globe, the clinical data generated by neutron therapy might help to develop biologically driven treatment planning algorithms. Also FNT might experience its resurgence as a combinational partner of modern immunotherapies

Heat Shock Protein 70 (Hsp70) Peptide Activated Natural Killer (NK) Cells for the Treatment of Patients with Non-Small Cell Lung Cancer (NSCLC) after Radiochemotherapy (RCTx) – From Preclinical Studies to a Clinical Phase II Trial

Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and non-small cell lung cancer (NSCLC) in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2014. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum-based radiochemotherapy (RCTx) with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with RCTx alone. As secondary endpoints overall survival, toxicity, quality-of-life, and biological responses will be determined in both study groups

Stereotactic radiosurgery of brain metastases.

Brain metastases are a common problem in solid malignancies and still represent a major cause of morbidity and mortality. With the ongoing improvement in systemic therapies, the expectations on the efficacy of brain metastases directed treatment options are growing. As local therapies against brain metastases continue to evolve, treatment patterns have shifted from a palliative "one-treatment-fits-all" towards an individualized, patient adapted approach. In this article we review the evidence for stereotactic radiation treatment based on the current literature. Stereotactic radiosurgery (SRS) as a local high precision approach for the primary treatment of asymptomatic brain metastases has gained wide acceptance. It leads to lasting tumor control with only minor side effects compared to whole brain radiotherapy, since there is only little dose delivered to the healthy brain. The same holds true for hypofractionated stereotactic radiotherapy (HFSRT) for large metastases or for lesions close to organs at risk (e.g. the brainstem). New treatment indications such as neoadjuvant SRS followed by surgical resection or postoperative local therapy to the resection cavity show promising data and are also highlighted in this manuscript. With the evolution of local treatment options, optimal patient selection becomes more and more crucial. This article aims to aid decision making by outlining prognostic factors, treatment techniques and indications and common dose prescriptions

HFSRT of the resection cavity in patients with brain metastases.

Aim of this single center, retrospective study was to assess the efficacy and safety of linear accelerator-based hypofractionated stereotactic radiotherapy (HFSRT) to the resection cavity of brain metastases after surgical resection. Local control (LC), locoregional control (LRC = new brain metastases outside of the treatment volume), overall survival (OS) as well as acute and late toxicity were evaluated.46 patients with large (> 3 cm) or symptomatic brain metastases were treated with HFSRT. Median resection cavity volume was 14.16 cm(3) (range 1.44-38.68 cm(3)) and median planning target volume (PTV) was 26.19 cm(3) (range 3.45-63.97 cm(3)). Patients were treated with 35 Gy in 7 fractions prescribed to the 95-100 % isodose line in a stereotactic treatment setup. LC and LRC were assessed by follow-up magnetic resonance imaging.The 1-year LC rate was 88 % and LRC was 48 %; 57% of all patients showed cranial progression after HFSRT (4% local, 44% locoregional, 9% local and locoregional). The median follow-up was 19 months; median OS for the whole cohort was 25 months. Tumor histology and recursive partitioning analysis score were significant predictors for OS. HFSRT was tolerated well without any severe acute side effects > grade 2 according to CTCAE criteria.HFSRT after surgical resection of brain metastases was tolerated well without any severe acute side effects and led to excellent LC and a favorable OS. Since more than half of the patients showed cranial progression after local irradiation of the resection cavity, close patient follow-up is warranted. A prospective evaluation in clinical trials is currently being performed

Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress

We describe here the mechanism of platelet adhesion to immobilized von Willebrand factor (VWF) and subsequent formation of platelet-derived microparticles mediated by glycoprotein Ibα (GPIbα) under high shear stress. As visualized in whole blood perfused in a flow chamber, platelet attachment to VWF involved one or few membrane areas of 0.05 to 0.1 μm2 that formed discrete adhesion points (DAPs) capable of resisting force in excess of 160 pN. Under the influence of hydrodynamic drag, membrane tethers developed between the moving platelet body and DAPs firmly adherent to immobilized VWF. Continued stretching eventually caused the separation of many such tethers, leaving on the surface tube-shaped or spherical microparticles with a diameter as low as 50 to 100 nm. Adhesion receptors (GPIbα, αIIbβ3) and phosphatidylserine were expressed on the surface of these microparticles, which were procoagulant. Shearing platelet-rich plasma at the rate of 10 000 s–1 in a cone-and-plate viscosimeter increased microparticle counts up to 55-fold above baseline. Blocking the GPIb-VWF interaction abolished microparticle generation in both experimental conditions. Thus, a biomechanical process mediated by GPIbα-VWF bonds in rapidly flowing blood may not only initiate platelet arrest onto reactive vascular surfaces but also generate procoagulant microparticles that further enhance thrombus formation

In-field stereotactic body radiotherapy (SBRT) reirradiation for pulmonary malignancies as a multicentre analysis of the German Society of Radiation Oncology (DEGRO)

Data of thoracic in-field reirradiation with two courses of stereotactic body radiotherapy (SBRT) is scarce. Aim of this study is to investigate feasibility and safety of this approach. Patients with a second course of thoracic SBRT and planning target volume (PTV) overlap were analyzed in this retrospective, multicenter study. All plans and clinical data were centrally collected. 27 patients from 8 centers have been amenable for evaluation: 12 with non-small-cell lung cancer, 16 with metastases, treated from 2009 (oldest first course) to 2020 (latest second course). A median dose of 38.5 Gy to the 65%-isodose over a median of 5 fractions was prescribed in the first course and 40 Gy in 5 fractions for the second SBRT-course. Median PTV of the second SBRT was 29.5 cm$^{3}$, median PTV overlap 22 cm$^{3}$. With a median interval of 20.2 months between the two SBRT-courses, 1-year OS, and -LCR were 78.3% and 70.3% respectively. 3 patients developed grade 1 and one grade 2 pneumonitis. No grade > 2 toxicity was observed. Peripheral location and dose were the only factors correlating with tumor control. A second SBRT-course with PTV overlap appears safe and achieves reasonable local control

Textural features in pre-treatment [F18]-FDG-PET/CT are correlated with risk of local recurrence and disease-specific survival in early stage NSCLC patients receiving primary stereotactic radiation therapy

BACKGROUND: Textural features in FDG-PET have been shown to provide prognostic information in a variety of tumor entities. Here we evaluate their predictive value for recurrence and prognosis in NSCLC patients receiving primary stereotactic radiation therapy (SBRT). METHODS: 45 patients with early stage NSCLC (T1 or T2 tumor, no lymph node or distant metastases) were included in this retrospective study and followed over a median of 21.4 months (range 3.1-71.1). All patients were considered non-operable due to concomitant disease and referred to SBRT as the primary treatment modality. Pre-treatment FDG-PET/CT scans were obtained from all patients. SUV and volume-based analysis as well as extraction of textural features based on neighborhood gray-tone difference matrices (NGTDM) and gray-level co-occurence matrices (GLCM) were performed using InterView Fusion™ (Mediso Inc., Budapest). The ability to predict local recurrence (LR), lymph node (LN) and distant metastases (DM) was measured using the receiver operating characteristic (ROC). Univariate and multivariate analysis of overall and disease-specific survival were executed. RESULTS: 7 out of 45 patients (16%) experienced LR, 11 (24%) LN and 11 (24%) DM. ROC revealed a significant correlation of several textural parameters with LR with an AUC value for entropy of 0.872. While there was also a significant correlation of LR with tumor size in the overall cohort, only texture was predictive when examining T1 (tumor diameter 3 cm) subgroups. No correlation of the examined PET parameters with LN or DM was shown. In univariate survival analysis, both heterogeneity and tumor size were predictive for disease-specific survival, but only texture determined by entropy was determined as an independent factor in multivariate analysis (hazard ratio 7.48, p = .016). Overall survival was not significantly correlated to any examined parameter, most likely due to the high comorbidity in our cohort. CONCLUSIONS: Our study adds to the growing evidence that tumor heterogeneity as described by FDG-PET texture is associated with response to radiation therapy in NSCLC. The results may be helpful into identifying patients who might profit from an intensified treatment regime, but need to be verified in a prospective patient cohort before being incorporated into routine clinical practice

Heat shock protein 70 (Hsp70) peptide activated Natural Killer (NK) cells for the treatment of patients with Non-Small Cell Lung Cancer (NSCLC) after radiochemotherapy (RCTx) - from preclinical studies to a clinical phase II trial.

Heat shock protein 70 (Hsp70) is frequently overexpressed in tumor cells. An unusual cell surface localization could be demonstrated on a large variety of solid tumors including lung, colorectal, breast, squamous cell carcinomas of the head and neck, prostate and pancreatic carcinomas, glioblastomas, sarcomas and hematological malignancies, but not on corresponding normal tissues. A membrane (m)Hsp70-positive phenotype can be determined either directly on single cell suspensions of tumor biopsies by flow cytometry using cmHsp70.1 monoclonal antibody or indirectly in the serum of patients using a novel lipHsp70 ELISA. A mHsp70-positive tumor phenotype has been associated with highly aggressive tumors, causing invasion and metastases and resistance to cell death. However, natural killer (NK), but not T cells were found to kill mHsp70-positive tumor cells after activation with a naturally occurring Hsp70 peptide (TKD) plus low dose IL-2 (TKD/IL-2). Safety and tolerability of ex vivo TKD/IL-2 stimulated, autologous NK cells has been demonstrated in patients with metastasized colorectal and NSCLC in a phase I clinical trial. Based on promising clinical results of the previous study, a phase II randomized clinical study was initiated in 2015. The primary objective of this multicenter proof-of-concept trial is to examine whether an adjuvant treatment of NSCLC patients after platinum based radiochemotherapy with TKD/IL-2 activated, autologous NK cells is clinically effective. As a mHsp70-positive tumor phenotype is associated with poor clinical outcome only mHsp70-positive tumor patients will be recruited into the trial. The primary endpoint of this study will be the comparison of the progression-free survival of patients treated with ex vivo activated NK cells compared to patients who were treated with radiochemotherapy alone. As secondary endpoints overall survival, toxicity, quality-of-life and biological responses will be determined in both study groups