Dose-intensified stereotactic body radiotherapy for painful vertebral metastases: A randomized phase 3 trial.

BACKGROUND: The purpose of this randomised study was to determine whether dose-intensified stereotactic body radiotherapy (SBRT) for painful vertebral metastases results in increased rates of pain improvement compared with conventional external beam radiotherapy (cEBRT) (control) 6 months after treatment. METHODS: This randomized, controlled phase 3 trial was conducted between November 2016 and January 2023, when it was stopped early. Patients were eligible if they were aged 18 years or older; had one or two painful, stable, or potentially unstable vertebral metastases; and had a life expectancy of 1 year or longer according to the investigator's estimates. Patients received 48.5 grays (Gy) in 10 fractions (with epidural involvement) or 40 Gy in five fractions (without epidural involvement) in the SBRT group and 30 Gy in 10 fractions or 20 Gy in five fractions in the cEBRT group, respectively. The primary end point was an improvement in the pain score at the treated site by at least 2 points (on a visual analog scale from 0 to 10 points) at 6-month follow-up. Data were analyzed on an intention-to-treat and per-protocol basis. RESULTS: Of 214 patients who were screened for eligibility, 63 were randomized 1:1 between SBRT (33 patients with 36 metastases) and cEBRT (30 patients with 31 metastases). The median age of all patients was 66 years, and 40 patients were men (63.5%). In the intention-to-treat analysis, the 6-month proportion of patients who had metastases with pain reduction by 2 or more points was significantly higher in the SBRT group versus the control group (69.4% vs. 41.9%, respectively; two-sided p = .02). Changes in opioid medication intake relative to baseline were nonsignificant between the groups. No differences were observed in vertebral compression fracture or adverse event rates between the groups. CONCLUSIONS: Dose-intensified SBRT improved pain score more effectively than cEBRT at 6 months.

Treatment of ambulatory patients with metastatic epidural spinal cord compression: a systematic review and meta-analysis.

OBJECTIVE: Approximately 10% of patients with spinal metastases develop metastatic epidural spinal cord compression (MESCC), which left undiagnosed and untreated can lead to the loss of ambulation. Timely diagnosis and efficient multidisciplinary treatment are critically important to optimize neurological outcomes. This meta-analysis aimed to determine the most efficient treatment for ambulatory patients with MESCC. METHODS: The authors conducted a systematic review and meta-analysis of the treatment of mobile patients with MESCC in terms of outcomes described as local control (LC), ambulatory function, quality of life (QOL), morbidity, and overall survival (OS). RESULTS: Overall, 54 papers (4101 patients) were included. A trend toward improved LC with stereotactic body radiotherapy (SBRT) compared with conventional external beam radiotherapy (cEBRT) was demonstrated: random effects modeling 1-year LC rate 86% (95% CI 84%-88%) versus 81% (95% CI 74%-86%) (p > 0.05), respectively, and common effects modeling 1-year LC rate 85% (95% CI 82%-87%) versus 76% (95% CI 74%-78%) (p < 0.05). Surgery followed by adjuvant radiotherapy, either cEBRT or SBRT, showed no significant benefit in either LC (OR 0.88, 95% CI 0.65-1.19) or ambulatory function (OR 1.51, 95% CI 0.83-2.74) compared with radiotherapy without surgery. There was a significant benefit of surgery compared with cEBRT regarding QOL, and furthermore SBRT alone provided long-term improvement in QOL. The type of treatment was not a significant predictor of OS, but fully ambulatory status was significantly associated with improved OS (HR 0.46-0.52, relative risk 1.79-2.3). Radiation-induced myelopathy is a rare complication of SBRT (2 patients [0.1%] in the included papers). The morbidity rate associated with surgery was relatively high, with a 10% wound complication rate and 1.6% hardware-failure rate. CONCLUSIONS: SBRT is an extremely promising treatment modality being integrated into treatment algorithms and provides durable LC. In mobile patients with MESCC, surgery does not improve LC, survival, or ambulatory function; nonetheless, there is a significant benefit of surgery in terms of QOL. In patients with MESCC without neurological deficit, the role of surgery is still debatable as studies demonstrate good LC for patients who undergo SBRT without preceding surgery. However, surgery can provide safe margins for the administration of the ablative dose of SBRT to the entire tumor volume within the constraints of spinal cord tolerance. Further randomized controlled trials are needed on the benefit of surgery before SBRT in mobile patients with MESCC. With the excellent results of separation surgery and SBRT, the role of highly invasive vertebrectomy is diminishing given the complication rate and morbidity of these procedures.

Long-Term Results of a Phase 1 Dose Escalation Trial of Ablative Stereotactic Body Radiation Therapy.

PURPOSE: Stereotactic body radiation therapy is increasingly used for oligometastatic disease as well as palliation, but treatment protocols for nonspine bone and nodal metastases are lacking, with a wide variety of schedules applied. METHODS AND MATERIALS: A prospective dose-escalation trial was initiated, involving 90 patients, among whom 52 (58%) had primary prostate tumors, 13 had breast tumors (14%), and 25 (28%) had other primary tumor types. All visible lymph node or nonspine bone oligometastases were treated in 3 consecutive cohorts: 5 × 7.0 Gy, 3 × 10.0 Gy, or 1 × 20.0 Gy. RESULTS: Initial results revealed no dose-limiting toxicity after a median follow-up of 17.2 months. This update provides information on long-term toxicity, local failure (LF), and progression-free survival (PFS). After a median follow-up of 50 months, no new safety signals were observed. Grade 2 toxicity was 13%, 7% and 10% in the respective cohorts (P = .9), without grade 3 to 5 toxicities. LF rates were 9%, 3%, and 6% (P = .5) for the respective treatment groups, with an overall cumulative risk of LF of 7% (95% CI, 2-12) at 4 years. Median PFS was 16.5 months (95% CI, 9.8-21.5), and 4-year PFS was 21% (95% CI, 14-32). Median overall survival across groups was not reached (95% CI, 52.8 - not reached), 4-year OS was 68% (95% CI, 59-78). A subset of patients (23%) remained long-term disease-free, 37% had oligoprogressive disease at first recurrence and 40% developed polymetastatic relapse. CONCLUSIONS: The safe and effective use of dose-escalated single-fraction stereotactic body radiation therapy for bone and lymph node metastases is supported by this trial, especially considering patient-convenience and cost-effectiveness. Caution is needed when generalizing these outcomes beyond breast and prostate cancer, given their underrepresentation in our study.

Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors.

PURPOSE: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. METHODS AND MATERIALS: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses. RESULTS: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively. CONCLUSIONS: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.

Metastases-directed stereotactic body radiotherapy in combination with targeted therapy or immunotherapy: systematic review and consensus recommendations by the EORTC-ESTRO OligoCare consortium.

Stereotactic body radiotherapy (SBRT) for patients with metastatic cancer, especially when characterised by a low tumour burden (ie, oligometastatic disease), receiving targeted therapy or immunotherapy has become a frequently practised and guideline-supported treatment strategy. Despite the increasing use in routine clinical practice, there is little information on the safety of combining SBRT with modern targeted therapy or immunotherapy and a paucity of high-level evidence to guide clinical management. A systematic literature review was performed to identify the toxicity profiles of combined metastases-directed SBRT and targeted therapy or immunotherapy. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was sought about risk mitigation strategies of metastases-directed SBRT combined with targeted therapy or immunotherapy; a potential need for and length of interruption to targeted therapy or immunotherapy around SBRT delivery; and potential adaptations of radiation dose and fractionation. Results of this systematic review and consensus process compile the best available evidence for safe combination of metastases-directed SBRT and targeted therapy or immunotherapy for patients with metastatic or oligometastatic cancer and aim to guide today's clinical practice and the design of future clinical trials.

Parameterisation of Respiratory Impedance in Lung Cancer Patients From Forced Oscillation Lung Function Test.

OBJECTIVE: This study aims to analyze the contribution and application of forced oscillation technique (FOT) devices in lung cancer assessment. Two devices and corresponding methods can be feasible to distinguish among various degrees of lung tissue heterogeneity. METHODS: The outcome respiratory impedance Zrs (in terms of resistance Rrs and reactance Xrs) is calculated for FOT and is interpreted in physiological terms by being fitted with a fractional-order impedance mathematical model (FOIM). The non-parametric data obtained from the measured signals of pressure and flow is correlated with an analogous electrical model to the respiratory system resistance, compliance, and elastance. The mechanical properties of the lung can be captured through Gr to define the damping properties and Hr to describe the elastance of the lung tissue, their ratio representing tissue heterogeneity ηr. RESULTS: We validated our hypotheses and methods in 17 lung cancer patients where we showed that FOT is suitable for non-invasively measuring their respiratory impedance. FOIM models are efficient in capturing frequency-dependent impedance value variations. Increased heterogeneity and structural changes in the lungs have been observed. The results present inter- and intra-patient variability for the performed measurements. CONCLUSION: The proposed methods and assessment of the respiratory impedance with FOT have been demonstrated useful for characterizing mechanical properties in lung cancer patients. SIGNIFICANCE: This correlation analysis between the measured clinical data motivates the use of the FOT devices in lung cancer patients for diagnosis of lung properties and follow-up of the respiratory function modified due to the applied radiotherapy treatment.

Epidemiology of spinal metastases, metastatic epidural spinal cord compression and pathologic vertebral compression fractures in patients with solid tumors: A systematic review.

Introduction: Spinal metastases (SM) are a frequent complication of cancer and may lead to pathologic vertebral compression fractures (pVCF) and/or metastatic epidural spinal cord compression (MESCC). Based on autopsy studies, it is estimated that about one third of all cancer patients will develop SM. These data may not provide a correct estimation of the incidence in clinical practice. Objective: This systematic review (SR) aims to provide a more accurate estimation of the incidence of SM, MESCC and pVCF in a clinical setting. Methods: We performed a SR of papers regarding epidemiology of SM, pVCF, and MESCC in patients with solid tumors conform PRISMA guidelines. A search was conducted in the PubMed and Web of Science database using the terms epidemiology, prevalence, incidence, global burden of disease, cost of disease, spinal metastas*, metastatic epidural spinal cord compression, pathologic fracture, vertebral compression fracture, vertebral metastas* and spinal neoplasms. Papers published between 1975 and august 2021 were included. Quality was evaluated by the STROBE criteria. Results: While 56 studies were included, none of them reports the actual definition used for MESCC and pVCF, inevitably introducing heterogenity. The overall cumulative incidence of SM and MESCC is 15.67% and 2.84% respectively in patients with a solid tumor. We calculated a mean cumulative incidence in patients with SM of 9.56% (95% CI 5.70%-13.42%) for MESCC and 12.63% (95% CI 7.00%-18.25%) for pVCF. Studies show an important delay between onset of symptoms and diagnosis. Conclusions: While the overall cumulative incidence for clinically diagnosed SM in patients with a solid tumor is 15.67%, autopsy studies reveal that SM are present in 30% by the time they die, suggesting underdiagnosing of SM. Approximately 1 out of 10 patients with SM will develop MESCC and another 12.6% will develop a pVCF. Understanding these epidemiologic data, should increase awareness for first symptoms, allowing early diagnosis and subsequent treatment, thus improving overall outcome.

Precision of image-guided spinal stereotactic ablative radiotherapy and impact of positioning variables.

Background and purpose: Spinal stereotactic ablative body radiotherapy (SABR) requires high precision. We evaluate the intrafraction motion during cone-beam computed tomography (CBCT) guided SABR with different immobilization techniques. Material and methods: Fifty-seven consecutive patients were treated for 62 spinal lesions with SABR with positioning corrected in six degrees of freedom. A surface monitoring system was used for patient set up and to ensure patient immobilization in 65% of patients. Intrafractional motion was defined as the difference between the last CBCT before the start of treatment and the first CT afterwards. Results: For all 194 fractions, the mean intrafractional motion was 0.1 cm (0-1.1 cm) in vertical direction, 0.1 cm (0-1.1 cm) in longitudinal direction and 0.1 cm (0-0.5 cm) in lateral direction. A mean pitch of 0.6° (0-4.3°), a roll of 0.5° (0-3.4°) and a rotational motion of 0.4° (0-3.9°) was observed. 95.5% of the translational errors and 95.4% of the rotational errors were within safety range. There was a significantly higher rotational motion for patients with arms along the body (p = 0.01) and without the use of the body mask (p = 0.05). For cervical locations a higher rotational motion was seen, although not significant (p = 0.1). The acquisition of an extra CBCT was correlated with a higher rotational (pitch) motion (p = 0 < 0.01). Conclusion: Very high precision in CBCT guided and surface-guided spinal SABR was observed in this cohort. The lowest intrafraction motion was seen in patients treated with arms above their head and a body mask. The use of IGRT with surface monitoring is an added value for patient monitoring leading to treatment interruption if necessary.

Completeness of Reporting Oligometastatic Disease Characteristics in the Literature and Influence on Oligometastatic Disease Classification Using the ESTRO/EORTC Nomenclature.

PURPOSE: There is increasing evidence for the integration of locally ablative therapy into multimodality treatment of oligometastatic disease (OMD). To support standardised data collection, analysis, and comparison, a consensus OMD classification based on fundamental disease and treatment characteristics has previously been established. This study investigated the completeness of reporting the proposed OMD characteristics in literature and evaluated whether the proposed OMD classification system can be applied to the historical data. METHODS AND MATERIALS: A systematic literature review was performed in Medline, Embase, and Cochrane, searching for prospective and retrospective studies, where stereotactic body radiation therapy was a treatment component of OMD. Reporting of the OMD characteristics as described in the European Organisation for Research and Treatment of Cancer/European Society for Radiotherapy and Oncology classification was analyzed, feasibility to retrospectively classify the proposed OMD states was investigated, and the effect of the categorization on overall survival (OS) was evaluated. RESULTS: Our study shows incomplete reporting of the proposed OMD characteristics. The most fully reported characteristic was type of involved organs (88/95 studies); history of cancer progression was the least reported (not mentioned in 50/95 studies). Retrospective OMD classification of existing literature was only possible for 7 of the 95 studies. With respect to categorization as de novo, repeat, or induced OMD, homogeneous patient cohorts were observed in 21 of the 95 studies, most frequently de novo OMD in 20 studies. Differences in OS at 2, 3, or 5 years were not statistically significant between the different states. OS was significantly influenced by primary tumor histology, with superior OS observed for prostate cancer and worst OS observed for non-small cell lung cancer. CONCLUSIONS: The largely incomplete reporting of the proposed OMD characteristics hampers a retrospective classification of existing literature. To facilitate future comparison of individual studies, as well as validation of the OMD classification, comprehensive reporting of OMD characteristics using standardised terminology is recommended, as proposed by the European Organisation for Research and Treatment of Cancer/European Society for Radiotherapy and Oncology classification system and following the European Society for Radiotherapy and Oncology/American Society for Radiation Oncology consensus.

Comparing treatment uncertainty for ultra- vs. standard-hypofractionated breast radiation therapy based on in-vivo dosimetry.

Background and purpose: Postoperative ultrahypofractionated radiation therapy (UHFRT) in 5 fractions (fx) for breast cancer patients is as effective and safe as conventionally hypofractionated RT (HFRT) in 15 fx, liberating time for higher-level daily online Image-Guided Radiation Therapy (IGRT) corrections. In this retrospective study, treatment uncertainties occurring in patients treated with 5fx (5fx-group) were evaluated using electronic portal imaging device (EPID)-based in-vivo dosimetry (EIVD) and compared with the results from patients treated with conventionally HFRT (15fx-group) to validate the new technique and to evaluate if the shorter treatment schedule could have a positive effect on the treatment uncertainties. Materials and methods: EPID-based integrated transit dose images were acquired for each treatment fraction in the 5fx-group (203 patients) and on the first 3 days of treatment and weekly thereafter in the 15fx-group (203 patients). A total of 1015 EIVD measurements in the 5fx-group and 1144 in the 15fx-group were acquired. Of the latter group, 755 had been treated with online IGRT correction (i.e., Online-IGRT 15fx-group). Results: In the 15fx-group 12.0% of fractions failed (FFs) compared to 3.8% in the 5fx-group and 6.9% in the online-IGRT 15fx-group. Causes for FFs in the 15fx-group compared with the 5fx-group were patient positioning (7.4% vs. 2.2%), technical issues (3.1% vs. 1.2%) and breast swelling (1.4% vs. 0.5%). In the online-IGRT 15fx-group, 2.5% were attributed to patient positioning, 3.8% to technical issues and 0.5% to breast swelling. Conclusions: EIVD demonstrated that UHFRT for breast cancer results in less FFs compared to standard HFRT. A large proportion of this decrease could be explained by using daily online IGRT.

Multimodality Treatment including Surgery Related to the Type of N2 Involvement in Locally Advanced Non-Small Cell Lung Cancer.

For patients with locally advanced non-small cell lung cancer (NSCLC) or positive N1 nodes, multimodality treatment is indicated. However, the optimal management of patients presenting with ipsilateral positive mediastinal nodes (N2 disease) has not been determined yet. Different treatment regimens consisting of chemotherapy, radiation therapy, and surgery have been proposed and implemented previously. In more recent years, immunotherapy and targeted therapies have been added as therapeutic options. The role of surgery is currently redefined. Recent studies have shown that surgical resection after induction immunotherapy or targeted therapy is feasible and yields good short-term results. In this review, we summarize the latest data on multimodality treatment options for stage IIIA-N2 locally advanced NSCLC, depending on the extent of nodal involvement.

Model Calibration of Pharmacokinetic-Pharmacodynamic Lung Tumour Dynamics for Anticancer Therapies.

Individual curves for tumor growth can be expressed as mathematical models. Herein we exploited a pharmacokinetic-pharmacodynamic (PKPD) model to accurately predict the lung growth curves when using data from a clinical study. Our analysis included 19 patients with non-small cell lung cancer treated with specific hypofractionated regimens, defined as stereotactic body radiation therapy (SBRT). The results exhibited the utility of the PKPD model for testing growth hypotheses of the lung tumor against clinical data. The model fitted the observed progression behavior of the lung tumors expressed by measuring the tumor volume of the patients before and after treatment from CT screening. The changes in dynamics were best captured by the parameter identified as the patients' response to treatment. Median follow-up times for the tumor volume after SBRT were 126 days. These results have proven the use of mathematical modeling in preclinical anticancer investigations as a potential prognostic tool.

Optimal delineation of the clinical target volume for thymomas in the post-resection setting: A multi-center study.

BACKGROUND: The definition of the clinical target volume (CTV) for post-operative radiotherapy (PORT) for thymoma is largely unexplored. The aim of this study was to analyze the difference in CTV delineation between radiation oncologists (RTO) and surgeons. METHODS: This retrospective multi-center study enrolled 31 patients who underwent PORT for a thymoma from five hospitals. Three CTVs were delineated per patient: one CTV by the RTO, one CTV by the surgeon (blinded to the results of the RTO) and a joint CTV after collaboration. Volumes (cm3), Hausdorff distances (HD) and Dice similarity coefficients (DSC) were analyzed. RESULTS: RTO delineated significantly bigger CTVs than surgeons (mean: 93.9 ± 63.1, versus 57.9 ± 61.3 cm3, p = 0.003). Agreement was poor between RO and surgeons, with a low mean DSC (0.34 ± 0.21) and high mean HD of 4.5 (±2.2) cm. Collaborative delineation resulted in significantly smaller volumes compared to RTO (mean 57.1 ± 58.6 cm3, p < 0.001). A mean volume of 18.9 (±38.1) cm3 was included in joint contours, but missed by RTO. Conversely, a mean volume of 55.7 (±39.9) cm3 was included in RTO's delineations, but not in the joint delineations. CONCLUSIONS: To the best of our knowledge, this is the first study investigating CTV definition in thymoma. We demonstrated a significant variability between RTO and surgeons. Joint delineation prompted revisions in smaller CTV as well as favoring the surgeons' judgement, suggesting that surgeons provided relevant insight into other risk areas than RTO. We recommend a multidisciplinary approach to PORT for thymomas in clinical practice.

New Pulmonary Infiltrates Observed on Computed Tomography-Based Image Guidance for Radiotherapy Warrant Diagnostic Workup for Coronavirus Disease 2019.

INTRODUCTION: Screening for coronavirus disease 2019 (COVID-19) exposure, coupled with engaged decision making to prioritize cancer treatment in parallel with reducing risk of exposure and infection, is crucial in the management of COVID-19 during cancer treatment. After two reported case studies of imaging findings during daily computed tomography (CT)-based image-guided radiotherapy (RT) scans, a call for submission of anonymized case reports was published with the objective of rapidly determining if there was a correlation between the onset of new pulmonary infiltrates found during RT and COVID-19. We hereby report the results of the aggregate analysis. METHODS: Data of deidentified case reports for patients who developed biochemically confirmed COVID-19 during RT were submitted through an online portal. Information requested included a patient's sex, age, cancer diagnosis and treatment, and COVID-19 diagnosis and outcome. Coplanar CT-based imaging was requested to reveal the presence or absence of ground-glass opacities or infiltrates. RESULTS: A total of seven reports were submitted from Turkey, Spain, Belgium, Egypt, and the United States. Results and imaging from the patients reported by Suppli et al. and McGinnis et al. were included for a total of nine patients for analysis. All patients were confirmed COVID-19 positive using polymerase chain reaction-based methods or nasopharyngeal swabs. Of the nine patients analyzed, abnormalities consistent with ground-glass opacities or infiltrates were observed in eight patients. CONCLUSIONS: This is the largest case series revealing the potential use of CT-based image guidance during RT as a tool for identifying patients who need further workup for COVID-19. Considerations for reviewing image guidance for new pulmonary infiltrates and immediate COVID-19 testing in patients who develop new infiltrates even without COVID-19 symptoms are strongly encouraged.

The HILUS-Trial-a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy.

INTRODUCTION: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. METHODS: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. RESULTS: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0-10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the "hottest" 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. CONCLUSIONS: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions).

Stereotactic Ablative Radiation Therapy to All Lesions in Patients With Oligometastatic Cancers: A Phase 1 Dose-Escalation Trial.

PURPOSE: Increasing evidence suggests that patients with a limited number of metastases benefit from SABR to all lesions. However, the optimal dose and fractionation remain unknown. This is particularly true for bone and lymph node metastases. Therefore, a prospective, single-center, dose-escalation trial was initiated. METHODS: Dose-Escalation trial of STereotactic ablative body RadiOtherapY for non-spine bone and lymph node metastases (DESTROY) was an open-label phase 1 trial evaluating SABR to nonspine bone and lymph node lesions in patients with up to 3 metastases. Patients with European Cooperative Oncology Group performance status ≤1, an estimated life expectancy of at least 6 months, and histologically confirmed nonhematological malignancy were eligible. Three SABR fractionation regimens, ie, 5 fractions of 7.0 Gy versus 3 fractions of 10.0 Gy versus a single fraction of 20.0 Gy, were applied in 3 consecutive patient cohorts. The rate of ≥grade 3 toxicity, scored according to the Common Toxicity Criteria for Adverse Events v. 4.03, up to 6 months after SABR, was the primary endpoint. The trial was registered on clinicaltrials.gov (NCT03486431). RESULTS: Between July 2017 and December 2018, 90 patients were enrolled. In total 101 metastases were treated. No ≥grade 3 toxicity was observed in any of the enrolled patients (95% CI 0.0%-12.3% for the first cohort with 28 analyzable patients; 95% CI 0.0%-11.6% for the second and third cohort with 30 analyzable patients each). Treatment-related grade 2 toxicities occurred in 4 out of 30 versus 2 out of 30 versus 2 out of 30 patients for the 5, 3 and 1 fraction schedule, respectively. Actuarial local control rate at 12 months was 94.5%. CONCLUSION: All 3 treatment schedules were feasible and effective with remarkably low toxicity rates and high local control rates. From a patient and resource point of view, the single-fraction schedule is undoubtedly most convenient.

Oncological outcome, postoperative complications, and mammographic changes after intraoperative radiotherapy with electrons (IOERT) as a boost in a large single-institution cohort of breast cancer patients.

Advantages of using intraoperative radiotherapy with electrons (IOERT) as a boosting modality in breast-conserving therapy include the direct visualization of the tumor bed, a reduced skin dose, and patient convenience. We report oncological outcome, postoperative complication rate, and mammographic changes on follow-up imaging in women treated at our institution with IOERT as a boost modality in breast-conserving therapy for early-stage breast carcinoma. Between January 2007 and June 2018, 763 consecutive patients were enrolled. During breast-conserving surgery, an IOERT boost of 9 Gy was applied, followed by whole breast irradiation (WBI). At a median follow-up of 62.2 months (range: 0.5-135), 13 in-breast recurrences were observed, yielding a local tumor control rate of 98.4% at 5 years. In multivariable analysis, high tumor grading was predictive for local recurrence (HR = 5.6; 95%CI: 1.19-26.2). A total of 27 (3.5%) patients developed any kind of postoperative complication. None of the tumor characteristics nor any of the IOERT technical parameters were predictive for development of a postoperative complication. On follow-up imaging, 145 patients with mammographic changes BIRADS score ≥3 were found of which 50.3% required a biopsy. Only 17 patients had positive biopsies; none of the IOERT parameters were predictive for false-positive imaging. A 9 Gy IOERT boost combined with postoperative WBI provided outstanding local control rates, was well-tolerated, with limited postoperative complications. However, radiologists must be aware of a presumable higher prevalence of mammographic changes after IORT as a boost.

Outcome and toxicity of hypofractionated image-guided SABR for spinal oligometastases.

BACKGROUND: To investigate progression free survival (PFS), local control (LC) and overall survival (OS) outcomes for patients treated with spine hypofractionated stereotactic ablative radiotherapy (SABR) and to evaluate possible predictors of rapid progression in view of a correct patient selection for this potentially curative SABR. MATERIALS AND METHODS: A cohort of 59 patients with spinal metastases were treated with SABR. Patient selection criteria were the following: histologically proven diagnosis of a solid tumor, a World Health Organization (WHO) score ≤ 2, life expectancy > 6 months, Spinal Instability Neoplastic Score (SINS) ≤ 12 points and presenting with radically treated oligometastatic disease (≤5 lesions) or stable polymetastatic disease with an oligoprogressive lesion. RESULTS: From March 2015 to June 2019, 59 patients were treated with Linac-based SABR to 64 spinal metastases with a median follow-up of 55 months. SABR was standard delivered every other day in 3 to 10 fractions with median prescription dose of 27 Gy (range 21-49 Gy).The 1-,2- and 5-year PFS was 98%, 85% and 75% for all patients. OS at 5 years for all patients was 92%. Metachronous lesions (p < 0.01; HR = 7.1) and oligometastatic (vs. oligoprogressive) lesions (p = 0.02; HR = 0.3) were associated with higher PFS in uni- and multivariate Cox regression analysis. No significant predictors in multivariate analysis were demonstrated for rapid progressors.Vertebral compression fractures developed de novo in 6.3% (4/64) of cases. The median time to fracture was 11 months (range 7-15) after treatment. No other adverse events ≥ 3 grade were observed. CONCLUSIONS: Tumor control and toxicity after high-dose hypofractionated SABR was evaluated in patients with spinal oligometastases. High rates of efficacy and minimal toxicity were demonstrated. Oligometastatic patients with metachronous spinal metastases seem to benefit the most from SABR.

Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial.

BACKGROUND: About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit and new treatment strategies are therefore needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR). METHODS: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (E-arm) or the control-arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. Primary endpoint is PFS at 1.5-years based on blinded radiological review, and secondary endpoints are overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed. DISCUSSION: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal treatment approach is based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s) and the memory effect. The first results are expected end 2023. TRIAL REGISTRATION: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.