Stereotactic ultrahypofractionated MR-guided radiotherapy for localized prostate cancer - Acute toxicity and patient-reported outcomes in the prospective, multicenter SMILE phase II trial.

Background: Due to superior image quality and daily adaptive planning, MR-guided stereotactic body radiation therapy (MRgSBRT) has the potential to further widen the therapeutic window in radiotherapy of localized prostate cancer. This study reports on acute toxicity rates and patient-reported outcomes after MR-guided adaptive ultrahypofractionated radiotherapy for localized prostate cancer within the prospective, multicenter phase II SMILE trial. Materials and methods: A total of 69 patients with localized prostate cancer underwent MRgSBRT with daily online plan adaptation. Inclusion criteria comprised a tumor stage ≤ T3a, serum PSA value ≤ 20 ng/ml, ISUP Grade group ≤ 4. A dose of 37.5 Gy was prescribed to the PTV in five fractions on alternating days with an optional simultaneous boost of 40 Gy to the dominant intraprostatic lesion defined by multiparametric MRI. Acute genitourinary (GU-) and gastrointestinal (GI-) toxicity, as defined by CTCAE v. 5.0 and RTOG as well as patient-reported outcomes according to EORTC QLQ-C30 and -PR25 scores were analyzed at completion of radiotherapy, 6 and 12 weeks after radiotherapy and compared to baseline symptoms. Results: There were no toxicity-related treatment discontinuations. At the 12-week follow-up visit, no grade 3 + toxicities were reported according to CTCAE. Up until the 12-week visit, in total 16 patients (23 %) experienced a grade 2 GU or GI toxicity. Toxicity rates peaked at the end of radiation therapy and subsided within the 12-week follow-up period. At the 12-week follow-up visit, no residual grade 2 GU toxicities were reported and 1 patient (1 %) had residual grade 2 enteritic symptoms. With exception to a significant improvement in the emotional functioning score following MRgSBRT, no clinically meaningful changes in the global health status nor in relevant subscores were reported. Conclusion: Daily online-adaptive MRgSBRT for localized prostate cancer resulted in an excellent overall toxicity profile without any major negative impact on quality of life.

Efficacy and safety of SBRT for spine metastases: A systematic review and meta-analysis for preparation of an ESTRO practice guideline.

BACKGROUND AND PURPOSE: Advances in characterizing cancer biology and the growing availability of novel targeted agents and immune therapeutics have significantly changed the prognosis of many patients with metastatic disease. Palliative radiotherapy needs to adapt to these developments. In this study, we summarize the available evidence for stereotactic body radiotherapy (SBRT) in the treatment of spinal metastases. MATERIALS AND METHODS: A systematic review and meta-analysis was performed using PRISMA methodology, including publications from January 2005 to September 2021, with the exception of the randomized phase III trial RTOG-0631 which was added in April 2023. Re-irradiation was excluded. For meta-analysis, a random-effects model was used to pool the data. Heterogeneity was assessed with the I2-test, assuming substantial and considerable as I2 > 50 % and I2 > 75 %, respectively. A p-value < 0.05 was considered statistically significant. RESULTS: A total of 69 studies assessing the outcomes of 7236 metastases in 5736 patients were analyzed. SBRT for spine metastases showed high efficacy, with a pooled overall pain response rate of 83 % (95 % confidence interval [CI] 68 %-94 %), pooled complete pain response of 36 % (95 % CI: 20 %-53 %), and 1-year local control rate of 94 % (95 % CI: 86 %-99 %), although with high levels of heterogeneity among studies (I2 = 93 %, I2 = 86 %, and 86 %, respectively). Furthermore, SBRT was safe, with a pooled vertebral fracture rate of 9 % (95 % CI: 4 %-16 %), pooled radiation induced myelopathy rate of 0 % (95 % CI 0-2 %), and pooled pain flare rate of 6 % (95 % CI: 3 %-17 %), although with mixed levels of heterogeneity among the studies (I2 = 92 %, I2 = 0 %, and 95 %, respectively). Only 1.7 % of vertebral fractures required surgical stabilization. CONCLUSION: Spine SBRT is characterized by a favorable efficacy and safety profile, providing durable results for pain control and disease control, which is particularly relevant for oligometastatic patients.

ESTRO clinical practice guideline: Stereotactic body radiotherapy for spine metastases.

BACKGROUND AND PURPOSE: Recent progress in diagnostics and treatment of metastatic cancer patients have improved survival substantially. These developments also affect local therapies, with treatment aims shifting from short-term palliation to long-term symptom or disease control. There is consequently a need to better define the value of stereotactic body radiotherapy (SBRT) for the treatment of spinal metastases. METHODS: This ESTRO clinical practice guideline is based on a systematic literature review conducted according to PRISMA standards, which formed the basis for answering four key questions about the indication and practice of SBRT for spine metastases. RESULTS: The analysis of the key questions based on current evidence yielded 22 recommendations and 5 statements with varying levels of endorsement, all achieving a consensus among experts of at least 75%. In the majority, the level of evidence supporting the recommendations and statements was moderate or expert opinion, only, indicating that spine SBRT is still an evolving field of clinical research. Recommendations were established concerning the selection of appropriate patients with painful spine metastases and oligometastatic disease. Recommendations about the practice of spinal SBRT covered technical planning aspects including dose and fractionation, patient positioning, immobilization and image-guided SBRT delivery. Finally, recommendations were developed regarding quality assurance protocols, including description of potential SBRT-related toxicity and risk mitigation strategies. CONCLUSIONS: This ESTRO clinical practice guideline provides evidence-based recommendations and statements regarding the selection of patients with spinal metastases for SBRT and its safe implementation and practice. Enrollment of patients into well-designed prospective clinical trials addressing clinically relevant questions is considered important.

Stereotactic MRI-guided radiation therapy for localized prostate cancer (SMILE): a prospective, multicentric phase-II-trial.

BACKGROUND: Normofractionated radiation regimes for definitive prostate cancer treatment usually extend over 7-8 weeks. Recently, moderate hypofractionation with doses per fraction between 2.2 and 4 Gy has been shown to be safe and feasible with oncologic non-inferiority compared to normofractionation. Radiobiologic considerations lead to the assumption that prostate cancer might benefit in particular from hypofractionation in terms of tumor control and toxicity. First data related to ultrahypofractionation demonstrate that the overall treatment time can be reduced to 5-7 fractions with single doses > 6 Gy safely, even with simultaneous focal boosting of macroscopic tumor(s). With MR-guided linear accelerators (MR-linacs) entering clinical routine, invasive fiducial implantations become unnecessary. The aim of the multicentric SMILE study is to evaluate the use of MRI-guided stereotactic radiotherapy for localized prostate cancer in 5 fractions regarding safety and feasibility. METHODS: The study is designed as a prospective, one-armed, two-stage, multi-center phase-II-trial with 68 patients planned. Low- and intermediate-risk localized prostate cancer patients will be eligible for the study as well as early high-risk patients (cT3a and/or Gleason Score ≤ 8 and/or PSA ≤ 20 ng/ml) according to d'Amico. All patients will receive definitive MRI-guided stereotactic radiation therapy with a total dose of 37.5 Gy in 5 fractions (single dose 7.5 Gy) on alternating days. A focal simultaneous integrated boost to MRI-defined tumor(s) up to 40 Gy can optionally be applied. The primary composite endpoint includes the assessment of urogenital or gastrointestinal toxicity ≥ grade 2 or treatment-related discontinuation of therapy. The use of MRI-guided radiotherapy enables online plan adaptation and intrafractional gating to ensure optimal target volume coverage and protection of organs at risk. DISCUSSION: With moderate hypofractionation being the standard in definitive radiation therapy for localized prostate cancer at many institutions, ultrahypofractionation could be the next step towards reducing treatment time without compromising oncologic outcomes and toxicities. MRI-guided radiotherapy could qualify as an advantageous tool as no invasive procedures have to precede in therapeutic workflows. Furthermore, MRI guidance combined with gating and plan adaptation might be essential in order to increase treatment effectivity and reduce toxicity at the same time.

Intrafractional stability of MR-guided online adaptive SBRT for prostate cancer.

BACKGROUND: MR-guided online adaptive stereotactic body radiation therapy (SBRT) for prostate cancer aims to reduce toxicity by full compensation of interfractional uncertainties. However, the process of online adaptation currently takes approximately 45 min during which intrafractional movements remain unaccounted for. This study aims to analyze the dosimetric benefit of online adaptation and to evaluate its robustness over the duration of one treatment fraction. METHODS: Baseline MR-scans at a MR-linear accelerator were acquired for ten healthy male volunteers for generation of mock-prostate SBRT plans with a dose prescription of 5 × 7.25 Gy. On a separate day, online MR-guided adaptation (ViewRay® MRIdian) was performed, and thereafter MR images were acquired every 15 min for 1 h to assess the stability of the adapted plan. RESULTS: A dosimetric benefit of online MR-guided adaptive re-planning was observed in 90% of volunteers. The median D95CTV- and D95PTV-coverage was improved from 34.8 to 35.5 Gy and from 30.7 to 34.6 Gy, respectively. Improved target coverage was not associated with higher dose to the organs at risk, most importantly the rectum (median D1ccrectum baseline plan vs. adapted plan 33.3 Gy vs. 32.3 Gy). The benefit of online adaptation remained stable over 45 min for all volunteers. However, at 60 min, CTV-coverage was below a threshold of 32.5 Gy in 30% of volunteers (30.6 Gy, 32.0 Gy, 32.3 Gy). CONCLUSION: The dosimetric benefit of MR-guided online adaptation for prostate SBRT was robust over 45 min in all volunteers. However, intrafractional uncertainties became dosimetrically relevant at 60 min and we therefore recommend verification imaging before delivery of MR-guided online adapted SBRT.

Quality assurance of radiotherapy in the ongoing EORTC 1420 "Best of" trial for early stage oropharyngeal, supraglottic and hypopharyngeal carcinoma: results of the benchmark case procedure.

INTRODUCTION: The current phase III EORTC 1420 Best-of trial (NCT02984410) compares the swallowing function after transoral surgery versus intensity modulated radiotherapy (RT) in patients with early-stage carcinoma of the oropharynx, supraglottis and hypopharynx. We report the analysis of the Benchmark Case (BC) procedures before patient recruitment with special attention to dysphagia/aspiration related structures (DARS). MATERIALS AND METHODS: Submitted RT volumes and plans from participating centers were analyzed and compared against the gold-standard expert delineations and dose distributions. Descriptive analysis of protocol deviations was conducted. Mean Sorensen-Dice similarity index (mDSI) and Hausdorff distance (mHD) were applied to evaluate the inter-observer variability (IOV). RESULTS: 65% (23/35) of the institutions needed more than one submission to achieve Quality assurance (RTQA) clearance. OAR volume delineations were the cause for rejection in 53% (40/76) of cases. IOV could be improved in 5 out of 12 OARs by more than 10 mm after resubmission (mHD). Despite this, final IOV for critical OARs in delineation remained significant among DARS by choosing an aleatory threshold of 0.7 (mDSI) and 15 mm (mHD). CONCLUSIONS: This is to our knowledge the largest BC analysis among Head and neck RTQA programs performed in the framework of a prospective trial. Benchmarking identified non-common OARs and target delineations errors as the main source of deviations and IOV could be reduced in a significant number of cases after this process. Due to the substantial resources involved with benchmarking, future benchmark analyses should assess fully the impact on patients' clinical outcome.

Independent external validation using the EORTC HNCG-ROG 1219 DAHANCA trial data of NTCP models for acute oral mucositis.

PURPOSE: To externally validate previously published Normal Tissue Complication Probability (NTCP) models developed by separate teams for grade 3 oral mucositis (g3OM). MATERIALS AND METHODS: Two models were validated: a logistic model, based on 144 head and neck cancer (HNC) patients receiving induction chemotherapy followed by chemo-IMRT; a multivariable logistic model for prediction of g3OM for 253 patients receiving radical treatment for the head and neck squamous cell carcinoma (HNSCC). The EORTC HNCG-ROG 1219 DAHANCA trial dataset, consisting of 169 patients was used as the validation cohort. This cohort was treated with accelerated fractionated chemo-IMRT, with/without the hypoxic radiosensitizer Nimorazole for HNSCC. External validity was assessed using the scaled Brier score. Calibration was assessed in terms of calibration curves as well as measures of mean and weak calibration. Hosmer-Lemeshow was used for goodness-of-fit test. Discrimination was calculated using the area under the receiver operating curve (AUC-ROC). RESULTS: The prevalence of g3OM in the validation cohort (35.5%) was similar to that of two development cohorts, i.e. 38.7% and 31.9% for Bhide logistic and Otter multivariable logistic models respectively. The scaled Brier scores showed good overall model performance. Perfect calibration was observed in the prevalence range of 20% to 40%. AUC-ROC was acceptable in external validation (0.67). The Hosmer-Lemeshow test showed good agreement between predicted and observed outcomes for two models. CONCLUSION: The NTCP models were validated and lead to valid predictions in a wide range of diverse treatment techniques and patient characteristics, also when Nimorazole is added as hypoxic radiosensitizer.

High-dose re-irradiation of intracranial lesions - Efficacy and safety including dosimetric analysis based on accumulated EQD2Gy dose EQD calculation.

INTRODUCTION: The use of cranial re-irradiation is growing with improving overall survival and the advent of high-precision radiotherapy techniques. Still the value of re-irradiation needs careful evaluation regarding safety and efficacy. We analyzed dosimetric and clinical data of patients receiving cranial re-irradiation using EQD2 sum plans. METHODS AND MATERIAL: We retrospectively analyzed the data of 76 patients who received repeated cranial radiotherapy from 02/2013 to 09/2016. 34 patients suffered from recurrent primary brain tumors, 42 from brain metastases. Dosimetric analysis was performed accumulating EQD2 dose distributions based on rigid image registration. Clinical and radiological data was collected at follow-ups including toxicity, local control and overall survival. RESULTS: In total 76 patients had at least 2 courses of intracranial radiotherapy. The median accumulated prescription EQD2 dose was 96.5 Gy2 for all radiation courses combined. The median D(0.1 cc) of the brain for patients receiving more than 100 Gy2 was 114 Gy2 with a highest dose of 161.5 Gy2. 74% of patients suffered from low grade (G1-G2) acute toxicity, only two high grade (>G3) toxicities were recorded.Median overall survival from the time of first re-irradiation was 57 weeks (range 4-186 weeks). The median time to local failure for patients with a primary brain tumor was not reached and 24 weeks (range 1-77 weeks) for patients with brain metastases. CONCLUSION: Repeated radiotherapy appears both safe and efficient in patients with recurrent primary or secondary brain tumors with doses to the brain up to 120 Gy2 EQD2, doses below 100 Gy2 for brainstem and doses below 75 Gy2 EQD2 to chiasm and optic nerves.

FDG PET versus CT radiomics to predict outcome in malignant pleural mesothelioma patients.

BACKGROUND: Careful selection of malignant pleural mesothelioma (MPM) patients for curative treatment is of highest importance, as the multimodal treatment regimen is challenging for patients and harbors a high risk of substantial toxicity. Radiomics-a quantitative method for image analysis-has shown its prognostic ability in different tumor entities and could therefore play an important role in optimizing patient selection for radical cancer treatment. So far, radiomics as a prognostic tool in MPM was not investigated. MATERIALS AND METHODS: This study is based on 72 MPM patients treated with surgery in a curative intent at our institution between 2009 and 2017. Pre-treatment Fluorine-18 fluorodeoxyglucose (FDG) PET and CT scans were used for radiomics outcome modeling. After extraction of 1404 CT and 1410 FDG PET features from each image, a preselection by principal component analysis was performed to include only robust, non-redundant features for the cox regression to predict the progression-free survival (PFS) and the overall survival (OS). Results were validated on a separate cohort. Additionally, SUVmax and SUVmean, and volume were tested for their prognostic ability for PFS and OS. RESULTS: For the PFS a concordance index (c-index) of 0.67 (95% CI 0.52-0.82) and 0.66 (95% CI 0.57-0.78) for the training cohort (n = 36) and internal validation cohort (n = 36), respectively, were obtained for the PET radiomics model. The PFS advantage of the low-risk group translated also into an OS advantage. On CT images, no radiomics model could be trained. SUV max and SUV mean were also not prognostic in terms of PFS and OS. CONCLUSION: We were able to build a successful FDG PET radiomics model for the prediction of PFS in MPM. Radiomics could serve as a tool to aid clinical decision support systems for treatment of MPM in future.

Re-irradiation in the thorax - An analysis of efficacy and safety based on accumulated EQD2 doses.

INTRODUCTION: Thoracic re-irradiation remains a challenge regarding the balance of local efficacy and acceptable toxicities. In this retrospective analysis we analyzed dosimetrical and clinical data of patients treated with thoracic re-irradiation based on accumulated EQD2Gy doses. METHODS AND MATERIAL: We retrospectively analyzed the data of 42 consecutive single-institutional patients treated with repeated courses of thoracic radiotherapy from 12/2011 to 01/2017. Accumulated EQD2 dose distributions were calculated and dose parameters for organs at risk and target volumes were analysed. RESULTS: The median prescription dose was 42.2 Gy (10-70.6 Gy) for all RT courses. The median Dmean of both lungs was 10.1 Gy3 (range: 1.9 Gy3-17.9 Gy3) with a maximum D0.1 cc of 253.86 Gy3. The median D0.1 cc of the esophagus was 62.2 Gy3 with a maximum of 103.78 Gy3. The maximum D0.1 cc for the bronchial tree was 187.33 Gy3 (median 74.35 Gy3) and for the Aorta 216.1 Gy3 (median 70.9 Gy3). Median OS after first re-irradiation was 19 months (range 1-45 months). 12-month local control after a course of re-irradiation was 52.6%. 80% of patients suffered from a G1-G2 toxicity, most frequently coughing. One patient suffered from a G5 complication probably unrelated to re-irradiation. CONCLUSION: Even though several organs at risk received maximum accumulated doses of >100 Gy3, thoracic reirradiation resulted in an acceptable toxicity profile. Local tumor control and overall survival remained encouraging even after multiple courses of thoracic radiotherapy.

Survival outcome of non-small cell lung cancer patients: Comparing results between the database of the Comprehensive Cancer Center Zürich and the Epidemiological Cancer Registry Zurich and Zug.

BACKGROUND: Cancer cases among the population of the canton Zurich, are registered in the Cancer Registry of the cantons of Zurich and Zug (KKR). The Thoracic Oncology Center, founded in 2011 is one of 17 multidisciplinary centers within the Comprehensive Cancer Center Zurich (CCCZ). METHODS: The aim of the current study is to quantify the mortality risk of patients with NSCLC and identify differences on survival and other factors between patients receiving their primary treatment at the CCCZ and those treated elsewhere and registered by KKR. The differential effect between CCCZ and KKR cohorts on survival: overall, by stage, sex and age, is explored. Stratified log-rank and Wilcoxon tests, Cox models and restricted mean survival times (RMST) are estimated. Propensity score matching (PSM) is also used to adjust for confounding factors. RESULTS: Analysis included 848 NSCLC cases from the CCCZ and 1759 from the KKR, diagnosed between January 2011 and December 2015. At a median follow-up of 57 months, overall survival (OS) was significantly superior for patients treated at the CCCZ compared to KKR [Median OS: 36.0 months (95%CI: 31.0-45.0) and 12.0 months (95%CI: 11.0-13.0), respectively, stratified log-rank p < 0.001; adjusted HR = 1.31, (95% CI: 1.18-1.46), difference in RMST up to 72 months: 13.8 months (95%CI: 11.5-16.2), p < 0.001]. The effect of cohort was significant for stages III and IV (overall and also by sex and age). After PSM OS remained significantly superior for patients treated at the CCCZ compared to KKR. CONCLUSIONS: The survival probability for patients in the CCCZ cohort was superior to that of patients in the canton Zürich treated outside the center. This analysis provides further evidence of the importance of the volume of experience and the availability of a multidisciplinary organization and research environment, as delivered by a comprehensive cancer center, on the outcome of patients with NSCLC.

Challenges in the treatment of breast cancer brain metastases: evidence, unresolved questions, and a practical algorithm.

Breast cancer is the leading cause of brain metastases in women. Large randomized clinical trials that have evaluated local therapies in patients with brain metastases include patients with brain metastases from a variety of cancer types. The incidence of brain metastases in the breast cancer population continues to grow, which is, aside from the rising breast cancer incidence, mainly attributable to improvements in systemic therapies leading to more durable control of extracranial metastatic disease and prolonged survival. The management of breast cancer brain metastases remains challenging, even more so with the continued advancement of local and highly effective systemic therapies. For most patients, a metastases-directed initial approach (i.e., radiation, surgery) represents the most appropriate initial therapy. Treatment should be based on multidisciplinary team discussions and a shared decision with the patients taking into account the risks and benefits of each therapeutic modality with the goal of prolonging survival while maintaining quality of life. In this narrative review, a multidisciplinary group of experts will address challenging questions in the context of current scientific literature and propose a therapeutic algorithm for breast cancer patients with brain metastases.

Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial.

OBJECTIVES: Chemo-radiotherapy (CRT) and concurrent PD-1 inhibition has shown promising results in pre-clinical models. So far, the feasibility of delivering concurrent CRT and PD-1/PD-L1 inhibition has never been assessed in a clinical trial. MATERIAL AND METHODS: NICOLAS is a phase-II trial evaluating the safety and efficacy of nivolumab combined with CRT in stage III NSCLC. Patients received 3 cycles of platinum-based chemotherapy and concurrent RT (66 Gy/33fractions). Nivolumab started concurrently with RT. The primary endpoint was 6-month post-RT rate of grade-≥3-pneumonitis. A formal interim safety analysis (IA) was scheduled when the first 21 patients reached 3 months follow-up post-RT. An early positive safety conclusion would be reached at IA if there were no grade ≥3-pneumonitis in those patients. Efficacy evaluation was planned provided the safety conclusion was reached. RESULTS AND CONCLUSION: As of 13 December 2018, 82 patients were recruited with median follow-up of 13.4 months. The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed. For the first 21 patients, no grade-≥3-pneumonitis was observed by the end of the 3-month post-RT follow-up period. The early safety IA provides evidence that the addition of nivolumab to concurrent CRT is safe and tolerable regarding the 6-month rate of pneumonitis grade ≥3 at the one-sided significance level of 5%. Following that, the 1-year progression-free survival will be evaluated in an expanded patient cohort. NICOLAS trial creates the opportunity for assessing the activity of the combination of checkpoint with concurrent CRT in larger prospective trials for locally advanced NSCLC.

MR-guidance in clinical reality: current treatment challenges and future perspectives.

Magnetic Resonance-guided radiotherapy (MRgRT) marks the beginning of a new era. MR is a versatile and suitable imaging modality for radiotherapy, as it enables direct visualization of the tumor and the surrounding organs at risk. Moreover, MRgRT provides real-time imaging to characterize and eventually track anatomical motion. Nevertheless, the successful translation of new technologies into clinical practice remains challenging. To date, the initial availability of next-generation hybrid MR-linac (MRL) systems is still limited and therefore, the focus of the present preview was on the initial applicability in current clinical practice and on future perspectives of this new technology for different treatment sites.MRgRT can be considered a groundbreaking new technology that is capable of creating new perspectives towards an individualized, patient-oriented planning and treatment approach, especially due to the ability to use daily online adaptation strategies. Furthermore, MRL systems overcome the limitations of conventional image-guided radiotherapy, especially in soft tissue, where target and organs at risk need accurate definition. Nevertheless, some concerns remain regarding the additional time needed to re-optimize dose distributions online, the reliability of the gating and tracking procedures and the interpretation of functional MR imaging markers and their potential changes during the course of treatment. Due to its continuous technological improvement and rapid clinical large-scale application in several anatomical settings, further studies may confirm the potential disruptive role of MRgRT in the evolving oncological environment.

The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases.

BACKGROUND: The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. METHODS: The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. RESULTS: Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. CONCLUSION: In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months.

Bevacizumab may improve quality of life, but not overall survival in glioblastoma: an epidemiological study.

Background: The vascular endothelial growth factor antibody bevacizumab (Avastin®), received approval for the treatment of recurrent glioblastoma in many countries including the USA and Switzerland, but not the European Union, in 2009. Here, we explored the hypothesis that the approval of bevacizumab improved outcome with glioblastoma on a population level. Patients and methods: The prognostic significance of epidemiological, molecular genetic, and clinical data including treatment for glioblastoma patients diagnosed from 2010 to 2014 in the Canton of Zurich, Switzerland, was retrospectively analyzed using log-rank test and Cox proportional hazards models. Data were compared with data for the years 2005-2009. Results: In total, 310 glioblastoma patients were identified in the years 2010-2014. Median overall survival was 13.5 months for patients with known isocitrate dehydrogenase (IDH) wild-type (wt) (IDH1R132H-non-mutant) tumors (N = 248), compared with 11.3 months for IDH wt patients (P = 0.761) before (2005-2009). In the IDH wt cohort, bevacizumab use at any time increased from 19% in 2005-2009 to 49% in 2010-2014. Multivariate analysis did not identify bevacizumab exposure at any time to be associated with survival. Yet, upon the second-line treatment, baseline doses of corticosteroids were reduced by more than half in 83% of patients on bevacizumab compared with 48% of the patients treated with bevacizumab-free regimens (P = 0.007). Conclusion: This epidemiological study of a small, but clinically well-annotated patient cohort fails to support the assumption that the strong increase of bevacizumab use since 2010 improved survival in glioblastoma although clinical benefit associated with decreased steroid use may have been achieved.

The SBRT database initiative of the German Society for Radiation Oncology (DEGRO): patterns of care and outcome analysis of stereotactic body radiotherapy (SBRT) for liver oligometastases in 474 patients with 623 metastases.

BACKGROUND: The intent of this pooled analysis as part of the German society for radiation oncology (DEGRO) stereotactic body radiotherapy (SBRT) initiative was to analyze the patterns of care of SBRT for liver oligometastases and to derive factors influencing treated metastases control and overall survival in a large patient cohort. METHODS: From 17 German and Swiss centers, data on all patients treated for liver oligometastases with SBRT since its introduction in 1997 has been collected and entered into a centralized database. In addition to patient and tumor characteristics, data on immobilization, image guidance and motion management as well as dose prescription and fractionation has been gathered. Besides dose response and survival statistics, time trends of the aforementioned variables have been investigated. RESULTS: In total, 474 patients with 623 liver oligometastases (median 1 lesion/patient; range 1­4) have been collected from 1997 until 2015. Predominant histologies were colorectal cancer (n = 213 pts.; 300 lesions) and breast cancer (n = 57; 81 lesions). All centers employed an SBRT specific setup. Initially, stereotactic coordinates and CT simulation were used for treatment set-up (55%), but eventually were replaced by CBCT guidance (28%) or more recently robotic tracking (17%). High variance in fraction (fx) number (median 1 fx; range 1­13) and dose per fraction (median: 18.5 Gy; range 3­37.5 Gy) was observed, although median BED remained consistently high after an initial learning curve. Median follow-up time was 15 months; median overall survival after SBRT was 24 months. One- and 2-year treated metastases control rate of treated lesions was 77% and 64%; if maximum isocenter biological equivalent dose (BED) was greater than 150 Gy EQD2Gy, it increased to 83% and 70%, respectively. Besides radiation dose colorectal and breast histology and motion management methods were associated with improved treated metastases control. CONCLUSION: After an initial learning curve with regards to total cumulative doses, consistently high biologically effective doses have been employed translating into high local tumor control at 1 and 2 years. The true impact of histology and motion management method on treated metastases control deserve deeper analysis. Overall survival is mainly influenced by histology and metastatic tumor burden.

Stereotactic body radiotherapy (SBRT) for multiple pulmonary oligometastases: Analysis of number and timing of repeat SBRT as impact factors on treatment safety and efficacy.

BACKGROUND: Stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by an excellent safety profile; however, experiences are mostly based on treatment of one single metastasis. It was the aim of this study to evaluate safety and efficacy of SBRT for multiple pulmonary metastases. PATIENTS AND METHODS: This study is based on a retrospective database of the DEGRO stereotactic working group, consisting of 637 patients with 858 treatments. Cox regression and logistic regression were used to analyze the association between the number of SBRT treatments or the number and the timing of repeat SBRT courses with overall survival (OS) and the risk of early death. RESULTS: Out of 637 patients, 145 patients were treated for multiple pulmonary metastases; 88 patients received all SBRT treatments within one month whereas 57 patients were treated with repeat SBRT separated by at least one month. Median OS for the total patient population was 23.5 months and OS was not significantly influenced by the overall number of SBRT treatments or the number and timing of repeat SBRT courses. The risk of early death within 3 and 6 months was not increased in patients treated with multiple SBRT treatments, and no grade 4 or grade 5 toxicity was observed in these patients. CONCLUSIONS: In appropriately selected patients, synchronous SBRT for multiple pulmonary oligometastases and repeat SBRT may have a comparable safety and efficacy profile compared to SBRT for one single oligometastasis.

Modelling the immunosuppressive effect of liver SBRT by simulating the dose to circulating lymphocytes: an in-silico planning study.

BACKGROUND: Tumor immune-evasion and associated failure of immunotherapy can potentially be overcome by radiotherapy, which however also has detrimental effects on tumor-infiltrating and circulating lymphocytes (CL). We therefore established a model to simulate the radiation-dose delivered to CL. METHODS: A MATLAB-model was established to quantify the CL-dose during SBRT of liver metastases by considering the factors: hepatic blood-flow, -velocity and transition-time of individual hepatic segments, as well as probability-based recirculation. The effects of intra-hepatic tumor-location and size, fractionation and treatment planning parameters (VMAT, 3DCRT, photon-energy, dose-rate and beam-on-time) were analyzed. A threshold dose ≥0.5Gy was considered inactivating CL and CL0.5 (%) is the proportion of inactivated CL. RESULTS: Mean liver dose was mostly influenced by treatment-modality, whereas CL0.5 was mostly influenced by beam-on-time. 3DCRT and VMAT (10MV-FFF) resulted in lowest CL0.5 values of 16 and 19%. Metastasis location influenced CL0.5, with a mean of 19% for both apical and basal and 31% for the central location. PTV-volume significantly increased CL0.5 from 27 to 67% (10MV-FFF) and from 31 to 98% (6MV-FFF) for PTV-volumes ranging from 14cm3 to 268cm3. CONCLUSION: A simulation-model was established, quantifying the strong effects of treatment-technique, tumor-location and tumor-volume on dose to CL with potential implications for immune-optimized treatment-planning in the future.

Correction to: Improved plan quality with automated radiotherapy planning for whole brain with hippocampus sparing: a comparison to the RTOG 0933 trial.

In the original publication [1] figure legends 2 and 4 have been swapped. The original article was updated to rectify this error.