Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

PURPOSE: Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. METHODS: 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS: 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24 months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). CONCLUSION: In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Trimodal Therapy Using an MR-guided Radiation Therapy Partial Bladder Tumor Boost in Muscle Invasive Bladder Cancer.

Purpose: Bladder preservation with trimodal therapy (TMT; maximal tumor resection followed by chemoradiation) is an effective paradigm for select patients with muscle invasive bladder cancer. We report our institutional experience of a TMT protocol using nonadaptive magnetic resonance imaging-guided radiation therapy (MRgRT) for partial bladder boost (PBB). Methods and Materials: A retrospective analysis was performed on consecutive patients with nonmetastatic muscle invasive bladder cancer who were treated with TMT using MRgRT between 2019 and 2022. Patients underwent intensity modulated RT-based nonadaptive MRgRT PBB contoured on True fast imaging with steady state precession (FISP) images (full bladder) followed sequentially by computed tomography-based RT to the whole empty bladder and pelvic lymph nodes with concurrent chemotherapy. MRgRT treatment time, table shifts, and dosimetric parameters of target coverage and normal tissue exposure were described. Prospectively assessed acute and late genitourinary and gastrointestinal (GI) toxicity were reported. Two-year local control was assessed with Kaplan-Meier methods. Results: Seventeen patients were identified for analysis. PBB planning target volume margins were ≤8 mm in 94% (n = 16) of cases. Dosimetric target coverage parameters were favorable and all normal tissue dose constraints were met. For MRgRT PBB fractions, median table shifts were 0.4 cm (range, 0-3.15), 0.45 cm (0-2.65), and 0.75 cm (0-4.8) in the X, Y, and Z planes, respectively. Median treatment time for MRgRT PBB fractions was 9 minutes (range, 6.9-17.4). We identified 32 out of 100 total MRgRT fractions that may have benefitted from online adaptation based on changes in organ position relative to planning target volume, predominantly because of small bowel (13/32, 41%) or rectum (8/32, 25%). Two patients discontinued RT prematurely. The incidence of highest-grade acute genitourinary toxicity was 1 to 2 (69%) and 3 (6%), whereas the incidence of acute GI toxicity was 1 to 2 (81%) and 3 (6%). There were no late grade 3 events; 17.6% had late grade 2 cystitis and none had late GI toxicity. With median follow-up of 18.2 months (95% CI, 12.4-22.5), the local control rate was 92%, and no patient has required salvage cystectomy. Conclusions: Nonadaptive MRgRT PBB is feasible with favorable dosimetry and low resource utilization. Larger studies are needed to evaluate for potential benefits in toxicity and local control associated with this approach in comparison to standard treatment techniques.

Stereotactic radiosurgery and anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors, or conventional chemotherapy for the management of melanoma brain metastases.

BACKGROUND: Immunotherapy and targeted BRAF/MEK inhibitors (i) have revolutionised the systemic management of advanced melanoma. Given the role of stereotactic radiosurgery (SRS) in the local management of brain metastases, we sought to evaluate clinical outcomes in patients with melanoma brain metastases (MBM) treated with SRS and various systemic therapies. METHODS: Patients were included if MBM were diagnosed and treated with SRS within 3 months of receiving anti-PD-1+CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, or conventional chemotherapy. Comparisons between groups were made for overall survival (OS), distant MBM control, local MBM, systemic progression-free survival (sPFS), and neurotoxicity. RESULTS: In total, 257 patients with 1048 MBM treated over 368 SRS sessions between 2011 and 2020 were identified. On MVA, treatment with anti-PD1+anti-CTLA-4, anti-PD-1, and BRAF/MEK-i improved distant intracranial control over conventional chemotherapy. No significant differences were noted in local control (LC) between groups (p = 0.78). Kaplan-Meier OS at 12 months for anti-PD-1 + CTLA-4 therapy, anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK-i, BRAF-i, and conventional chemotherapy was 68%, 59%, 45%, 62%, 21%, and 15%, respectively (p = <0.0001). The sPFS rates at 12 months were 57%, 53%, 42%, 45%, 14%, and 6% (p = <0.0001). No significant differences were noted in rates of radiation necrosis (p = 0.93). CONCLUSIONS: This is among the largest series evaluating MBM treated with SRS and various systemic therapy regimens. Our analysis noted significant differences in OS, distant MBM control, and sPFS by systemic therapy. No differences in LC or radiation necrosis risk were noted.

Clinical outcomes of non-small cell lung cancer brain metastases treated with stereotactic radiosurgery and immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, chemotherapy and immune checkpoint inhibitors, or chemotherapy alone.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used in the systemic management of non-small cell lung cancer (NSCLC) brain metastases (BMs). However, optimizing control of NSCLC BM with stereotactic radiosurgery (SRS) and various systemic therapies remains an area of investigation. METHODS: Between 2016 and 2019, the authors identified 171 NSCLC BM patients with 646 BMs treated with single-fraction SRS within 3 months of receiving treatment with ICIs (n = 56; 33%), EGFR-TKI (n = 30; 18%), chemotherapy and ICIs (n = 23; 14%), or standard chemotherapy alone (n = 62; 36%). Time-to-event analysis was conducted, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival from SRS. RESULTS: The median follow-up from BM diagnosis was 8.9 months (range 0.3-127 months). The 12-month Kaplan-Meier DIC rates were 37%, 53%, 41%, and 21% (p = 0.047) for the ICI, EGFR-TKI, ICI and chemotherapy, and chemotherapy-alone groups, respectively. On multivariate analysis, DIC was improved with EGFR-TKI (HR 0.4, 95% CI 0.3-0.8, p = 0.005) compared with conventional chemotherapy and treatment with SRS before systemic therapy (HR 0.5, 95% CI 0.3-0.9, p = 0.03) compared with after; and LC was improved with SRS before (HR 0.4, 95% CI 0.2-0.9, p = 0.03) or concurrently (HR 0.3, 95% CI 0.1-0.6, p = 0.003) compared with after. No differences in radionecrosis were noted by timing or type of systemic therapy. CONCLUSIONS: The authors' analysis showed significant differences in DIC based on receipt of systemic therapy and treatment with SRS before systemic therapy improved DIC. Prospective evaluation of the potential synergism between systemic therapy and SRS in NSCLC BM management is warranted.

Management of early-stage metastatic prostate cancer: appraisal of locoregional treatments and radiation therapy, with or without immunomodulation.

The current standard for the management of locally advanced and early stage metastatic prostate cancer relies on a backbone of androgen deprivation therapy (ADT) combined with radiotherapy (RT), a regimen that at a glance appears relatively straightforward. The emergence of newer diagnostic, genomic and imaging modalities have allowed for better disease risk-stratification and opened avenues for the development of more patient-centered treatment strategies. This review aims to highlight the central role of RT as part of a multi-modal approach and discuss established and emerging data for the management of locally advanced disease, biochemical recurrence, and oligometastatic disease, as well as the use of immunotherapies and radio-isotopes. This review will also briefly discuss ongoing clinical trials that provide new insights into the paradigm shift in the management of locally advanced prostate cancer.

Clinical assessment of a biophysical model for distinguishing tumor progression from radiation necrosis.

PURPOSE: The efficacy of an imaging-driven mechanistic biophysical model of tumor growth for distinguishing radiation necrosis from tumor progression in patients with enhancing lesions following stereotactic radiosurgery (SRS) for brain metastasis is validated. METHODS: We retrospectively assessed the model using 73 patients with 78 lesions and histologically confirmed radiation necrosis or tumor progression. Postcontrast T1-weighted MRI images were used to extract parameters for a mechanistic reaction-diffusion logistic growth model mechanically coupled to the surrounding tissue. The resulting model was then used to estimate mechanical stress fields, which were then compared with edema visualized on FLAIR imaging using DICE similarity coefficients. DICE, model, and standard radiographic morphometric analysis parameters were evaluated using a receiver operating characteristic (ROC) curve for prediction of radiation necrosis or tumor progression. Multivariate logistic regression models were then constructed using mechanistic model parameters or advanced radiomic features. An independent validation was performed to evaluate predictive performance. RESULTS: Tumor cell proliferation rate resulted in ROC AUC = 0.86, 95% CI: 0.76-0.95, P < 0.0001, 74% sensitivity and 95% specificity) and DICE similarity coefficient associated with high stresses demonstrated an ROC AUC = 0.93, 95% CI: 0.86-0.99, P < 0.0001, 81% sensitivity and 95% specificity. In a multivariate logistic regression model using an independent validation dataset, mechanistic modeling parameters had an ROC AUC of 0.95, with 94% sensitivity and 96% specificity. CONCLUSIONS: Imaging-driven biophysical modeling of tumor growth represents a novel method for accurately predicting clinically significant tumor behavior.

Strategies to Minimize Late Effects From Pelvic Radiotherapy.

During the past 30 years, radiation treatment techniques have significantly improved, from conventional external-beam radiation therapy, to three-dimensional conformal radiation therapy, to current intensity-modulated radiation therapy, benefiting patients who undergo treatment of pelvic malignancies. Modern treatment options also include proton beam irradiation as well as low and high dose rate brachytherapy. Although the acute adverse effects of these modalities are well documented in clinical trials, less well known are the true incidence and optimal management of those late adverse effects that can occur months to years later. In a population of survivors of cancer that is steadily increasing, with many such patients receiving radiotherapy at some time during their disease course, these late effects can become a considerable management and quality-of-life issue. This review will examine the range of late toxicities that can occur from pelvic radiotherapy and explore strategies to prevent and mitigate them.

The Role of Radiation Therapy in the Older Patient.

PURPOSE OF REVIEW: Older patients represent a unique subgroup of the cancer patient population for which the role of radiation therapy (RT) requires special consideration. This review will discuss many of these considerations as well as various radiation treatment techniques in the context of a variety of disease sites. RECENT FINDINGS: Several recent studies give insight into the management of older cancer patients considering their age, performance status, comorbid conditions, quality of life, genetics, cost, and individual goals. RT plays an evolving and pivotal role in providing optimal care for this population. Recent advances in RT technique allow for more precise treatment delivery and reduced toxicity. Studies evaluating the use of radiation therapy in breast, brain, lung, prostate, rectal, pancreatic, esophageal, and oligometastatic cancer are summarized and discussed in the context of treating the older patient population. Individual age, performance and functional status, comorbid conditions, and patients' objectives and goals should all be considered when presenting treatment options for older patients and age alone should not disqualify patients from curative intent treatments. When possible, hypofractionated courses should be utilized as outcomes are often equivalent and toxicities are reduced. In many cases, RT may be preferable to other treatment options due to decreased toxicity profile and acceptable disease control.

Predictors of Adverse Radiation Effect in Brain Metastasis Patients Treated With Stereotactic Radiosurgery and Immune Checkpoint Inhibitor Therapy.

PURPOSE: Immune checkpoint inhibitor (ICI) therapy has recently been found to improve survival in patients with a number of cancers, including those with metastatic disease. There is an association of adverse radiation effect (ARE) in patients with brain metastases who have been treated with stereotactic radiosurgery (SRS) and ICIs. METHODS AND MATERIALS: Single-institution retrospective review identified 1118 brain metastases treated with SRS between 2013 and 2018 that had received ICI therapy and 886 metastases that did not receive ICI. Toxicity grading was done via the Common Terminology Criteria for Adverse Events v4.0 grading criteria. Cumulative incidence of ARE was estimated using competing risks methodology; univariate and multivariable regression models were generated to estimate the subdistribution hazard (sHR) of ARE. RESULTS: Two-year cumulative incidence of ARE was 4.5% and 2.1% in patients treated with and without ICI, respectively (Gray's P = .004). Of the 52 metastases exhibiting ARE during the follow-up period, ARE severity by Common Terminology Criteria for Adverse Events v4 was grade 1 in 14 patients, grade 2 in 15, grade 3 in 9, and grade 4 in 14. There were no grade 5 events. Factors associated with an increased sHR of ARE on univariate analysis included ICI, metastasis volume, SRS dose, prescription isodose line, cavity-directed SRS, and V12. Multivariable analysis revealed prescription isodose line (sHR 0.95, P < .01) and ICI (sHR 2.58, P < .01) as significant predictors of ARE. Increasing V12 was associated with a rapidly increasing risk of adverse radiation effect in patients who received ICI. CONCLUSIONS: Our findings suggest that patients receiving ICI have an increased risk of ARE after radiosurgery for brain metastases, with large metastases being at particularly high risk.

Identification of CD37, cystatin A, and IL-23A gene expression in association with brain metastasis: analysis of a prospective trial.

PURPOSE/OBJECTIVES: We aimed to assess the predictive value of a lung cancer gene panel for the development of brain metastases. MATERIALS/METHODS: Between 2011 and 2015, 102 patients with lung cancer were prospectively enrolled in a clinical trial in which a diagnostic fine-needle aspirate was obtained. Gene expression was conducted on all samples that rendered a diagnosis of non-small cell lung cancer (NSCLC). Subsequent retrospective analysis of brain metastases-related outcomes was performed by reviewing patient electronic medical records. A competing risk multivariable regression was performed to estimate the adjusted hazard ratio for the development of brain metastases and non-brain metastases from NSCLC. RESULTS: A total of 49 of 102 patients had died by the last follow-up. Median time of follow-up was 13 months (range 0.23-67 months). A total of 17 patients developed brain metastases. Median survival time after diagnosis of brain metastases was 3.58 months (95% confidence interval (CI) 2.17, not available). A total of 30 patients developed metastases without any evidence of brain metastases until the time of death or last follow-up. Competing risk analysis identified three genes that were downregulated differentially in the patients with brain metastases versus non-brain metastatic disease: CD37 (0.017), cystatin A (0.022), and IL-23A (0.027). Other factors associated with brain metastases include: stage T ( P ⩽ 8.3e-6) and stage N ( P= 6.8e-4). CONCLUSIONS: We have identified three genes, CD37, cystatin A, and IL-23A, for which downregulation of gene expression was associated with a greater propensity for developing brain metastases. Validation of these biomarkers could have implications on surveillance patterns in patients with brain metastases from NSCLC.

Surgical resection and postoperative radiosurgery versus staged radiosurgery for large brain metastases.

PURPOSE: The purpose of this study was to retrospectively evaluate the new treatment paradigm of staged stereotactic radiosurgery (SRS) for the treatment of large brain metastases (BM) compared to the standard of surgical resection followed by SRS. METHODS: We evaluated 78 patients with large BM treated 2012-2017 with surgical resection and postoperative SRS (surgery + SRS) or staged SRS separated by 1 month. Overall survival (OS) was estimated using the Kaplan Meier method and compared across groups using the log-rank test. Cumulative incidence of neurologic death and local and distant brain failure (LF, DBF) were estimated using competing risk methodology. RESULTS: Forty patients were treated with surgery + SRS and 38 patients were treated with staged SRS. Median follow-up was 23.2 months (95% CI 20.5-39.3). Median OS was 13.2 months for staged SRS compared to surgery + SRS 9.7 months (p = 0.53). Cumulative incidence of neurologic death at 1 year was 23% after surgery + SRS, 27% after staged SRS (p = 0.69); cumulative incidence of LF at 1 year was 6% and 8% (p = 0.65) and 1-year DBF was 59% and 21% (p ≤ 0.01). Overall rates of leptomeningeal failure and radiation necrosis were similar between the groups (p = 0.63 and p = 1.0). CONCLUSIONS: Though surgery and postoperative SRS is the standard, staged SRS represents an attractive treatment paradigm for treating large BM without sacrificing LC or survival, and potentially decreases DBF. Prospective studies are needed to validate these findings.

Staged Stereotactic Radiosurgery for Large Brain Metastases: Local Control and Clinical Outcomes of a One-Two Punch Technique.

BACKGROUND: Treatment options are limited for large, unresectable brain metastases. OBJECTIVE: To report a single institution series of staged stereotactic radiosurgery (SRS) that allows for tumor response between treatments in order to optimize the therapeutic ratio. METHODS: Patients were treated with staged SRS separated by 1 mo with a median dose at first SRS of 15 Gy (range 10-21 Gy) and a median dose at second SRS of 14 Gy (range 10-18 Gy). Overall survival was evaluated using the Kaplan-Meier method. Cumulative incidences were estimated for neurological death, radiation necrosis, local failure (marginal or central), and distant brain failure. Absolute cumulative dose-volume histogram was created for each treated lesion. Logistic regression and competing risks regression were performed for each discrete dose received by a certain volume. RESULTS: Thirty-three patients with 39 lesions were treated with staged radiosurgery. Overall survival at 6 and 12 mo was 65.0% and 60.0%, respectively. Cumulative incidence of local failure at 6 and 12 mo was 3.2% and 13.3%, respectively. Of the patients who received staged therapy, 4 of 33 experienced local failure. Radiation necrosis was seen in 4 of 39 lesions. Two of 33 patients experienced a Radiation Therapy Oncology Group toxicity grade > 2 (2 patients had grade 4 toxicities). Dosimetric analysis revealed that dose (Gy) received by volume of brain (ie, VDose(Gy)) was associated with radiation necrosis, including the range V44.5Gy to V87.8Gy. CONCLUSION: Staged radiosurgery is a safe and effective option for large, unresectable brain metastases. Prospective studies are required to validate the findings in this study.

Early or late radiotherapy following gross or subtotal resection for atypical meningiomas: Clinical outcomes and local control.

We report a single institution series of surgery followed by either early adjuvant or late radiotherapy for atypical meningiomas (AM). AM patients, by WHO 2007 definition, underwent subtotal resection (STR) or gross total resection (GTR). Sixty-three of a total 115 patients then received fractionated or stereotactic radiation treatment, early adjuvant radiotherapy (≤4months after surgery) or late radiotherapy (at the time of recurrence). Kaplan Meier method was used for survival analysis with competing risk analysis used to assess local failure. Overall survival (OS) at 1, 2, and 5years for all patients was 87%, 85%, 66%, respectively. Progression free survival (PFS) at 1, 2, and 5years for all patients was 65%, 30%, and 18%, respectively. OS at 1, 2, and 5years was 75%, 72%, 55% for surgery alone, and 97%, 95%, 75% for surgery+radiotherapy (log-rank p-value=0.0026). PFS at 1, 2, and 5years for patients undergoing surgery without early adjuvant radiotherapy was 64%, 49%, and 27% versus 81%, 73%, and 59% for surgery+early adjuvant radiotherapy (log-rank p-value=0.0026). The cumulative incidence of local failure at 1, 2, and 5years for patients undergoing surgery without early External Beam Radiation Therapy (EBRT) was 18.7%, 35.0%, and 52.9%, respectively, versus 4.2%, 13.3%, and 20.0% for surgery and early EBRT (p-value=0.02). Adjuvant radiotherapy improves OS in patients with AM. Early adjuvant radiotherapy improves PFS, likely due to the improvement in local control seen with early adjuvant EBRT.

Impact of radiosurgical management of geriatric patients with brain metastases: Clinical and quality of life outcomes.

OBJECTIVES: Recent trials have shown that whole brain radiotherapy (WBRT) can worsen performance status, particularly in the geriatric population. We reviewed our institutional experience with geriatric patients (> 70 years) with brain metastases treated with radiosurgery (SRS) to determine clinical and quality of life (QOL) outcomes. METHODS: Between 7/2000 and 1/2013, a retrospective review was performed on 467 patients treated with SRS (114 geriatric patients). Overall survival (OS), cause of death, and WBRT were evaluated. A retrospective review of geriatric patients was performed with assessments of Karnofsky performance score (KPS, N=69), mini-mental status examinations (MMSE, N=39), and Spitzer QOL (SQOL, N=39) at initial interview, 6, and 12 months after SRS. Repeated Measures ANOVA was used to evaluate differences in quality of life values. Kaplan-Meier analysis estimated survival and time to WBRT. RESULTS: Geriatric patients had a shorter OS compared to non-geriatric patients (p<0.035). Fewer patients in the geriatric cohort received whole brain (p<0.001) or subsequent Gamma Knife stereotactic radiosurgery (GKRS) (p<0.025). No difference was seen in neurologic death rates (p<0.4). In geriatric patients, SQOL declined from 0 to 6 months (mean 6.5 to 5.9, respectively, p<0.02) and 0 to 12 months (mean 6.5 and 5.6, respectively, p<0.03). KPS and MMSE scores did not change over time. Grade 3 or 4 toxicity was 9% in geriatric patients. There was no grade 5 toxicity. CONCLUSION: Geriatric patients tolerate GKRS without a significant decline in KPS or MMSE and with acceptable toxicity profile. SRS also spares a significant proportion of geriatric patients from WBRT, and its associated toxicities.