SABR-Dual: a phase II/III trial of two-fraction versus five-fraction stereotactic radiotherapy for localized low- and favorable intermediate-risk prostate cancer.

BACKGROUND: Dose-escalated radiotherapy is known to improve progression free survival in patients with localized prostate cancer, and recent advances have led to the standardization of ultrahypofractionated stereotactic ablative radiotherapy (SABR) delivered in just 5-fractions. Based on the known effectiveness of the accepted though invasive 2-fraction treatment method of high-dose-rate brachytherapy and given the ubiquity of prostate cancer, a further reduction in the number of treatments of external-beam SABR is possible. This study aims to evaluate the safety, efficacy, and non-inferiority of generalizable 2-fraction SABR compared to the current 5-fraction regimen. METHODS: 502 patients will be enrolled on this phase II/III randomized control trial. Eligible patients will have previously untreated low- or favorable intermediate-risk adenocarcinoma of the prostate. Patients will be randomized between standard SABR of 40 Gy in 5 fractions given every-other-day and 27 Gy in 2 fractions at least two days apart but completing within seven days. MRI-based planning, radiopaque hydrogel spacer insertion, and fiducial marker placement are required, and SABR will be delivered on either a standard CT-guided linear accelerator or MR-LINAC. The primary endpoint will be freedom from disease progression, with additional secondary clinical, toxicity, and quality of life endpoints. DISCUSSION: This study will be the largest prospective randomized trial, adequately powered to demonstrate non-inferiority, comparing 2-fraction SABR to standard 5-fraction SABR for localized prostate cancer. As the protocol does not obligate use of an MRI-LINAC or other adaptive technologies, results will be broadly generalizable to the wider community. TRIAL REGISTRATION: This trial is registered on Clinicaltrials.gov: ClinicalTrials.gov Identifier: NCT06027892.

Converging survival trends in non-small cell lung cancer patients with and without brain metastasis receiving state-of-the-art treatment.

INTRODUCTION: Historically, patients with brain metastasis (BM) have been excluded from clinical trials investigating treatments for non-small cell lung cancer (NSCLC) due to their unfavorable prognosis. Advanced treatments have increased survival prospects for NSCLC patients with BM. This study evaluated the life expectancy of NSCLC patients with and without BM in the context of contemporary treatments. METHODS: Outcome data were collected for patients with advanced NSCLC attending a tertiary medical center between 2015 and 2020. Patients were stratified according to BM status and compared for overall survival (OS) using log-rank and Cox regression analyses. RESULTS: The cohort included 360 patients with NSCLC of whom 134 (37.2%) had BM. Most (95%) of cases of BM developed within the first two years: 63% at diagnosis, 18% during the first year, 14% during the second year. There was no significant difference in OS between patients without BM and those with BM (median 23.7 vs. 22.3 months, HR = 0.97, p = 0.82); patients with BM and a targetable or non-targetable mutation (40.2 vs. 31.4 months, HR = 0.93, p = 0.84, and 20.7 vs. 19.87 months, HR = 0.95, p = 0.75, respectively); and patients with symptomatic BM (23.7 vs. 19.8 months, HR = 0.95, p = 0.78). Treatment for BM (95% of patients) consisted of stereotactic radiosurgery or tyrosine kinase inhibitors, with corresponding intracranial control rates of 90% and 86%. CONCLUSION: The results imply that the presence of BM has no impact on the prognosis of NSCLC. The practice of excluding NSCLC patients with BM from clinical trials warrants reconsideration.

Arterial and Venous Thromboembolism in ALK-Rearrangement-Positive Non-small Cell Lung Cancer: A Population-Based Cohort Study.

INTRODUCTION: There is scarce data regarding the incidence of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in the molecular subtypes of non-small cell lung cancer (NSCLC). We aimed to investigate the association between Anaplastic Lymphoma Kinase (ALK)-positive NSCLC and thromboembolic events. METHODS: A retrospective population-based cohort study of the Clalit Health Services database, included patients with NSCLC diagnosed between 2012 and 2019. Patients exposed to ALK-tyrosine-kinase inhibitors (TKIs) were defined as ALK-positive. The outcome was VTE (at any site) or ATE (stroke or myocardial infarction) 6 months prior to the diagnosis of cancer, until 5 years post-diagnosis. The cumulative incidence of VTE and ATE and hazard-ratios (HR) with 95% CIs were calculated (at 6- 12- 24 and 60-months), using death as a competing risk. Cox proportional hazards multivariate regression was performed, with the Fine and Gray correction for competing risks. RESULTS: The study included 4762 patients, of which 155 (3.2%) were ALK-positive. The overall 5-year VTE incidence was 15.7% (95% CI, 14.7-16.6%). ALK-positive patients had a higher VTE risk compared to ALK-negative patients (HR 1.87 [95% CI, 1.31-2.68]) and a 12-month VTE incidence of 17.7% (13.9-22.7%) compared to 9.9% (9.1-10.9%) in ALK-negative patients. The overall 5-year ATE incidence was 7.6% [6.8-8.6%]. ALK positivity was not associated with ATE incidence (HR 1.24 [0.62-2.47]). CONCLUSIONS: In this study, we observed a higher VTE risk, but not ATE risk, in patients with ALK-rearranged NSCLC relative to those without ALK rearrangement. Prospective studies are warranted to evaluate thromboprophylaxis in ALK-positive NSCLC.

The Relationship of Diabetes Mellitus to Efficacy of Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Immune checkpoint inhibitors (ICI) are the new standard therapy in patients with metastatic NSCLC (mNSCLC). Metformin, previously associated with improved chemotherapy efficacy in diabetic and nondiabetic cancer patients, was recently associated with increased ICI efficacy. In this study, we aimed to explore the correlations between diabetes mellitus (DM), metformin use, and benefit from ICI in mNSCLC patients. METHODS: All mNSCLC patients treated with ICI in our center between February 2015 and April 2018 were identified. Demographic and clinical data were extracted retrospectively. Cox proportional hazards regression, t tests, and χ2 tests were employed to evaluate associations of progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR), with DM status, metformin use, and HbA1c levels, as appropriate. RESULTS: Of 249 mNSCLC patients treated with ICI, 57 (22.8%) had DM. Thirty-seven (64.9% of all diabetic patients) patients were treated with metformin. A significant negative correlation of DM with PFS and OS was demonstrated (HR 1.5 [1.01-2.06], p = 0.011, and HR 1.5 [1.08-2.08], p = 0.017, respectively). Metformin exposure had no significant correlation with PFS or OS in diabetic mNSCLC patients (HR 1.08 [0.61-1.93], p = 0.79, and HR 1.29 [0.69-2.39], p = 0.42, respectively). There were no differences between groups with respect to ORR and DCR. CONCLUSION: Our data show a potential negative relationship between DM and ICI efficacy in mNSCLC patients. In contrast to reports with chemotherapy, we found no positive relationship between metformin use and ICI therapy in diabetic patients with mNSCLC. Further studies are needed to evaluate the effect of metformin in nondiabetic mNSCLC patients.

Comparative Study of Two Cohorts of Newly Diagnosed Crohn's Disease Demonstrates Change in Therapeutic Strategies.

BACKGROUND: There has been a paradigm shift in the treatment of Crohn's disease (CD) involving the rapid introduction of biologics and/or immunomodulators after diagnosis. We wished to assess whether this was applied to patients with newly diagnosed CD in a tertiary inflammatory bowel disease referral centre in Israel. METHODS: Newly diagnosed CD patients were stratified into 2 groups: the early group was diagnosed between 2005 and 2007 and the late group was diagnosed between 2010 and 2012. Baseline demographics, medical and surgical treatments, disease course and complications during those 2 periods were analyzed. RESULTS: Each group included 60 patients. Significantly higher rates of immunomodulators and biologics were administered to patients in the late group compared to the early group (81.7 and 36.7% compared to 56.7 and 18.3%, p = 0.004 and p = 0.021, respectively). On the other hand, steroid therapy was less prevalent in the late (36.7%) group compared to that of the early group (56.7%), p = 0.059. Medical and surgical CD outcomes, including exacerbations/hospitalizations and surgeries, were comparable for both groups. CONCLUSIONS: There was a change in treatment strategy between 2005-2007 and 2010-2012, as reflected in higher proportions of biologics/immunomodulators for patients with newly diagnosed CD. This was associated with a steroid-sparing effect.

The role of a radiopaque peri-rectal hydrogel spacer in aiding accurate daily image-guidance for prostate stereotactic radiotherapy.

Introduction: Precise patient positioning with image guidance (IGRT) is essential for safe prostate radiotherapy. We present the first report of utilizing a CT-visible hydrogel spacer, used to decrease rectal radiation dose, as a surrogate fiducial marker to aid in daily IGRT with cone-beam CT (CBCT) in stereotactic radiotherapy (SABR) for prostate cancer. Materials and methods: Prior to CT simulation, patients underwent placement of three intraprostatic gold fiducial markers and radiopaque hydrogel spacer per standard practice. At treatment, after initial setup, a CBCT was acquired and fused to the planning CT based on 3-dimensional matching of the spacer. A second alignment was then performed based on the fiducial markers. The six directional shifts (three linear and three rotational) were recorded, and the differences compared. Results: 140 individual fractions across 41 consecutive patients were evaluated. Mean/median differences between hydrogel spacer-based and fiducial-based alignment in linear (vertical, longitudinal, lateral) and rotational (rotation, pitch, roll) shifts were 0.9/0.6mm, 0.8/0.5mm, and 0.6/0.4mm, and 0.38/0, 0.62/0, and 0.35/0 degrees, respectively. No difference was observed in 9.9%, 22.9%, and 22.14% of linear shifts, and 65.7%, 65%, and 66.4% rotational shifts, respectively. Significantly smaller differences were observed in the latter 70 fractions vs. the former, and results were consistent across evaluators. Conclusions: For precise daily IGRT with CBCT for prostate SABR, alignment using a radiopaque hydrogel spacer was highly comparable to intraprostatic fiducial markers. This represents the first report supporting an additional indication of IGRT for a CT-visible hydrogel spacer, to further enhance treatment accuracy and potentially obviate the need for the additional fiducial marker procedure.

Acute toxicity and early PSA response after two-fraction stereotactic radiotherapy for localized prostate cancer using peri-rectal spacing - Initial report of the SABR-Dual trial.

PURPOSE: SABR-Dual is a phase III trial with an initial phase-I safety cohort, of two-fraction stereotactic radiotherapy (SABR) with optional MRI-based focal boost, using peri-rectal spacing, for localized prostate cancer. This represents the initial report from the phase-I non-randomized cohort. MATERIALS AND METHODS: Subjects had favorable intermediate risk (FIR) or low risk (LR) prostate adenocarcinoma, and gland volume <80cc. All underwent radiopaque hydrogel spacer and fiducial marker placement prior to simulation (CT and 3-tesla T2 MRI). The clinical target volume included the entire prostate, and in FIR patients, 1-2cm of seminal vesicle (SV). A 2mm expansion was applied for planning target volume (PTV), and a dose of 27 Gy was prescribed to the PTV-prostate, 23 Gy to the PTV-SV, with an optional 30 Gy simultaneous boost (SIB) to an MRI-defined dominant lesion. Primary endpoint was 3-month patient-reported changes in quality of life based on the EPIC-26, IPSS, and SHIM questionnaires. Secondary endpoints were 6-month quality of life, acute toxicity (using CTCAEv5) and early PSA response. RESULTS: Among the 20 patients in the phase-I cohort, 95% had FIR disease, and 50% received an SIB. At median follow-up of 8 months, a 3-month minimally clinically important change occurred in 1/20 (5%), 6/20 (30%), 2/20 (10%), 4/20 (20%), and 5/20 (25%) in urinary incontinence, urinary obstructive, bowel, sexual, and hormonal domains. There was a mean increase of 1±5.4 in IPSS and decrease of 1.8±6.5 in SHIM scores. Rates of grade 2 urinary and bowel toxicity 10% and 0%, respectively, with no grade ≥3 toxicities. Mean PSA decrease at last follow-up was 70.4%±17.7%. CONCLUSION: This generalizable protocol of two-fraction prostate SABR using peri-rectal spacing is a safe approach for ultra-hypofractionated dose-escalation, with minimal acute toxicity. Longer-term outcomes and direct comparison with standard 5-fraction SABR are being studied in the phase-III randomized portion of SABR-Dual.

Same-day versus delayed simulation imaging after placement of a perirectal hydrogel spacer for prostate radiotherapy.

Introduction: Placement of a perirectal hydrogel spacer has been demonstrated to reduce the risk of rectal toxicity from prostate radiation. Practices vary regarding the timing of CT simulation after hydrogel placement, and the ideal schedule remains unknown. Methods: Thirty patients with localized prostate adenocarcinoma underwent transrectal ultrasound-guided placement of an iodinated SpaceOAR™ hydrogel prior to radiotherapy. Per evolving practice, 15 completed same-day simulation and 15 returned for simulation 1-2 weeks later. Hydrogel volume, perirectal distance, air-void volume, and rectal dosimetry per NRG GU005 were compared between CT simulation, 1st fraction Cone-Beam-CT (CBCT), and final CBCT. Results: CT simulation occurred 8.8 ± 2.4 days after placement in the delayed group, with no significant difference in the interval between simulation and 1st fraction between groups (p = 0.165). Greater observed de-creases in hydrogel volume (0.57 cc vs. 0.04 cc, p = 0.0002), and perirectal distance at both mid-gland (1.32 mm vs. 0.17 mm) and tallest point (2.40 mm vs. 0.04 mm) were seen on 1st-fraction CBCT in the same-day group (p = 0.0039; p = 0.0002). Per dosimetry recalculated on 1st fraction CBCT, five (D3 cc and D50%) versus one (D50%) rectal dose parameters were exceeded in the same-day and delayed groups, respectively, and 10 versus one parameters had a relative increase of ≥ 20%. Conclusion: Due to the evolving anatomic changes in the days following hydrogel placement, same-day simulation scanning may introduce unintended variability in rectal dosimetry at the time of prostate radiotherapy.

Correlations between pathogenic variants in DNA repair genes and anticancer treatment efficacy in stage IV non-small cell lung cancer: A large real-world cohort and review of the literature.

BACKGROUND: Mutations in genes involved in DNA damage repair (DDR), a hallmark of cancer, are associated with increased cancer cell sensitivity to certain therapies. This study sought to evaluate the association of DDR pathogenic variants with treatment efficacy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A retrospective cohort of consecutive patients with advanced NSCLC attending a tertiary medical center who underwent next-generation sequencing in 01/2015-8/2020 were clustered according to DDR gene status and compared for overall response rate (ORR), progression-free survival (PFS) (patients receiving systemic therapy), local PFS (patients receiving definitive radiotherapy), and overall survival (OS) using log-rank and Cox regression analyses. RESULTS: Of 225 patients with a clear tumor status, 42 had a pathogenic/likely pathogenic DDR variant (pDDR), and 183 had no DDR variant (wtDDR). Overall survival was similar in the two groups (24.2 vs. 23.1 months, p = 0.63). The pDDR group had a higher median local PFS after radiotherapy (median 45 months vs. 9.9 months, respectively; p = 0.044), a higher ORR (88.9% vs. 36.2%, p = 0.04), and a longer median PFS (not reached vs. 6.0 months, p = 0.01) in patients treated with immune checkpoint blockade. There was no difference in ORR, median PFS, and median OS in patients treated with platinum-based chemotherapy. CONCLUSION: Our retrospective data suggest that in patients with stage 4 NSCLC, pathogenic variants in DDR pathway genes may be associated with higher efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). This should be further explored prospectively.

Sarcoma incidence and subtype distribution in Israel - A population-based study.

INTRODUCTION: This report aimed to describe sarcoma incidence and subtype distribution in Israel, as well as evaluate accuracy of registration for sarcoma cases diagnosed at a single institution. METHODS: Incidence reports were issued for all sarcomas diagnosed between 1996-2017. Concordance between the WHO classification used in pathology reports and the diagnoses in the national registry were evaluated. Sarcoma subtype distribution was analysed. RESULTS: Between 1996-2017 sarcomas had an annual percent change of -2.1 in men and -1.5 in women. Concordance between the pathology report coding and registry in the INCR were 90 %. The most common subtypes were Kaposi sarcoma (KS), liposarcoma and leiomyosarcoma accounting for 21 %, 14.4 % and 10.8 % of all sarcomas, respectively. KS had the highest incidence with 1.6/100,000 persons. CONCLUSION: This is the first description of sarcoma incidence and subtype distribution in Israel. Sarcoma incidence in Israel has declined in the past two decades.

Bevacizumab for stereotactic radiosurgery-induced radiation necrosis in patients with non-small cell lung cancer treated with immune check-point inhibitors.

BACKGROUND: Bevacizumab was shown to be effective in the treatment of brain radiation necrosis (RN) attributed to the use of stereotactic radiosurgery (SRS). Data on its efficacy and safety in non-small cell lung cancer (NSCLC) patients treated with immune check-point inhibitors (ICI) is lacking. METHODS: A multi-center retrospective analysis of all consecutive patients with NSCLC treated with ICI, who received bevacizumab for post-SRS RN between April 2017 and June 2020. Improvement in RN-associated symptoms, RN radiological improvement, and decrease in corticosteroid dose following bevacizumab initiation were assessed. RESULTS: Thirteen patients were identified. The median time from diagnosis of RN to initiation of bevacizumab was 3 months (range 1.1-7.8 months), and the median number of bevacizumab cycles before assessment was 2 (range, 1-5). Patients continued ICI during treatment with bevacizumab. Improvement in RN-associated symptoms was observed in 11 patients (85%). In ten patients (77%) the daily dose of dexamethasone was decreased. Radiological improvement of RN occurred in all 11 cases available for radiological assessment (100%). Treatment was withheld in two patients for grade 3-4 toxicity. At a median follow up of 11.9 months (range 2.0-35.4 months), one patient experienced a recurrent episode of RN; the estimated median survival since RN diagnosis was 21.9 months (95% CI 3.8-40.2 months). CONCLUSION: Treatment with bevacizumab appears to be safe and effective for the treatment of SRS-induced RN in patients with NSCLC treated with ICI. This is the first series to report on the use of bevacizumab in this clinical scenario.

Venous thromboembolism incidence and risk assessment in lung cancer patients treated with immune checkpoint inhibitors.

BACKGROUND: There are scarce data on venous thromboembolism (VTE) rates among non-small cell lung cancer (NSCLC) patients treated with immune-checkpoint inhibitors (ICI). The Khorana Score (KS), used to guide thromboprophylaxis in cancer patients, was validated in patients receiving chemotherapy. OBJECTIVE: To assess VTE rates and KS performance among NSCLC patients treated with ICI or chemotherapy. METHODS: We performed a retrospective cohort study of NSCLC patients starting either ICI or platinum-based chemotherapy. The 6-month cumulative incidence of VTE in the ICI and chemotherapy cohorts and hazard ratios (HR) with 95% confidence intervals (CI) were calculated, using death as a competing risk. Subgroup analysis of low (0-1) and high (≥2) KS risk groups was performed. RESULTS: The study included 345 NSCLC patients receiving single agent ICI (n = 176) or chemotherapy (n = 169). The 6-month cumulative incidence of VTE was 7.1% in the chemotherapy cohort and 4.5% in the ICI cohort (HR for chemotherapy = 1.6, 95% CI 0.66-3.9). Among chemotherapy treated patients, the high-risk KS group had a trend toward a higher VTE incidence, compared with patients with a low-risk KS (HR 3.04, 95% CI 0.82-11.22). Among ICI-treated patients, the high-risk KS group had a trend toward a lower VTE incidence compared with the low-risk group (HR 0.17, 95% CI 0.02-1.36). CONCLUSIONS: VTE rates were higher among NSCLC patients treated with platinum-based chemotherapy than those treated with ICI alone, though the precision of the relative estimate is low. The KS did not identify high-risk ICI-treated patients, suggesting that an ICI-specific risk model is warranted.

Lower tumor volume is associated with increased benefit from immune checkpoint inhibitors in patients with advanced non-small-cell lung cancer.

AIM: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment for advanced non-small-cell lung cancer (NSCLC), yet many patients do not benefit from Programmed cell death protein 1 (PD-1) axis inhibitors, emphasizing the need for additional markers for better patient selection. Our aim was to evaluate the association between tumor volume and response to ICI. METHODS: This retrospective ethically-approved study included all consecutive patients with advanced NSCLC who were evaluated with a fluorodeoxyglucose-positron emission tomography scan, prior to the first administration of a single-agent ICI between 1/2016 and 6/2017. Tumor burden was calculated based on total body metabolic tumor volume and sum of all measurable lesions (SOML). RESULTS: Median SOML was 88 mm, and was inversely and significantly associated with progression-free survival (PFS) (hazard ratio [HR] 2, CI 1.28-3.37, P = .003) and overall survival (OS) (HR 2.36, CI 1.13-4.94, P = .02). SOML≤80 mm had a significantly longer PFS compared to patients with a SOML≥80 mm (median PFS 9.7 vs 3.7 months, respectively, HR for progression 2.26, CI 1.1-4.5, P = .02). Patients with a SOML≤80 also had longer median OS compared to patients with SOML≥80 (median OS 12 vs 9.8 months, respectively, HR for death 3.1, CI 1.2-8, P = .018). CONCLUSIONS: Low tumor burden was associated with higher response rates (RR), and better PFS and OS in advanced NSCLC patients treated with ICI. These results may improve the selection of patients for treatment with single-agent ICI, as opposed to the combination with chemotherapy, which might be more appropriate for patients with high tumor burden. Prospective analysis is warranted.

Treatment beyond progression with immune checkpoint inhibitors in non-small-cell lung cancer.

Aim: The treatment paradigm of advanced non-small-cell lung cancer has recently changed with the introduction of immune checkpoint inhibitors (ICIs). It is common practice to continue treatment beyond progression (TBP) in selected cases. The aim of this study was to evaluate real life practice and outcomes related to TBP. Materials & methods: We retrospectively evaluated advanced non-small-cell lung cancer patients treated with ICI therapy and identified patients who were treated beyond progression. Results: Of 207 patients included in this analysis, 22% patients received TBP. A total of 36% achieved a clinical benefit. A total of 27% patients had a progression-free interval over 6 months after receiving TBP. Conclusion: A subset of patients who were treated beyond progression with ICI achieved a clinically meaningful response with durable disease control.

Intracranial hemorrhage with direct oral anticoagulants in patients with brain metastases.

Direct oral anticoagulants (DOACs) are increasingly prescribed in treatment of cancer-associated thrombosis, but limited data exist regarding safety of DOACs in patients with brain metastases. We aimed to determine the incidence of intracranial hemorrhage (ICH) in patients with brain metastases receiving DOACs or low-molecular-weight heparin (LMWH) for venous thromboembolism or atrial fibrillation. An international 2-center retrospective cohort study was designed. Follow-up started on the first day of concomitant anticoagulation and brain tumor diagnosis. At least 2 brain imaging studies were mandated. The primary outcome was the cumulative incidence of any spontaneous ICH at 12-month follow-up with death as a competing risk. Major ICH was defined as spontaneous, ≥10 mL in volume, symptomatic, or requiring surgical intervention. Imaging studies were centrally reviewed by a neuroradiologist blinded for anticoagulant type. PANWARDS (platelets, albumin, no congestive heart failure, warfarin, age, race, diastolic blood pressure, stroke) score for prediction of ICH was calculated. We included 96 patients with brain metastases (41 DOAC, 55 LMWH). The 12-month cumulative incidence of major ICH was 5.1% in DOAC-treated patients and 11.1% in those treated with LMWH (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.09-2.21). When anticoagulation was analyzed as a time-varying covariate, the risk of any ICH did not differ between DOAC- and LMWH-treated patients (HR, 0.98; 95% CI, 0.28-3.40). PANWARDS score was not associated with ICH risk. This international 2-center study suggests comparable safety of LMWH and DOACs in patients with brain metastases.