Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer.

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer. Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression. Design, Setting, and Participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION. Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel. Main Outcomes and Measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods. Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel. Conclusions and Relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

Research productivity of RANZCR radiation oncology trainees from 2014 to 2023.

INTRODUCTION: The aim of this study was to describe the research productivity among RANZCR Radiation Oncology (RO) trainees. METHODS: Publicly available data on RO fellows, who were awarded the RANZCR fellowship between July 2014 and June 2023, was extracted from the RANZCR Annual Reports. Fellows who had qualified overseas and did not undertake full RANZCR training were excluded. A PubMed search was performed for publications by each fellow in the 5 years prior, and 6 months, after the estimated completion of training. Research productivity was defined as the number of first-author and any-author publications per trainee. RESULTS: In total, 168 eligible RO fellows were included in this study. 104 (62%) and 118 (70%) fellows had first-author and any-author publications during training, respectively. A total of 203 first-author and 308 unique any-author publications were identified, with mean first-author and any-author publications per trainee of 1.21 (SD = 2.37) and 2.02 (SD = 3.71), respectively. Trainee research was most commonly published in JMIRO (34% of first-author and 27% of any-author publications). There were significant differences in the number of first-author publications by gender (P = 0.04) and training jurisdictions (P = 0.03). There were also differences in the number of any-author publications by gender (P = 0.002) and training jurisdictions (P = 0.03). There was a significant increase in any-author publications over the 9-year study period (P = 0.005). CONCLUSION: This is the first study evaluating research productivity among RO fellows during training. We identified disparities in research productivity by gender and training jurisdictions. This offers opportunities to tailor efforts to better support a vibrant and productive research culture across the RO training program.

Challenges of estimating treatment effects after a positive interim analysis.

BACKGROUND: This research investigates why a beneficial treatment effect reported at the first interim analysis (IA) may diminish at a subsequent analysis (SA). We examined three challenges in interpreting treatment effects from randomized clinical trials (RCTs) after the first positive IA: overestimation bias; non-proportional hazards; and heterogeneity in recruitment. We investigate how a penalized estimation method can address overestimation bias, and discuss additional factors to consider when interpreting positive IA results. METHODS: We identified oncology RCTs reporting positive results at the initial IA and a SA for event-free (EFS) and overall survival (OS). We modeled: (1) the hazard ratio at IA (HRIA) versus its timing as measured by the information fraction (IF; i.e., events at IA versus total events sought); and (2), the ratio of HRIA to HRSA (rHR) versus the IF. This was repeated for HRIA adjusted for overestimation bias. Examples of the other two challenges were sought. RESULTS: Amongst 71 RCTs, HRIA were positively associated with the IF (slope: EFS 0.83, 95 % CI 0.44-1.22; OS 0.25, 95 % CI 0.10-0.41). HRIA tended to exaggerate HRSA, and more so the lower the IF (slope rHR versus IF: EFS 0.10, 95 % CI - 0.22 to 0.42; OS 0.26, 95 % CI 0.07-0.46). Adjusted HRIA did not exaggerate HRSA (slope rHR versus IF: EFS - 0.14, 95 % CI - 0.67 to 0.39; OS 0.02, 95 % CI - 0.26 to 0.30). Examples of two other challenges are shown. CONCLUSION: Overestimation bias, non-proportional hazards, and heterogeneity in recruitment and other important treatments should be considered when communicating estimates of treatment effects from positive IAs.

Protocol for a systematic review with prospective individual patient data meta-analysis in EGFR-mutant NSCLC with brain metastases to assess the effect of SRS+osimertinib compared to osimertinib alone: the STARLET Collaboration.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) with activating mutations in the epidermal growth factor receptor (EGFR) gene are a heterogeneous population who often develop brain metastases (BM). The optimal management of patients with asymptomatic brain metastases is unclear given the activity of newer-generation targeted therapies in the central nervous system. We present a protocol for an individual patient data (IPD) prospective meta-analysis to evaluate whether the addition of stereotactic radiosurgery (SRS) before osimertinib treatment will lead to better control of intracranial metastatic disease. This is a clinically relevant question that will inform practice. METHODS: Randomised controlled trials will be eligible if they include participants with BM arising from EGFR-mutant NSCLC and suitable to receive osimertinib both in the first-line and second-line settings (P); comparisons of SRS followed by osimertinib versus osimertinib alone (I, C) and intracranial disease control included as an endpoint (O). Systematic searches of Medline (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (EBSCO), PsychInfo, ClinicalTrials.gov and the WHO's International Clinical Trials Registry Platform's Search Portal will be undertaken. An IPD meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome is intracranial progression-free survival, as determined by response assessment in neuro-oncology-BM criteria. Secondary outcomes include overall survival, time to whole brain radiotherapy, quality of life, and adverse events of special interest. Effect differences will be explored among prespecified subgroups. ETHICS AND DISSEMINATION: Approved by each trial's ethics committee. Results will be relevant to clinicians, researchers, policymakers and patients, and will be disseminated via publications, presentations and media releases. PROSPERO REGISTRATION: CRD42022330532.

Health-related quality of life with comprehensive geriatric assessment guided care versus usual care in older adults with cancer: A systematic review and meta-analysis of randomized trials.

BACKGROUND: To evaluate if comprehensive geriatric assessment (CGA)-guided care improves health-related quality of life (HRQL) in older adults with cancer compared to usual care. METHODS: Relevant randomized controlled trials (RCTs) were identified through biomedical databases. Meta-analyses using DerSimonian-Laird model summarized the difference in the mean change of HRQL scores from baseline across various time points, with evidence certainty assessed by the GRADE tool. Logistic regression via generalized estimating equations analyzed predictors of HRQL improvement. RESULTS: Potential improvement in the global HRQL score by CGA-guided care at 3 months (Cohen's d 0.27, 95 % CI -0.03-0.58, moderate certainty), could not be excluded. Larger RCTs or those mandating CGA before initiating anti-cancer treatment were predictors of improved HRQL. CONCLUSION: The effects of CGA-guided care on HRQL were variable. Larger RCTs and those mandating pre-treatment CGA tended to report improved HRQL.

Stroke Risk in Survivors of Head and Neck Cancer.

Importance: Survivors of head and neck cancers (HNC) have increased risk of stroke. A comprehensive report using standardized methods is warranted to characterize the risk and to inform on survivorship strategy. Objective: To determine the stroke risk in subpopulations of survivors of HNC in Singapore. Design, Setting, and Participants: This national, registry-based, cross-sectional study aimed to estimate stroke risk in subgroups of the HNC population between January 2005 and December 2020. Participants were identified from the Singapore Cancer Registry, the Singapore Stroke Registry, and the Registry of Birth and Deaths using relevant International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification (ICD-10-AM) codes. HNC subgroups were defined based on patient demographic, disease, and treatment factors. Data were analyzed from September 2022 to September 2023. Exposure: Diagnosis of HNC. Main Outcomes and Measures: Both ischemic and hemorrhagic stroke were studied. The age-standardized incidence rate ratio (SIRR) and age-standardized incidence rate difference (SIRD) were reported. The Singapore general population (approximately 4 million) served as the reference group for these estimations. Results: A total of 9803 survivors of HNC (median [IQR] age at diagnosis, 58 [49-68] years; 7166 [73.1%] male) were identified. The most common HNC subsites were nasopharynx (4680 individuals [47.7%]), larynx (1228 individuals [12.5%]), and tongue (1059 individuals [10.8%]). A total of 337 individuals (3.4%) developed stroke over a median (IQR) follow-up of 42.5 (15.0-94.5) months. The overall SIRR was 2.46 (95% CI, 2.21-2.74), and the overall SIRD was 4.11 (95% CI, 3.37-4.85) strokes per 1000 person-years (PY). The cumulative incidence of stroke was 3% at 5 years and 7% at 10 years after HNC diagnosis. The SIRR was highest among individuals diagnosed at younger than 40 years (SIRR, 30.55 [95% CI, 16.24-52.35]). All population subsets defined by age, sex, race and ethnicity, HNC subsites (except tongue), stage, histology, and treatment modalities had increased risk of stroke compared with the general population. The SIRR and SIRD were significantly higher among individuals who had a primary radiation treatment approach (SIRR, 3.01 [95% CI, 2.64-3.43]; SIRD, 5.12 [95% CI, 4.18-6.29] strokes per 1000 PY) compared with a primary surgery approach (SIRR, 1.64 [95% CI, 1.31-2.05]; SIRD, 1.84 [95% CI, 0.923.67] strokes per 1000 PY). Conclusions and Relevance: In this cross-sectional study of survivors of HNC, elevated stroke risks were observed across different age, subsites, and treatment modalities, underscoring the importance of early screening and intervention.

Clinical Trial and Real-World Outcomes of Patients With Metastatic NSCLC in the Post-Platinum-Based Chemotherapy Failure Setting.

Introduction: A literature review was undertaken to identify clinical trials and real-world studies of patients with stage IV NSCLC who had progressed on or after treatment with platinum-based chemotherapy. Methods: The EMBASE and MEDLINE databases were used to search for English-language studies published between September 28, 2017, and September 28, 2021. Studies were included in the review if they (1) were clinical trials or real-world analyses of one or more treatment regimens for patients with stage IV NSCLC who had progressed on or after treatment with platinum-based chemotherapy, (2) contained an end point including efficacy, effectiveness, or safety, and (3) included 45 or more patients. Results: In total, there were 15 publications (nine unique trials and three real-world studies) included. Sample size ranged from 49 to 1253 patients. At least one treatment arm in eight of the nine clinical trials reported an overall response rate of ≥15%. Median progression-free survival (PFS) and overall survival ranged from 1.9 to 5.2 months and 5.4 to 15.4 months in clinical trials and 4.4 to 6.8 months and 8.3 to 18.0 months in real-world studies, respectively. Within studies reporting median PFS, a median PFS of more than or equal to 3 months was reported in eight of 11 clinical trials and both real-world studies. Discontinuation due to adverse events ranged from 1.9% to 18% across all included studies. Conclusions: Patients with stage IV NSCLC had limited response and a high burden of adverse events during treatment after progression on platinum-containing chemotherapy. There remains a pressing unmet need for additional, effective, and tolerable treatment options in this setting.

Management Paradigm of Central Nervous System Metastases in NSCLC: An Australian Perspective.

Life-prolonging central nervous system active systemic therapies for metastatic NSCLC have increased the complexity of managing brain metastases (BMs). Australian medical oncologists, radiation oncologists, and neurosurgeons discussed the evidence guiding the diverse clinical approaches to the management of BM in NSCLC. The Australian context is broadly applicable to other jurisdictions; therefore, we have documented these discussions as principles with broader applications. Patient management was stratified according to clinical and radiologic factors under two broad classifications of newly diagnosed BMs: symptomatic and asymptomatic. Other important considerations include the number and location of metastases, tumor histotypes, molecular subtype, and treatment purpose. Careful consideration of the pace and burden of symptoms, risk of worsening neurologic function at a short interval, and extracranial disease burden should determine whether central nervous system active systemic therapies are used alone or in combination with local therapies (surgery with or without radiation therapy). Most clinical trial evidence currently focuses on historical treatment options or a single treatment modality rather than the optimal sequencing of multiple modern therapies; therefore, an individualized approach is key in a rapidly changing therapeutic landscape.

Reirradiation versus systemic therapy versus combination therapy for recurrent high-grade glioma: a systematic review and meta-analysis of survival and toxicity.

PURPOSE: This review compares reirradiation (reRT), systemic therapy and combination therapy (reRT & systemic therapy) with regards to overall survival (OS), progression-free survival (PFS), adverse effects (AEs) and quality of life (QoL) in patients with recurrent high-grade glioma (rHGG). METHODS: A search was performed on PubMed, Scopus, Embase and CENTRAL. Studies reporting OS, PFS, AEs and/or QoL and encompassing the following groups were included; reirradiation vs systemic therapy, combination therapy vs systemic therapy, combination therapy vs reRT, and bevacizumab-based combination therapy vs reRT with/without non-bevacizumab-based systemic therapy. Meta-analyses were performed utilising a random effects model. Certainty of evidence was assessed using GRADE. RESULTS: Thirty-one studies (three randomised, twenty-eight non-randomised) comprising 2084 participants were included. In the combination therapy vs systemic therapy group, combination therapy improved PFS (HR 0.57 (95% CI 0.41-0.79); low certainty) and OS (HR 0.73 (95% CI 0.56-0.95); low certainty) and there was no difference in grade 3 + AEs (RR 1.03 (95% CI 0.57-1.86); very low certainty). In the combination therapy vs reRT group, combination therapy improved PFS (HR 0.52 (95% CI 0.38-0.72); low certainty) and OS (HR 0.69 (95% CI 0.52-0.93); low certainty). In the bevacizumab-based combination therapy vs reRT with/without non-bevacizumab-based systemic therapy group, adding bevacizumab improved PFS (HR 0.46 (95% CI 0.27-0.77); low certainty) and OS (HR 0.42 (95% CI 0.24-0.72; low certainty) and reduced radionecrosis (RR 0.17 (95% CI 0.06-0.48); low certainty). CONCLUSIONS: Combination therapy may improve OS and PFS with acceptable toxicities in patients with rHGG compared to reRT or systemic therapy alone. Particularly, combining bevacizumab with reRT prophylactically reduces radionecrosis. REGISTRATION: CRD42022291741.

Factors Predictive of Primary Resistance to Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Primary resistance to immune checkpoint inhibitors (ICI) is observed in routine clinical practice. We sought to determine factors predictive of primary resistance to ICI monotherapy, defined by the Society for Immunotherapy of Cancer (SITC) as progression within 6 months of ICI treatment with patients receiving at least 6 weeks of ICI monotherapy, in patients with advanced non-small-cell lung cancer (NSCLC). METHOD: Patients with stage IV NSCLC treated with at least 6 weeks of single-agent ICI at two tertiary hospitals in Singapore were included. A multivariate logistic regression model was utilised to elucidate factors predictive of primary resistance to ICI. RESULTS: Of the 108 eligible patients, 59 (54.6%) experienced primary resistance. The majority were male (65.7%), smokers (66.3%), Chinese (79.6%), had adenocarcinoma (76.9%), received Pembrolizumab (55.6%) and received immunotherapy treatment in the later line setting (≥2 lines) (61.1%). Female gender (aOR = 3.16, p = 0.041), a sixth-week neutrophil-to-lymphocyte ratio (NLR) of ≥3) (aOR = 3.454, p = 0.037) and a later line of immunotherapy treatment (≥2 lines) (aOR = 2.676, p = 0.040) were factors predictive of primary resistance to ICI monotherapy in patients with advanced NSCLC. CONCLUSIONS: Using SITC criteria, an elevated NLR (≥3) at 6 weeks, female gender and a later line of immunotherapy treatment (≥2 lines) were predictive factors of developing primary resistance to ICI monotherapy in patients with advanced NSCLC.

Dosimetric comparison between Intensity Modulated Radiation Therapy (IMRT) vs dual arc Volumetric Arc Therapy (VMAT) for nasopharyngeal cancer (NPC): Systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Previous non-randomised studies comparing dosimetric outcomes between advanced techniques such as IMRT and VMAT reported conflicting findings. We thus sought to perform a systematic review and meta-analysis to consolidate the findings of these studies. MATERIALS AND METHODS: We searched PUBMED and EMBASE for eligible studies from their time of inception to 10 March 2022. A random effects model was used to estimate the pooled mean differences (MDs) and their 95% confidence intervals(CIs) for target volume coverage, organ-at-risk(OAR) doses, monitor units(MUs) and treatment delivery times. We also performed a subgroup analysis to evaluate if different treatment planning systems (TPS) (Eclipse, Monaco and Pinnacle) used affected the pooled mean differences. RESULTS: A total of 17 studies (383 patients) were eligible to be included. The pooled results showed that dual arc VMAT reduced D2% of PTV (MD=0.71Gy,95%CI=0.14-1.27,P=0.01), mean left cochlea dose (MD=2.6Gy,95%CI=0.03-5.16,P=0.05), mean right cochlea dose (MD=3.4Gy,95%CI=0.7-6.1,P=0.01), MUs (MD=554.9,95%CI=245.8-863.9,P=0.0004), treatment delivery times (MD=6.7mins,95%CI=4.5-8.9,P<0.0001) and integral dose (MD=0.97Gy,95%CI=0.28-1.67,P=0.006). None of the other indices were significantly better for the IMRT plans. The subgroup analysis showed that the integral dose was significantly lower only for Eclipse (MD=0.88Gy, 95%CI=0.14-1.63, P=0.02). The total MUs was significantly lower only for Eclipse (MD=1035.2, 95%CI=624.6-1445.9, P<0.0001) and Pinnacle (MD=293, 95%CI=15.6-570.5, P=0.04). Similarly, delivery time was also significantly lower only for Eclipse (MD=6.1mins, 95%CI=5.7-6.5, P<0.0001) and Pinnacle (MD=4.9mins, 95%CI=2.6-7.2, P<0.0001). The subgroup analysis however showed that target coverage was superior for the IMRT plans for both Pinnacle (MD=0.48Gy, 95%CI=0.31-0.66, P<0.0001) and Monaco (MD=0.12Gy, 95%CI=0.07-0.17, P<0.0001). CONCLUSION: Dual-arc VMAT plans improved OAR doses, MUs and treatment times as compared to IMRT plans. The different TPS used may modify dosimetric outcomes.

Restaging of rectal cancer with hybrid positron emission tomography magnetic resonance imaging after preoperative chemoradiotherapy.

Introduction: This study determines the sensitivity and specificity of positron emission tomography/magnetic resonance imaging (PET/MRI) parameters in predicting treatment response in patients with localised rectal cancer who have undergone preoperative chemoradiotherapy (CRT). Method: Patients with stage I-III adenocarcinoma of the rectum planned for preoperative CRT followed by surgery were recruited. Patients had PET/MRI scans at baseline and 6-8 weeks post-CRT. Functional MRI and PET parameters were assessed for their diagnostic accuracy for tumour regression grade (TRG). Nonparametric receiver operating characteristic analysis was employed to determine the area under the ROC curve (AUC), and the sensitivity and specificity of each quantile cut-off. Results: A total of 31 patients were recruited, of whom 20 completed study protocol. All patients included had mid or lower rectal tumours. There were 16 patients (80%) with node-positive disease at presentation. The median time to surgery was 75.5 days (range 52-106 days). Histopathological assessment revealed 20% good responders (TRG 1/2), and the remaining 80% of patients had a poor response (TRG 3/4). When predicting good responders, the AUC values for percent maximum thickness reduction and percent apparent diffusion coefficient (ADC) change were 0.82 and 0.73, respectively. A maximum thickness reduction cut-off of >47% and a percent ADC change of >20% yielded a sensitivity and specificity of 75%/95% and 75%/73%, respectively. Conclusion: Parameters such as percent maximum thickness reduction and percent ADC change may be useful for predicting good responders in patients undergoing preoperative CRT for rectal cancer. Larger studies are warranted to establish the utility of PET/MRI in rectal cancer staging.

Should adjuvant radiotherapy be used in atypical meningioma (WHO grade 2) following gross total resection? A systematic review and Meta-analysis.

BACKGROUND: The role of adjuvant radiotherapy (RT) following gross total resection (GTR) in atypical meningioma (AM) is not well established and its benefit remains unclear. We aim to evaluate the survival benefit of adjuvant RT in AM following GTR. METHODS: We searched biomedical databases for studies published between January 1964-February 2021 and included studies reporting primary outcomes of 5-year PFS, 5-year OS and had survival curves for restricted mean survival time (RMST) calculations. Data extracted from survival curves were pooled and analyzed using a random-effects model. Hazard ratio (HR) was calculated for sensitivity analysis. RESULTS: We included 12 non-randomized studies comprising 1,078 patients. 803 (74.5%) patients were treated with GTR alone and 275 (25.5%) patients received adjuvant RT. In 9 studies, RT included 3 D conformal RT, intensity modulated RT, or fractionated stereotactic radiotherapy); in 3 studies, stereotactic radiosurgery was also used. Median dose of RT was 59.4 Gy. Adjuvant RT resulted in an increase of 3.9 months for restricted mean PFS truncated at 5 years (95% CI 0.23-7.72; p = 0.037) and a 22% reduction in the hazard of disease progression or death (hazards ratio 0.78; 95% CI 0.46-1.33; p = 0.370). Restricted mean OS, truncated at 5 years, was improved with adjuvant RT by 1.1 months (95% CI 0.37-1.81; p = 0.003) and a 21% reduction in the hazard of death from any cause (HR 0.79; 95% CI 0.51-1.24; p = 0.310). Meta-regression analysis of the RMST of EBRT dose did not reveal any significant difference in PFS or OS between studies reporting median dose of <59.4 Gy vs. ≥ 59.4 Gy. CONCLUSION: Adjuvant RT following GTR in patients with AM improved restricted mean PFS and OS. While we await the results from ongoing randomized controlled trials, adjuvant RT should be recommended.

Real-world experience of consolidation durvalumab after concurrent chemoradiotherapy in stage III non-small cell lung cancer.

BACKGROUND: Durvalumab consolidation is associated with improved survival following concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC). Given the heterogeneity of stage III NSCLC patients, in this study we evaluated the efficacy and safety of durvalumab in the real-world setting. METHOD: Unresectable stage III NSCLC patients were retrospectively studied: one cohort received CCRT, another had CCRT-durvalumab. Primary endpoints were progression-free survival (PFS) and overall survival (OS), secondary endpoints were relapse rate and safety. In CCRT-durvalumab cohort, association between blood markers with survival and pneumonitis risk were analyzed. RESULTS: A total of 84 patients were enrolled: 45 received CCRT, and 39 received CCRT-durvalumab. Median PFS was 17.5 months for CCRT-durvalumab and 8.9 months for CCRT-alone (HR 0.47, p = 0.038). Median OS was not-reached for CCRT-durvalumab and 22.3 months for CCRT-alone (HR 0.35, p = 0.024). Both EGFR-positive and wild-type (WT) patients had numerically improved PFS with durvalumab consolidation compared to CCRT-alone, 17.5 versus 10.9 months and 11.8 versus 6.63 months, respectively (interaction p-value = 0.608). Grade 2+ pneumonitis was detected in 25% of patients in the durvalumab cohort. Most pneumonitis occurred at 3.5 weeks after durvalumab initiation. Baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3 and ≥5 were associated with shorter PFS with durvalumab. Week 6 platelet-lymphocyte-ratio ≥ 180 was associated with a lower risk of pneumonitis. CONCLUSION: In this real-world study, durvalumab consolidation post CCRT was associated with a statistically significant improvement in PFS and OS. Effect of durvalumab on PFS was not modified by EGFR status. Active surveillance for pneumonitis is crucial. Baseline NLR may help to predict the benefit of treatment with durvalumab.

Stereotactic body radiation therapy versus conventional external beam radiation therapy for painful bone metastases: A systematic review and meta-analysis of randomized trials.

PURPOSE: To compare the efficacy and safety of stereotactic body radiation therapy (SBRT) and conventional external beam radiation therapy (cEBRT) in patients with previously unirradiated painful bone metastases (BM). METHODS: We searched biomedical databases for eligible randomized controlled trials (RCTs). The outcomes of interest were pain response, local progression, overall survival (OS) and adverse events. We used established tools to assess the quality of the individual trials and certainty of the pooled evidence. We performed meta-analyses using random effects models. RESULTS: Six RCTs were identified. SBRT improved complete pain response rates at 3 months (OR, 3.38; 95% CI, 1.88-6.07; high certainty), reduced local progression rates (OR, 0.19; 95% CI, 0.06-0.62; high certainty) and increased pain flare rates. There were no differences for other outcomes. CONCLUSION: Among patients with previously unirradiated painful BM, SBRT significantly improved complete pain response rates at 3 months, delayed local progression and increased pain flare rates.

Booster doses of COVID-19 vaccines for patients with haematological and solid cancer: a systematic review and individual patient data meta-analysis.

IMPORTANCE: Patients with cancer have an increased risk of severe disease and mortality from COVID-19, as the disease and antineoplastic therapy cause reduced vaccine immunogenicity. Booster doses have been proposed to enhance protection, and efficacy data are emerging from several studies. OBJECTIVE: To evaluate the proportion of COVID-19 primary vaccination non-responders with cancer who seroconvert after a booster dose. METHODS: PubMed, EMBASE, CENTRAL and medRxiv were searched from 1st January 2021 to 10th March 2022. Quality was assessed using the Joanna Briggs Institute Critical Appraisal checklist. RESULTS: After the eligibility assessment, 22 studies were included in this systematic review and 17 for meta-analysis of seroconversion in non-responders, pooling a total of 849 patients with haematological cancer and 82 patients with solid cancer. Haematological cancer non-responders exhibited lower seroconversion at 44% (95% CI 36-53%) than solid cancer at 80% (95% CI 69-87%). Individual patient data meta-analysis found the odds of having a meaningful rise in antibody titres to be significantly associated with increased duration between the second and third dose (OR 1.02, 95% CI 1.00-1.03, P ≤ 0.05), age of patient (OR 0.960, 95% CI 0.934-0.987, P ≤ 0.05) and cancer type. With patients with haematological cancer as a reference, patients with lung cancer had 16.8 times the odds of achieving a meaningful increase in antibody titres (OR 16.8, 95% CI 2.95-318, P ≤ 0.05) and gastrointestinal cancer patients had 25.4 times the odds of achieving a meaningful increase in antibody titres (OR 25.4, 95% CI 5.26-492.21, P ≤ 0.05). CONCLUSIONS: administration of a COVID-19 vaccine booster dose is effective in improving seroconversion and antibody levels. Patients with haematological cancer consistently demonstrate poorer response to booster vaccines than patients with solid cancer.

Survival rates and safety associated with chemoradiotherapy followed by surgery and chemoradiotherapy alone for patients with T4 esophageal cancer: a systematic review and meta-analysis.

BACKGROUND: The optimal treatment approach for T4 esophageal cancer is not well established. We aimed to perform a systematic review and meta-analysis to determine the survival rates and safety of chemoradiotherapy followed by surgery (CRT-S) and chemoradiotherapy alone (CRT) in patients with T4 Nany M0 esophageal cancer. MATERIALS AND METHODS: We searched databases for eligible prospective or retrospective studies. The outcomes of interest were overall survival (OS) at 1, 3 and 5 years, treatment-related fistula formation and mortality rates. Meta-analyses were performed using the random effects models separately for studies evaluating CRT-S and CRT. Subgroup analyses were performed based on histology, radiation dose, chemotherapy regimen and duration of the interval between CRT and surgery. RESULTS: We identified 23 studies including 1,119 patients with predominantly squamous cell carcinoma (93%) and adenocarcinoma (3%) histology. The OS rates of patients receiving CRT-S were 65%, 36% and 20% at 1, 3 and 5 years, respectively. The OS rates of patients receiving CRT were 30%, 11% and 10% at 1, 3 and 5 years, respectively. Treatment-related fistula formation rates were 4% for CRT-S and 9% for CRT. Treatment-related mortality rates were 3% for both groups. Subgroup analyses showed that the interval of >2 months between CRT and surgery was associated with significantly improved OS rates at 1, 3 and 5 years. CONCLUSION: Chemoradiotherapy is an efficacious treatment approach for T4 esophageal cancer, with clinically acceptable rates of treatment-related fistula formation and mortality. Tri-modality approach with surgery can be considered in carefully selected patients. Our study findings should be interpreted with caution due to the lack of high-quality evidence. Randomized controlled trials are warranted to confirm these findings.

Efficacy of covid-19 vaccines in immunocompromised patients: systematic review and meta-analysis.

OBJECTIVE: To compare the efficacy of covid-19 vaccines between immunocompromised and immunocompetent people. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Embase, Central Register of Controlled Trials, COVID-19 Open Research Dataset Challenge (CORD-19), and WHO covid-19 databases for studies published between 1 December 2020 and 5 November 2021. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched in November 2021 to identify registered but as yet unpublished or ongoing studies. STUDY SELECTION: Prospective observational studies comparing the efficacy of covid-19 vaccination in immunocompromised and immunocompetent participants. METHODS: A frequentist random effects meta-analysis was used to separately pool relative and absolute risks of seroconversion after the first and second doses of a covid-19 vaccine. Systematic review without meta-analysis of SARS-CoV-2 antibody titre levels was performed after first, second, and third vaccine doses and the seroconversion rate after a third dose. Risk of bias and certainty of evidence were assessed. RESULTS: 82 studies were included in the meta-analysis. Of these studies, 77 (94%) used mRNA vaccines, 16 (20%) viral vector vaccines, and 4 (5%) inactivated whole virus vaccines. 63 studies were assessed to be at low risk of bias and 19 at moderate risk of bias. After one vaccine dose, seroconversion was about half as likely in patients with haematological cancers (risk ratio 0.40, 95% confidence interval 0.32 to 0.50, I2=80%; absolute risk 0.29, 95% confidence interval 0.20 to 0.40, I2=89%), immune mediated inflammatory disorders (0.53, 0.39 to 0.71, I2=89%; 0.29, 0.11 to 0.58, I2=97%), and solid cancers (0.55, 0.46 to 0.65, I2=78%; 0.44, 0.36 to 0.53, I2=84%) compared with immunocompetent controls, whereas organ transplant recipients were 16 times less likely to seroconvert (0.06, 0.04 to 0.09, I2=0%; 0.06, 0.04 to 0.08, I2=0%). After a second dose, seroconversion remained least likely in transplant recipients (0.39, 0.32 to 0.46, I2=92%; 0.35, 0.26 to 0.46), with only a third achieving seroconversion. Seroconversion was increasingly likely in patients with haematological cancers (0.63, 0.57 to 0.69, I2=88%; 0.62, 0.54 to 0.70, I2=90%), immune mediated inflammatory disorders (0.75, 0.69 to 0.82, I2=92%; 0.77, 0.66 to 0.85, I2=93%), and solid cancers (0.90, 0.88 to 0.93, I2=51%; 0.89, 0.86 to 0.91, I2=49%). Seroconversion was similar between people with HIV and immunocompetent controls (1.00, 0.98 to 1.01, I2=0%; 0.97, 0.83 to 1.00, I2=89%). Systematic review of 11 studies showed that a third dose of a covid-19 mRNA vaccine was associated with seroconversion among vaccine non-responders with solid cancers, haematological cancers, and immune mediated inflammatory disorders, although response was variable in transplant recipients and inadequately studied in people with HIV and those receiving non-mRNA vaccines. CONCLUSION: Seroconversion rates after covid-19 vaccination were significantly lower in immunocompromised patients, especially organ transplant recipients. A second dose was associated with consistently improved seroconversion across all patient groups, albeit at a lower magnitude for organ transplant recipients. Targeted interventions for immunocompromised patients, including a third (booster) dose, should be performed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021272088.

Is there any survival benefit from post-operative radiation in brain metastases? A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The benefits of adding upfront post-operative radiation, either whole-brain (WBRT) or cavity, after resection of brain metastases have been debated, particularly due to the long-term sequalae post radiation. We sought to compare the efficacy and safety between post-operative radiation versus resection alone. METHODS: We searched various biomedical databases from 1983 to 2018, for eligible randomized controlled trials (RCT). Outcomes studied were local recurrence (LR), overall survival (OS) and serious (Grade 3 + ) adverse events. We used the random effects model to pool outcomes. Methodological quality of each study was assessed using the Cochrane Risk of Bias tool. We employed the GRADE approach to assess the certainty of evidence. RESULTS: We included 5 RCTs comprising of 673 patients. The pooled odds ratio (OR) for LR is 0.26 (95% confidence interval (CI) 0.19-0.37, P < 0.001, GRADE certainty high), strongly supporting the use of post-operative radiation. Meta-regression analysis done comparing cavity and WBRT, did not show any difference in LR. The pooled hazard ratio (HR) for overall survival (OS) is 1.1 (95% CI 0.90-1.34, P = 0.37, GRADE certainty high). The treatment-related toxicities could not be pooled; the 2 studies which reported this did not find differences between the approaches. The risk of bias across the included studies was low. CONCLUSION: Our analysis confirms that upfront post-operative radiation significantly reduces the risk of LR. However, the lack of improvement in OS suggests that local control alone may not impact survival. Balancing local control, and neuro-cognitive effects of WBRT, cavity radiation seems to be a safe and effective option.

Impact of cancer diagnoses on the outcomes of patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: The COVID-19 has caused significant mortality and morbidity across the globe. Patients with cancer are especially vulnerable given their immunocompromised state. We aimed to determine the proportion of COVID-19 patients with cancer, their severity and mortality outcomes through a systematic review and meta-analysis (MA). METHODS: Systematic review was performed through online databases, PubMed, Medline and Google Scholar, with keywords listed in the Methods section (1 November 2019-31 December 2020). Studies with clinical outcomes of at least 10 COVID-19 patients and at least one with a diagnosis of cancer were included. The studies for MA were assessed with PRISMA guidelines and appraised with Newcastle-Ottawa Scale. The data were pooled using a random-effects model using STATA software. The main outcomes were planned before data collection, including proportion of patients with cancer among COVID-19 populations, relative risk (RR) of severe outcomes and death of patients with cancer compared with general COVID-19 patients. RESULTS: We identified 57 case series (63 413 patients), with 230 patients with cancer with individual patient data (IPD). We found that the pooled proportion of cancer among COVID-19 patients was 0.04 (95% CI 0.03 to 0.05, I2=97.69%, p<0.001). The pooled RR of death was 1.44 (95% CI 1.19 to 1.76) between patients with cancer and the general population with COVID-19 infection. The pooled RR of severe outcome was 1.49 (95% CI 1.18 to 1.87) between cancer and general COVID-19 patients. The presence of lung cancer and stage IV cancer did not result in significantly increased RR of severe outcome. Among the available IPD, only age and gender were associated with severe outcomes. CONCLUSION: Patients with cancer were at a higher risk of severe and death outcomes from COVID-19 infection as compared with general COVID-19 populations. Limitations of this study include publication bias. A collaborative effort is required for a more complete database.