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.

Tumour growth rate predicts overall survival in patients with recurrent WHO grade 4 glioma.

PURPOSE: Accurate prognostication may aid in the selection of patients who will benefit from surgery at recurrent WHO grade 4 glioma. This study aimed to evaluate the role of serial tumour volumetric measurements for prognostication at first tumour recurrence. METHODS: We retrospectively analyzed patients with histologically-diagnosed WHO grade 4 glioma at initial and at first tumour recurrence at a tertiary hospital between May 2000 and September 2018. We performed auto-segmentation using ITK-SNAP software, followed by manual adjustment to measure serial contrast-enhanced T1W (CE-T1W) and T2W lesional volume changes on all MRI images performed between initial resection and repeat surgery. RESULTS: Thirty patients met inclusion criteria; the median overall survival using Kaplan-Meier analysis from second surgery was 10.5 months. Seventeen (56.7%) patients received treatment post second surgery. Univariate cox regression analysis showed that greater rate of increase in lesional volume on CE-T1W (HR = 2.57; 95% CI [1.18, 5.57]; p = 0.02) in the last 2 MRI scans leading up to the second surgery was associated with a higher mortality likelihood. Patients with higher Karnofsky Performance Score (KPS) (HR = 0.97; 95% CI [0.95, 0.99]; p = 0.01) and who received further treatment following second surgery (HR = 0.43; 95% CI [0.19, 0.98]; p = 0.04) were shown to have a better survival. CONCLUSION: Higher rate of CE-T1W lesional growth on the last 2 MRI images prior to surgery at recurrence was associated with increase mortality risk. A larger prospective study is required to determine and validate the threshold to distinguish rapidly progressive tumour with poor prognosis.

Prophylactic irradiation of tracts in patients with malignant pleural mesothelioma: A systematic review and meta-analysis of randomized trials.

INTRODUCTION: The role of prophylactic irradiation of tracts (PIT) to prevent tumor seeding at the site of a diagnostic or therapeutic intervention in patients with malignant pleural mesothelioma (MPM) is controversial. This study aimed to determine the efficacy of PITs in preventing procedure tract metastases (PTM) after a chest wall procedure in MPM. MATERIALS AND METHODS: We searched various databases from inception date to April 2020 for randomized controlled trials (RCTs) comparing PIT with no PIT in patients who had a chest wall procedure for MPM. We assessed the risk of bias of individual RCT using the RoB2 tool. The primary outcome was the occurrence of PTM. Meta-analysis was performed using random-effects model. We employed the GRADE approach to assess the certainty of the evidence. RESULTS: We identified five RCTs including 737 patients. Two RCTs had a low risk of bias. PIT was associated with a significant reduction in the odds of PTM (odd ratio, 0.55; 95 % confidence interval, 0.32 to 0.95; P-value = 0.03; I2 = 13 %; GRADE: moderate certainty). One RCT reported no difference in overall survival outcome with the use of PIT. None of the RCTs performed subgroup analyses. Sensitivity analyses showed similar results when limited to RCTs with low risk of bias. CONCLUSION: PIT significantly reduces the occurrence of PTM in patients with MPM who had a diagnostic or therapeutic chest wall procedure.

Palliative radiotherapy for bladder cancer: a systematic review and meta-analysis.

BACKGROUND/PURPOSE: The optimal dose fractionation for palliative radiotherapy (RT) in patients with symptomatic advanced bladder cancer is unclear. This study aimed to determine if a higher dose of RT was associated with improved symptoms response rates. METHODS: We searched PubMed, Central and Embase for eligible studies published from 1990 to 2019. The primary outcomes were symptoms response rates for hematuria, dysuria and frequency. Secondary outcomes included treatment-related adverse events and quality of life. RESULTS: We found one randomized, four prospective and eight retrospective non-comparative observational studies including 1320 patients who received palliative bladder radiotherapy for symptom relief. The dose fractionation schedules varied across studies ranging from 8 Gy single fraction to 60 Gy in 2 to 8 Gy per fraction. The pooled response rates for hematuria, dyuria and frequency symptoms were 74%, 58% and 71% respectively. A higher dose of RT was not associated with improved response rates of hematuria and frequency. However, a higher dose of RT was associated with a longer duration of hematuria response and reduced response of dysuria. Grade 3 gastrointestinal and genitourinary toxicity occurred in up to 26% of patients. Health-related quality of life (HRQOL) outcomes were reported in one study. CONCLUSION: This systematic review demonstrates that a higher dose of bladder RT was not associated with improved response rates of hematuria and frequency symptoms but was associated with reduced response of dysuria. Higher doses of bladder RT was associated with more durable hematuria response. Prospective studies to determine the effects of palliative bladder radiotherapy on HRQOL outcomes are warranted.

Impact of programmed death-ligand 1 expression on the patients of stage IV non-small cell lung cancer harboring epidermal growth factor receptor mutation: a systematic review and meta-analysis.

BACKGROUND: To determine the impact of programed death-ligand 1 (PD-L1) expression on progression-free survival (PFS) outcomes in stage IV epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) treated with first-line EGFR tyrosine kinase inhibitors (TKIs). MATERIAL AND METHODS: We searched biomedical databases for studies comparing PFS outcomes of PD-L1-positive versus (vs) PD-L1-negative tumors. We assessed the methodological quality of eligible studies using ROBINS-I tool. We employed a two-staged meta-analysis approach by reconstructing individual patient data of each study from the published Kaplan-Meier curves and then pooling the individual hazard ratios (HRs) and weighted mean differences (WMDs) for restricted mean PFS time at 6 (RMPFST6) and 12 (RMPFST12) months using random-effect models. We assessed the quality of summarized evidence using GRADE approach. RESULTS: We identified five non-randomized comparative studies including 435 patients. The overall risk of bias in the methodological quality of included studies was moderate. PD-L1-positive tumors were associated with significantly worse PFS outcomes compared to PD-L1-negative tumors (HR: 2.41, 95% confidence interval (CI): 1.59-3.66, p < .001; WMD in RMPFST6: -1.01, 95% CI: -1.65 to -0.37, p = .002; WMD in RMPFST12: -2.64, 95% CI: -4.40 to -0.88, p = .003). Subgroup analysis showed that the effect of PD-L1 expression on PFS outcomes was greater for studies using older-generation rather than third-generation TKIs (HR: 2.69 vs 1.22, p = .069; WMD in RMPFST6: -1.23 vs -0.07, p = .005; WMD in RMPFST12: -3.29 vs -0.12, p = .003). The quality of summarized evidence was judged to be low. CONCLUSION: There is low certainty in the evidence to suggest that positive PD-L1 expression is associated with inferior disease control and survival outcomes in patients with stage IV EGFR-mutated NSCLC treated with first-line EGFR TKIs.

Are heart doses associated with survival in patients with non-small cell lung cancer who received post-operative thoracic radiotherapy?: A national population-based study.

The aim of this retrospective national cohort study is to assess the association between various radiation heart dosimetric parameters (RHDPs), acute myocardial infarct (AMI) and overall survival (OS) outcomes in non-small cell lung cancer (NSCLC) patients treated with post-operative thoracic radiotherapy (PORT) using contemporary radiation techniques.We identified patients with stage I to III NSCLC treated with PORT at the 2 national cancer institutions from 2007 to 2014. We linked their electronic medical records to the national AMI and death registries. Univariable Cox regression was performed to assess the association between various RHDPs, AMI, and OS.We included 43 eligible patients with median follow-up of 36.6 months. Median age was 64 years. Majority of the patients had pathological stage III disease (72%). Median prescription dose was 60Gy. Median mean heart dose (MHD) was 9.4Gy. There were no AMI events. The 5-year OS was 34%. Univariable Cox regression showed that age was significantly associated with OS (hazard ratio, 1.06; 95% confidence interval, 1.01 to 1.10; P = .008). Radiation heart doses, including MHD, volume of heart receiving at least 5, 25, 30, 40, 50Gy and dose to 30% of heart volume, were not significantly associated with OS.There is insufficient evidence to conclude that RHDPs are associated with OS for patients with NSCLC treated with PORT in this study. Studies with larger sample size and longer term follow-up are needed to assess AMI outcome.

Discordance of epidermal growth factor receptor mutation between primary lung tumor and paired distant metastases in non-small cell lung cancer: A systematic review and meta-analysis.

PURPOSE: To evaluate the rate of discordance of epidermal growth factor receptor (EGFR) mutation between primary lung tumor and paired distant metastases in non-small-cell lung cancer (NSCLC). METHODS: We performed a meta-analysis of 17 studies (518 cases) assessing discordance rates of EGFR mutation in primary tumors and paired distant metastases. We performed subgroup analyses based on EGFR mutation status in primary tumor (mutant or wildtype), site of distant metastasis (bone, central nervous system (CNS) or lung/ pleural), methods of testing (direct sequencing or allele-specific testing) and timing of metastasis (synchronous or metachronous). RESULTS: The overall discordance rate in EGFR mutation was low at 10.36% (95% CI = 4.23% to 18.79%) and varied widely between studies (I2 = 83.18%). The EGFR discordance rate was statistically significantly higher in bone metastases (45.49%, 95% CI = 14.13 to 79.02) than CNS (17.26%, 95% CI = 7.64 to 29.74; P = 0.002) and lung/ pleural metastases (8.17%, 95% CI = 3.35 to 14.85; P < 0.001). Subgroup analyses did not demonstrate any significant effect modification on the discordance rates by the EGFR mutation status in primary lung tumor, methods of testing and timing of metastasis. CONCLUSION: The overall discordance rate in EGFR mutation between primary lung tumor and paired distant metastases in NSCLC is low, although higher discordance rates were observed in bone metastases compared with CNS and lung/pleural metastases. Future studies assessing the impact of EGFR mutation discordance on treatment outcomes are required.

Re-irradiation for recurrent glioblastoma (GBM): a systematic review and meta-analysis.

PURPOSE: To determine the efficacy and toxicity of re-irradiation for patients with recurrent GBM. MATERIALS AND METHODS: We searched various biomedical databases from 1998 to 2018, for eligible studies where patients were treated with re-irradiation for recurrent GBM. Outcomes of interest were 6 and 12-month overall survival (OS-6, OS-12), 6 and 12-month progression free survival (PFS-6, PFS-12) and serious (Grade 3 +) adverse events (AE). We used the random effects model to pool outcomes across studies and compared pre-defined subgroups using interaction test. Methodological quality of each study was assessed using the Newcastle-Ottawa scoring system. RESULTS: We found 50 eligible non-comparative studies including 2095 patients. Of these, 42% were of good or fair quality. The pooled results were as follows: OS-6 rate 73% (95% confidence interval (CI) 69-77%), OS-12 rate 36% (95% CI 32-40%), PFS-6 rate 43% (95% CI 35-50%), PFS-12 rate 17% (95% CI 13-20%), and Grade 3 + AE rate 7% (95% CI 4-10%). Subgroup analysis showed that prospective studies reported higher toxicity rates, and studies which utilized brachytherapy to have a longer OS-12. Within the external beam radiotherapy group, there was no dose-response [above or below 36 Gy in 2 Gy equivalent doses (EQD2)]. However, a short fractionation regimen (≤ 5 fractions) seemed to provide superior PFS-6. CONCLUSION: The available evidence, albeit mostly level III, suggests that re-irradiation provides encouraging disease control and survival rates. Toxicity was not uniformly reported, but seemed to be low from the included studies. Randomized controlled trials (RCT) are needed to establish the optimal management strategy for recurrent GBM.

Adoption of prophylactic cranial irradiation (PCI) for extensive stage small cell lung cancer (ES-SCLC): a population based outcome study.

BACKGROUND: The survival benefit of PCI in ES-SCLC reported by a European randomized trial (RCT) in 2007 was not replicated by a Japanese RCT published in 2017. This study aimed to evaluate the uptake of PCI before and after publication of the European RCT and its association with survival in ES-SCLC. METHODS: We identified eligible patients in the only two Singapore national cancer centres from 2003 to 2010. We linked their electronic medical records to the national death registry. We described the utilization of PCI in patients diagnosed from 2003 to 2006 (pre-adoption cohort) with patients diagnosed from 2007 to 2010 (post-adoption cohort). We performed univariable and multivariable Cox regression analysis to assess the association between PCI and survival. RESULTS: We identified 224 patients with ES-SCLC with no brain metastases. Among the 71 patients who had at least stable disease after first line chemotherapy, there was an increase in the use of PCI from the period 2007 to 2010 compared with 2003 to 2006 (32% versus 10%, P = 0.044). PCI was associated with improved OS (hazard ratio 0.22, 95% CI 0.10 to 0.47, P < 0.001) compared to no PCI in the multivariable analysis. CONCLUSION: There was an increase in the adoption of PCI for ES-SCLC since 2007. PCI was associated with improved survival in patients who did not have mandatory MRI brain imaging prior to PCI and had stable disease or better after first line chemotherapy, suggesting that the results of the European RCT are reproducible in the real-world practice.

Diagnosis and Management of Radiation Necrosis in Patients With Brain Metastases.

The use of radiotherapy, either in the form of stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT), remains the cornerstone for the treatment of brain metastases (BM). As the survival of patients with BM is being prolonged, due to improved systemic therapy (i.e., for better extra-cranial control) and increased use of SRS (i.e., for improved intra-cranial control), patients are clinically manifesting late effects of radiotherapy. One of these late effects is radiation necrosis (RN). Unfortunately, symptomatic RN is notoriously hard to diagnose and manage. The features of RN overlap considerably with tumor recurrence, and misdiagnosing RN as tumor recurrence may lead to deleterious treatment which may cause detrimental effects to the patient. In this review, we will explore the pathophysiology of RN, risk factors for its development, and the strategies to evaluate and manage RN.

Association between radiation heart dosimetric parameters, myocardial infarct and overall survival in stage 3 non-small cell lung cancer treated with definitive thoracic radiotherapy.

OBJECTIVES: The aim of this retrospective observational study is to assess the association between various radiation heart dosimetric parameters (RHDPs) and acute myocardial infarct (AMI) and overall survival (OS) outcomes in stage III non-small cell lung cancer (NSCLC) treated with definitive radiotherapy with or without chemotherapy. MATERIALS AND METHODS: We identified eligible patients treated at two institutions from 2007 to 2014. We linked their electronic medical records to the national AMI and death registries. We performed univariable and multivariable Cox regressions analysis to assess the association between various RHDPs, AMI and OS. RESULTS: 120 eligible patients were included with a median follow-up of 17.6 months. Median age was 65.5 years. Median prescription dose was 60 Gy. Median mean heart dose (MHD) was 12.6 Gy. Univariable analysis showed that higher MHD (hazard ratio (HR), 1.03; 95% confidence interval (CI), 1.01-1.06; P = .008) and volume of heart receiving at least 5 Gy (V5) (HR, 1.01; 95% CI, 1.00-1.03; P = .042) were associated with increased hazards for AMI. Univariable analysis showed that higher MHD, V5, V25, V30, V40, V50 and dose to 30% of heart volume were associated with increased hazards for death. Multivariable analysis showed that there was no statistically significant association between various RHDPs and OS. CONCLUSION: The incidence of AMI is low among stage III NSCLC treated with definitive radiotherapy with or without chemotherapy. There is insufficient evidence to conclude that RHDPs are associated with AMI or OS in our study.

Palliative radiotherapy for gastric cancer: a systematic review and meta-analysis.

BACKGROUND/PURPOSE: To review the efficacy and toxicity of palliative radiotherapy (RT) for symptomatic locally advanced gastric cancer (GC) and to determine the optimal RT schedule for symptom palliation. METHODS: We searched MEDLINE and CENTRAL for eligible studies published from 1995 to 2015. Outcomes of interest were relief of bleeding, pain and obstruction. RESULTS: Seven non-comparative observational studies were included. There were large variations in RT dose and fractionation. The pooled overall response rates for bleeding, pain and obstruction symptoms were 74%, 67% and 68% respectively. There was no difference in response rate of bleeding between regimens with high biological equivalent dose (BED) of ≥ 39Gy versus regimens with low BED<39Gy regimens (p value =0.39). Grade 3 to 4 toxicities occurred in up to 15% of patients for patients treated with RT alone and up to 25% of patients treated with chemoradiotherapy. Health-related quality of life (HRQL) outcomes were not reported. CONCLUSION: More than two-thirds of patients receiving RT would have a clinical benefit. Low BED regimens appear to be adequate for symptom palliation. Toxicity rates appear acceptable for patients treated with RT alone. The optimal dose fractionation regimen for symptom palliation remains unclear. Prospective studies to determine the effects of palliative gastric RT on HRQL outcomes are warranted.

Impact of epidermal growth factor receptor sensitizing mutations on outcomes of patients with non-small cell lung cancer treated with definitive thoracic radiation therapy: a systematic review and meta-analysis.

BACKGROUND: To determine if the presence of epidermal growth factor receptor (EGFR) sensitizing mutations improves tumor control and survival outcomes in patients with non-metastatic non-small cell lung cancer (NSCLC) who received definitive thoracic radiation therapy (TRT) with or without chemotherapy. MATERIALS AND METHODS: We searched MEDLINE for eligible comparative studies which compared the outcomes of patients treated with definitive TRT according to EGFR mutation status. Meta-analysis was performed using random effects model. Outcomes of interest were tumor overall response rate (ORR), loco-regional (LRR), distant recurrence rates (DRR), relapse-free survival (RFS), overall survival (OS) and adverse events (AE). RESULTS: We found seven studies including 537 patients with stage III NSCLC. Up to 45% of patients in the studies had mutations in exon 19 and 21. Patients harbouring EGFR sensitizing mutations had a trend towards improvement in ORR (risk ratio 1.17, 95% confidence interval 0.99-1.37, P = 0.06) compared to EGFR wild type status. There were no significant differences in LRR, DRR, RFS, OS and AE outcomes between the EGFR mutant and EGFR wild type groups. CONCLUSIONS: The presence of EGFR sensitizing mutations may improve tumour response rate but not survival in patients with localized NSCLC treated with definitive thoracic radiation therapy with or without chemotherapy.

EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: EGFR TKIs alone have demonstrated activity against intracranial disease in EGFR mutant non-small cell lung cancer (NSCLC). This study aimed to determine if upfront cranial radiotherapy improves intracranial disease control and survival outcomes in EGFR mutant NSCLC with brain metastases relative to TKIs alone. MATERIALS AND METHODS: We searched MEDLINE and various conference proceedings from 2008 to July 2014 for eligible studies where patients received upfront cranial radiotherapy or TKIs alone. Outcomes of interest were overall intracranial disease response rate (ORR), four-month intracranial disease progression-free survival (PFS), two-year overall survival (OS) and neurological adverse events (AE). We used random effects models to pool outcomes across studies and compared them using interaction tests. RESULTS: We found 12 non-comparative observational studies (n=363) with severe methodological limitations. Upfront cranial radiotherapy results in similar intracranial disease ORR (relative risk (RR) 0.93, 95% confidence interval (CI) 0.82-1.06; interaction p value (p)=0.53), improved four-month intracranial disease PFS (RR 1.06, 95% CI 1.00-1.12; p=0.03), improved two-year OS (RR 1.33, 95% CI 1.00-1.77; p=0.05) but caused more neurological AEs than TKIs alone. CONCLUSION: There is evidence, albeit of low quality, that upfront cranial radiotherapy may improve intracranial disease control and survival outcomes compared with TKI alone.

Accuracy of (18)F-flurodeoxyglucose-positron emission tomography/computed tomography in the staging of newly diagnosed nasopharyngeal carcinoma: a systematic review and meta-analysis.

BACKGROUND: The specific role of 18F-flurodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in staging of nasopharyngeal carcinoma (NPC) remains to be validated. A systematic review and meta-analysis were performed to assess the accuracy of staging FDG-PET/CT for newly diagnosed NPC. METHODS: We searched various biomedical databases and conference proceedings for relevant studies. We determined the pooled sensitivities and specificities, diagnostic odds ratios (DOR) and constructed summary receiver operating characteristic (SROC) curves using the hierarchical regression model. RESULTS: 15 relevant studies including 851 patients were identified. Five addressed primary tumor (T), nine addressed regional lymph nodes (N) and seven addressed distant metastasis (M). The combined sensitivity estimate for FDG-PET/CT in T classification was 0.77 (95% confidence interval [CI] 0.59-0.95). For N classification, combined sensitivity was 0.84 (95% CI 0.76-0.91), specificity was 0.90 (95% CI 0.83-0.97), DOR was 82.4 (23.2-292.6) and Q*-index was 0.90. For M classification, the combined sensitivity estimate was 0.87 (95% CI 0.74-1.00), specificity was 0.98 (95% CI 0.96-1.00), DOR was 120.9 (43.0-340.0) and Q*-index was 0.89. CONCLUSION: FDG-PET/CT showed good accuracy in N and M but not T classification for newly diagnosed NPC. FDG-PET/CT, together with Magnetic resonance imaging (MRI) of the nasopharynx, should be part of the routine staging investigations.

Clinical outcome of palliative radiotherapy for locally advanced symptomatic gastric cancer in the modern era.

The purpose of this study was to report the outcomes of patients with symptomatic locally advanced/recurrent gastric cancer treated with radiotherapy (RT) using modern 3-dimensional conformal techniques.We retrospectively reviewed patients who had palliative RT for index symptoms of gastric bleeding, pain, and obstruction. Study endpoints included symptom response, median survival, and treatment toxicity.Of 115 patients with median age of 77 years, 78 (67.8%) patients had metastatic disease at the time of treatment. Index symptoms were gastric bleeding, pain, and obstruction in 89.6%, 9.2%, and 14.3% of patients, respectively. Dose fractionation regimen ranged from 8-Gy single fraction to 40 Gy in 16 fractions. One hundred eleven patients (93.3%) were computed tomography (CT) planned. Median follow-up was 85 days. Response rates for bleeding, pain, and obstruction were 80.6% (83/103), 45.5% (5/11), and 52.9% (9/17), respectively, and median duration of response was 99 days, 233 days, and 97 days, respectively. Median survival was 85 days. Actuarial 12-month survival was 15.3%. There was no difference in response rates between low (≤39 Gy) and high (>39 Gy) biologically effective dose (BED) regimens (α/ß ratio = 10). Median survival was significantly longer in patients who responded to RT compared with patients who did not (113.5 vs 47 days, P < 0.001). Three patients (2.6%) had grade 3 Common Toxicity Criteria equivalent toxicity (nausea/vomiting/anorexia).External beam RT delivered using 3-dimensional conformal techniques is highly effective and well tolerated in the local palliation of gastric cancer, with palliation lasting the majority of patient's lives. Short (≤39 Gy BED) RT schedules are adequate for effective symptom palliation. A phase II study of palliative gastric RT is ongoing.

Surgery or radiosurgery plus whole brain radiotherapy versus surgery or radiosurgery alone for brain metastases.

BACKGROUND: The benefits of adding upfront whole-brain radiotherapy (WBRT) to surgery or stereotactic radiosurgery (SRS) when compared to surgery or SRS alone for treatment of brain metastases are unclear. OBJECTIVES: To compare the efficacy and safety of surgery or SRS plus WBRT with that of surgery or SRS alone for treatment of brain metastases in patients with systemic cancer. SEARCH METHODS: We searched MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials (CENTRAL) up to May 2013 and annual meeting proceedings of ASCO and ASTRO up to September 2012 for relevant studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing surgery or SRS plus WBRT with surgery or SRS alone for treatment of brain metastases. DATA COLLECTION AND ANALYSIS: Two review authors undertook the quality assessment and data extraction. The primary outcome was overall survival (OS). Secondary outcomes include progression free survival (PFS), local and distant intracranial disease progression, neurocognitive function (NF), health related quality of life (HRQL) and neurological adverse events. Hazard ratios (HR), risk ratio (RR), confidence intervals (CI), P-values (P) were estimated with random effects models using Revman 5.1 MAIN RESULTS: We identified five RCTs including 663 patients with one to four brain metastases. The risk of bias associated with lack of blinding was high and impacted to a greater or lesser extent on the quality of evidence for all of the outcomes. Adding upfront WBRT decreased the relative risk of any intracranial disease progression at one year by 53% (RR 0.47, 95% CI 0.34 to 0.66, P value < 0.0001, I(2) =34%, Chi(2) P value = 0.21, low quality evidence) but there was no clear evidence of a difference in  OS (HR 1.11, 95% CI 0.83 to 1.48, P value = 0.47, I(2) = 52%, Chi(2) P value = 0.08, low quality evidence) and PFS (HR 0.76, 95% CI 0.53 to 1.10, P value = 0.14, I(2) = 16%, Chi(2) P value = 0.28, low quality evidence). Subgroup analyses showed that the effects on overall survival were similar regardless of types of focal therapy used, number of brain metastases, dose and sequence of WBRT. The evaluation of the impact of upfront WBRT on NF, HRQL and neurological adverse events was limited by the unclear and high risk of reporting, performance and detection bias, and inconsistency in the instruments and methods used to measure and report results across studies. AUTHORS' CONCLUSIONS: There is low quality evidence that adding upfront WBRT to surgery or SRS decreases any intracranial disease progression at one year. There was no clear evidence of an effect on overall and progression free survival. The impact of upfront WBRT on neurocognitive function, health related quality of life and neurological adverse events was undetermined due to the high risk of performance and detection bias, and inconsistency in the instruments and methods used to measure and report results across studies.

Outcome of 6 fractions of 5.3 Gray HDR brachytherapy in combination with external beam radiotherapy for treatment of cervical cancer.

OBJECTIVE: To review the characteristics, outcomes and toxicities of cervical cancer patients treated with 6 fractions of brachytherapy after external beam radiotherapy (EBRT). METHODS: All patients diagnosed with cervical cancer from 2000 to 2009 who were referred for radical treatment and who received 6 fractions of brachytherapy were retrospectively reviewed. Overall survival (OS), disease free survival (DFS), local control (LC), distant control (DC) rate, acute and late toxicities were the primary endpoints. RESULTS: Thirty-two patients with mainly advanced stage squamous cell carcinoma were identified and reviewed. Patients received EBRT of 45 to 50.4 Gy in 1.8 Gy daily fractions followed by 6 sessions of 3 channel brachytherapy of 5.3 Gy prescribed to point H. Response rates to treatment were good, with no residual disease in 84% six weeks after the completion of treatment. With a median follow up time of 8.1 years, the five-year OS, DFS, LC and distant control rates were 75%, 68.5%, 92.8% and 76.9% respectively. None of the patients developed any G3-4 acute toxicity but one patient who had advanced disease developed G3-4 proctitis with a fistula formation. CONCLUSIONS: HDR brachytherapy utilizing 6 fractions of 5.3 Gy prescribed to point H with concurrent chemo-radiation is superior in terms of OS and LC to regimens that deliver a lower EQD2 dose to point A/H and is associated with very low rates of toxicities.

Internal audit of a comprehensive IMRT program for prostate cancer: a model for centers in developing countries?

PURPOSE: With improving regional prosperity, significant capital investments have been made to rapidly expand radiotherapy capacity across Southeast Asia. Yet little has been reported on the implementation of adequate quality assurance (QA) in patient management. The objective of this study is to perform an in-depth QA assessment of our definitive intensity-modulated radiotherapy (IMRT) program for prostate cancer since its inception. METHODS AND MATERIALS: The department's prostate IMRT program was modeled after that of the University of California San Francisco. A departmental protocol consisting of radiotherapy volume/dose and hormone sequencing/duration and a set of 18 dose objectives to the target and critical organs were developed, and all plans were presented at the weekly departmental QA rounds. All patients treated with definitive IMRT for nonmetastatic prostate cancer were retrospectively reviewed. Protocol adherence, dosimetry data, toxicities, and outcomes were evaluated. RESULTS: Since 2005, 76 patients received IMRT: 54 with whole-pelvis and 22 with prostate-only treatment. Of the 1,140 recorded dosimetric end points, 39 (3.3%) did not meet the protocol criteria. At QA rounds, no plans required a revision. Only one major protocol violation was observed. Two and two cases of Grade 3-4 acute and late toxicities, respectively, were observed. Five (8.8%) patients developed proctitis, but only one required argon laser therapy. CONCLUSIONS: Our comprehensive, practice-adapted QA measures appeared to ensure that we were able to consistently generate conforming IMRT plans with acceptable toxicities. These measures can be easily integrated into other clinics contemplating on developing such a program.

Radical radiotherapy in stage I non-small cell lung cancer (NSCLC)--Singapore National Cancer Centre experience.

INTRODUCTION: The aim of this study was to assess the outcome of radical treatment for stage I non-small cell lung cancer (NSCLC) with external beam radiation therapy. MATERIALS AND METHODS: A retrospective series of 23 patients with stage I NSCLC treated radically with radiotherapy from September 1997 to December 2004 at the National Cancer Centre, Singapore. Eighteen patients had 3D conformal radiotherapy and 5 patients had 2D planning. The median radiation dose delivered was 55 Gy (range, 50 to 67.5 in 20 to 33 fractions). The estimated median BED(10) was 63.9 Gy (range, 57.6 to 70.1). Complete response (CR) rates, overall survival and cause-specific survival rates were analysed for evaluation of treatment results. Local regional failure was defined as disease in the ipsilateral lung and entire mediastinum. Recurrence at the contralateral lung and other distal organs was defined as distant metastases. Survival data were calculated using the Kaplan-Meier method and tested for significance with log-rank statistics. RESULTS: A total of 23 patients (16 males, 7 females) with a median age of 73 years (range, 45 to 88) were analysed. Six (26%) had stage IA and 17 (74%) had stage IB disease. Eleven patients refused surgery and 12 patients were medically inoperable. The median follow-up was 18.9 months (range, 6.2 to 117.4). The overall survival at 2 years and 3 years was 54.7% and 24.3% respectively. The overall cause-specific survival was 57.4% at 2 years and 25.6% at 3 years. Radiological CR was obtained in 6/23 patients (26%) and the median survival was 24.8 months as compared to 20 months in patients who attained partial response (PR) or unknown response (P = 0.24). The median survival for 12 patients who received a BED(10) of > or =63.9Gy was not reached as compared to 20 months in 11 patients with BED(10) of <63.9 Gy (P = 0.03). Sixteen patients died, 14 due to disease recurrence or progression and 2 of unrelated causes. Seven patients (29.2%) remained alive. The longest surviving patient had a follow-up time of 117.4 months. Four of these 7 patients were disease-free and 3 were alive with disease (2 with bone metastases and 1 with recurrence in the primary site). CONCLUSION: Our data are consistent with the reported literature for stage I NSCLC treated with radical radiotherapy. Patients who received a higher dose of radiation have a better outcome. The 3-year cause-specific survival of 25.6% is less than ideal and further investigations into dose escalation with modern radiotherapy techniques and perhaps the addition of chemotherapy or new targeted agents to radiation are warranted to improve the outcome.