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.

GAGE mediates radio resistance in cervical cancers via the regulation of chromatin accessibility.

Radiotherapy (RT) resistance is a major cause of treatment failure in cancers that use definitive RT as their primary treatment modality. This study identifies the cancer/testis (CT) antigen G antigen (GAGE) as a mediator of radio resistance in cervical cancers. Elevated GAGE expression positively associates with de novo RT resistance in clinical samples. GAGE, specifically the GAGE12 protein variant, confers RT resistance through synemin-dependent chromatin localization, promoting the association of histone deacetylase 1/2 (HDAC1/2) to its inhibitor actin. This cumulates to elevated histone 3 lysine 56 acetylation (H3K56Ac) levels, increased chromatin accessibility, and improved DNA repair efficiency. Molecular or pharmacological disruption of the GAGE-associated complex restores radiosensitivity. Molecularly, this study demonstrates the role of GAGE in the regulation of chromatin dynamics. Clinically, this study puts forward the utility of GAGE as a pre-screening biomarker to identify poor responders at initial diagnosis and the therapeutic potential of agents that target GAGE and its associated complex in combination with radiotherapy to improve outcomes.

Outcomes of oesophageal cancer treated with neoadjuvant compared with definitive chemoradiotherapy.

INTRODUCTION: We report outcomes of patients with oesophageal cancer treated with neoadjuvant chemoradiotherapy (NACRT) plus surgery or definitive chemoradiotherapy (chemoRT) at our institution. METHODS: We retrospectively reviewed patients who underwent chemoRT from 2005 to 2017. The primary outcome was overall survival (OS). Secondary outcomes were disease-free survival (DFS) and toxicities. RESULTS: We identified 96 patients with median age of 64 years and squamous cell carcinoma in 82.3%. Twenty-nine patients (30.2%) received NACRT plus surgery, 67 patients (69.8%) received definitive chemoRT. Median follow-up was 13.5 months. The 3/5-year OS were 26.4%/13.4%, and 59.6%/51.6% in the definitive chemoRT and NACRT plus surgery groups, respectively. The 3/5-year DFS were 19.3%/12.3%, and 55.7%/37.2% in the definitive chemoRT and NACRT plus surgery groups, respectively. NACRT plus surgery significantly improved OS (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.22-0.72, P<0.01) and DFS (subhazard ratio [SHR] 5.21, 95 CI 1.20-22.7, P=0.03). Multivariable analysis for OS in the definitive chemoRT group indicated stage (1-2 vs 3-4a; HR 2.17, 95% CI 1.15-4.11, P=0.02) and feeding tube (no tube versus tube; HR 1.85, 95% CI 1.00-3.43, P=0.05) as significantly associated with OS. The cumulative incidence of local recurrence was significantly higher in the definitive chemoRT group (SHR 5.21, 95 CI 1.2022.7, P=0.03). Nineteen patients (65.5%) had postoperative complications. CONCLUSION: NACRT plus surgery improved OS and DFS. However, in view of treatment-related complications, careful selection of patients is warranted. With the predominant histology of our cohort being squamous cell carcinoma (SCC), our results may be more relevant for those with SCC.

Radiotherapy to the brain: what are the consequences of this age-old treatment?

Radiotherapy (RT) has been widely used in the management of benign and malignant brain tumors for decades. However, complications can develop as a result of adjacent structures being exposed to radiation. As such, careful selection of patients and deciding on the most suitable modality of RT are crucial to minimize complications. In general, complications can be subdivided based on its timeline of onset; acute (few days to weeks), early delayed (1-6 months) and late (>6 months). Late complications such as cognitive decline and radiation necrosis can be debilitating and negatively impacts quality-of-life. New strategies to reduce RT-related complications such as with hippocampal sparing-WBRT, memantine, and focal RT (e.g., stereotactic radiosurgery) have had promising results and are being adopted in clinical practice. This review will focus on RT-related complications in the brain, with a focus on WBRT or SRS-related late adverse events, as well as measures to mitigate these complications.

Stereotactic Body Radiotherapy for Oligometastatic Disease in Non-small Cell Lung Cancer.

Metastatic non-small cell lung cancer (NSCLC) is associated with a limited survival when treated with palliative intent platinum-based chemotherapy alone. Recent advances in imaging and therapeutic strategy have identified a subset of patients with limited metastases who may benefit from early local ablative therapy with either surgery or radiotherapy, in addition to standard treatment. Stereotactic body radiotherapy (SBRT) is increasingly used in the treatment of extra-cranial oligometastatic NSCLC (OM-NSCLC) due its non-invasive conduct and ability to deliver high doses. Clinical evidence supporting the use of SBRT in OM-NSCLC is emerging and consistently demonstrates significant benefit in local control and progression-free survival. Here, we discuss the definition of oligometastases (OM), review current available data on SBRT treatment in extra-cranial OM-NSCLC including evidence for site-specific SBRT in lung, liver, and adrenal metastases.

Does external beam radiation boost to pelvic lymph nodes improve outcomes in patients with locally advanced cervical cancer?

BACKGROUND: Current recommendation for locally advanced cervical cancer includes pelvic external beam radiation therapy (EBRT) with concurrent chemotherapy followed by brachytherapy. Involvement of pelvic lymph nodes is an important prognostic factor in locally advanced cervical cancer and recurrence commonly occurs despite definitive treatment. To date, there is no standard guideline on whether an EBRT boost should be applied to involved pelvic lymph nodes. Our study aims to assess if pelvic EBRT boost would reduce recurrence, benefit survival, and affect associated toxicities. METHODS: We conducted a retrospective review of locally advanced cervical cancer cases treated with definitive treatment at our institution. Involvement of pelvic lymph nodes were assessed on CT, MRI (> 10 mm or suspicious features) or PET scan (SUVmax > 2.5). EBRT dose ranged from 45 to 50.4 Gy with nodal boost ranging from 3.6-19.8 Gy. RESULTS: Between 2008 to 2015, 139 patients with locally advanced cervical cancer underwent treatment. Sixty-seven patients had positive pelvic lymph nodes, of which 53.7% received a nodal boost. Five-year recurrence free survival was 48.6% with vs. 64.5% without nodal boost (P = 0.169) and 5-year overall survival in those with positive pelvic lymph nodes was 74.3% with vs. 80.6% without nodal boost (P = 0.143). There was no significant difference in toxicity with nodal boost. CONCLUSIONS: EBRT boost to pelvic lymph nodes does not reduce recurrence or improve survival in locally advanced cervical cancer with lymph node involvement at diagnosis.

Radical radiotherapy in older patients with muscle invasive bladder cancer.

BACKGROUND: Muscle invasive bladder cancer (MIBC) is prevalent in the older patients, who are a vulnerable population with multiple co-morbidities and at increased risk of complications. Radical cystectomy is often not suitable, hence radical radiotherapy (RT) is an alternative option. We reviewed the outcomes of older patients treated with RT with or without concurrent chemotherapy (CRT) at our institution. METHODS: We retrospectively reviewed patients aged 65 years and above treated with radical RT for MIBC at our institution between March 2002 to January 2017. Data was collected from institutional medical records and RT databases. The primary outcome was 2- and 5-year overall survival (OS), recurrence free survival (RFS), and toxicities. Univariate cox proportional hazard regression models were performed to identify independent factors with significant impact on survival. RESULTS: We identified 45 patients (34 males, 11 females) with a median age of 77 years (range 65-95). All patients received maximal transurethral resection of the bladder tumour prior to RT. Median dose of total RT was 64 Gy (range 50-69.8 Gy). Twenty one patients (47%) received CRT. Planned treatment was completed in 42 (93.3%) patients. Median follow-up was 31 months (range 1-147 months). The 2- and 5-year OS was 64% and 44%, respectively. The 2- and 5-year RFS was 68% and 49%, respectively. Median RFS was 34 months (range 8-121 months). Median OS was 56 months (range 18-100 months). Univariate analysis showed that performance status (0-1 vs. 2-3; HR 2.7, 95% CI 1.07-6.8, p = 0.035) and International Society of Geriatric Oncology (SIOG) group (≤2 vs. >2; HR 3.23, 95% CI 1.12-8.64, p = 0.019) were significantly associated with increased hazard for death. One patient (2%) had grade 3 cystitis. CONCLUSION: Radical RT is well tolerated in older patients with MIBC. We report outcomes similar to published data. Older patients should be considered for curative treatment despite their age. However, careful selection is warranted as frail patients (PS ≥2; SIOG >2) may benefit less.