Which Bone-Modifying Agent is Associated with Better Outcomes in Patients with Skeletal Metastases from Lung Cancer? A Systematic Review and Network Meta-analysis.

BACKGROUND: Lung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer-related deaths. Metastatic bone disease occurs in 20% to 40% of patients with lung cancer, and these patients often present with pain or skeletal-related events (SREs) that are associated with decreased survival. Bone-modifying agents such as denosumab or bisphosphonates are routinely used; however, to our knowledge, there has been no quantitative synthesis of randomized controlled trial data to determine the most effective pharmacologic treatment of metastatic bone disease because of lung cancer. QUESTIONS/PURPOSES: We aimed to perform a network meta-analysis of randomized trials to identify the bone-modifying agent that is associated with the (1) highest overall survival, (2) longest time to SRE, (3) lowest SRE incidence, and (4) greatest likelihood of pain resolution. METHODS: We conducted our study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and pre-registered the analysis on PROSPERO (ID: CRD42019124364). We performed a librarian-assisted search of MEDLINE, PubMed, EMBASE, Cochrane Library, and Chinese databases including China National Knowledge Infrastructure and Wanfang Data. We included randomized controlled trials reporting outcomes specifically for patients with lung cancer treated with a bisphosphonate or denosumab. SREs included pathologic fractures, spinal cord compression, hypercalcemia of malignancy, or pain resulting in surgical intervention or radiation therapy. We excluded trials exclusively reporting surrogate outcomes such as changes in bone turnover markers. Screening, data extraction, risk of bias evaluation, and Grading of Recommendations Assessment, Development, and Evaluation evaluations were performed in duplicate. We included 131 randomized controlled trials that evaluated 11,105 patients with skeletal metastases from lung cancer. The network meta-analysis was performed using a frequentist model and the R statistical software. Results are reported as relative risks or mean differences, and the I2 value is reported for heterogeneity. The P-score, a measure of ranking certainty that accounts for standard error, is reported for each outcome. Heterogeneity in the network was considered moderate for overall survival and time to SRE, mild for the incidence of SRE, and low for pain resolution. RESULTS: For overall survival, denosumab was ranked above zoledronic acid and estimated to confer a mean of 3.3 months (95% CI 0.3-6.3) of increased overall survival compared with untreated patients (P-score = 89%). For the time to SRE, denosumab was ranked first with a mean of 9.1 additional SRE-free months (95% CI 6.7-11.5) compared with untreated patients (P-score = 99%), while zoledronic acid conferred an additional 4.8 SRE-free months (95% CI 3.6-6.1). Reduction in the incidence of SREs was not different between patients treated with denosumab (relative risk 0.54; 95% CI 0.33-0.87) and those treated with zoledronic acid (relative risk 0.56; 95% CI 0.46-0.67). Patients treated with the combination of ibandronate and systemic therapy were more likely to experience successful pain resolution than untreated patients (relative risk 2.4; 95% CI 1.8-3.2). CONCLUSION: In this comprehensive synthesis of all available randomized controlled trial evidence guiding the pharmacologic treatment of bone metastases from lung cancer, denosumab was ranked above zoledronic acid for overall survival and time to SRE and was not different for reducing the incidence of SRE. Both were superior to no treatment for each of these outcomes. Given this, we encourage physicians to consider the use of denosumab or zoledronic acid in treating this patient population. The combination of ibandronate and systemic therapy was the most effective at reducing pain because of metastases. No cost-effectiveness analysis has yet been performed for denosumab and zoledronic acid on patients with metastatic lung cancer, and this represents an avenue for future research. LEVEL OF EVIDENCE: Level I, therapeutic study.

High Prevalence of Erythrasma in Patients with Inverse Psoriasis: A Cross-sectional Study.

BACKGROUND: Inverse psoriasis is characterized by erythematous nonscaly plaques in intertriginous regions. Similarly, erythrasma, a superficial infection caused by Corynebacterium minutissimum (C. minutissimum), is also found in skin folds with red-brown lesions, making the distinction between psoriasis and erythrasma difficult. No studies have previously determined whether these two clinically similar cutaneous disorders can occur concurrently. METHODS: Thirty patients with inverse psoriatic plaques were examined using a standard Wood's lamp to visualize porphyrins associated with C. minutissimum. RESULTS: Just over half (56.6%) of patients with inverse psoriatic plaques showed evidence of this bacterium. Specifically, 45.5 percent of inverse psoriatic lesions were found to be positive for C. minutissimum, with the highest prevalence of erythrasma located in the gluteal cleft. CONCLUSION: Clinical suspicion for C. minutissimum should be high in patients with inverse psoriasis due to the organism's potential to trigger or exacerbate psoriatic lesions. Further studies are indicated to determine the response to treatment in patients with this combination.

The Impact of Academic Facility Type and Case Volume on Survival in Patients Undergoing Curative Radiation Therapy for Muscle-Invasive Bladder Cancer.

PURPOSE: Bladder-preserving curative radiation therapy (RT) has been established as an excellent treatment option for select patients with muscle-invasive bladder cancer (MIBC). However, some clinicians have concerns that good outcomes are only achievable at high-volume facilities (HVFs) and academic centers (ACs), questioning successful reproducibility of curative RT at smaller centers. This study sought to determine whether treatment at ACs or HVFs was associated with better overall survival (OS) than treatment at nonacademic centers or lower-volume facilities. METHODS AND MATERIALS: We performed a retrospective cohort study of National Cancer Database patients (n=2763) with cT2 to cT4 N0 M0 transitional cell MIBC who received curative RT (60-70 Gy) with or without concurrent chemotherapy. Cox proportional hazards models were used to estimate the instantaneous hazard of death as a function of univariate and multivariate patient characteristics and clinical measures. RESULTS: Univariate analysis showed that academic facility type was significantly associated with improved OS (hazard ratio [HR], 0.88; 95% confidence interval [CI] 0.79-0.98; P=.02) whereas higher case volume was not associated with improved survival (HR, 0.97; 95% CI 0.92-1.01; P=.15). Multivariate analysis showed no differences in OS for treatment at ACs versus nonacademic centers (HR, 0.94; 95% CI 0.84-1.06; P=.31) or HVFs versus lower-volume facilities (HR, 0.99; 95% CI 0.94-1.04; P=.60). The 2-year OS rate was 54.5% (95% CI 52.5%-56.4%), and the 5-year OS rate was 28.9% (95% CI 27.0%-30.8%). CONCLUSIONS: Although some providers are cautious about offering curative RT at all centers, this large hospital-based study suggests that facility type and volume are not significantly associated with OS for patients undergoing curative RT after we account for other clinically relevant risk factors. The results of this study demonstrate that curative RT in the treatment of MIBC may be considered for patients regardless of facility type or volume.

Five-fraction stereotactic radiosurgery (SRS) for single inoperable high-risk non-small cell lung cancer (NSCLC) brain metastases.

BACKGROUND: Achieving durable local control while limiting normal tissue toxicity with definitive radiation therapy in the management of high-risk brain metastases remains a radiobiological challenge. The objective of this study was to examine the local control and toxicity of a 5-fraction stereotactic radiosurgical approach for treatment of patients with inoperable single high-risk NSCLC brain metastases. METHODS: This retrospective analysis examines 20 patients who were deemed to have "high-risk" brain metastases. High-risk tumors were defined as those with a maximum diameter greater than 2 cm and/or those located within an eloquent cortex. Patients were evaluated by a neurosurgeon prior to treatment and determined to be inoperable due to tumor or patient characteristics. Patients were treated using the CyberKnife® SRS system in 5 fractions to a total dose of 30 Gy, 35 Gy, or 40 Gy. RESULTS: Twenty patients with a median age of 65.5 years were treated from April 2010 to August 2014 in 5 fractions to a median total dose of 35 Gy. At a median follow up of 11.3 months local tumor control was observed in 18 of 20 metastases (90 %). Both local failures were observed in patients receiving a lower dose of 30 Gy. Median pre-treatment dexamethasone dose was 10 mg/day and median post-treatment nadir dose was 0 mg/day. Salvage intracranial therapy was required in 45 % of patients. Symptomatic radionecrosis was observed in 4 of 20 patients (20 %), two of which were treated to 40 Gy and the remainder to 35 Gy. Kaplan-Meier 1-year, 2-year, and median survival were calculated to be 45 %, 20 %, and 13.2 months, respectively. CONCLUSIONS: Five-fraction SRS to a total dose of 35 Gy appears to be a safe and effective management strategy for single high-risk NSCLC brain metastases, while a total dose of 40 Gy leads to an excess risk of neurotoxicity.