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ContextManagement of locally recurrent prostate cancer after definitive radiotherapy remains controversial due to the perceived high rates of severe genitourinary (GU) and gastrointestinal (GI) toxicity associated with any local salvage modality.ObjectiveTo quantitatively compare the efficacy and toxicity of salvage radical prostatectomy (RP), high-intensity focused ultrasound (HIFU), cryotherapy, stereotactic body radiotherapy (SBRT), low-dose-rate (LDR) brachytherapy, and high-dose-rate (HDR) brachytherapy.Evidence acquisitionWe performed a systematic review of PubMed, EMBASE, and MEDLINE. Two- and 5-yr recurrence-free survival (RFS) rates and crude incidences of severe GU and GI toxicity were extracted as endpoints of interest. Random-effect meta-analyses were conducted to characterize summary effect sizes and quantify heterogeneity. Estimates for each modality were then compared with RP after adjusting for individual study-level covariates using mixed-effect regression models, while allowing for differences in between-study variance across treatment modalities.Evidence synthesisA total of 150 studies were included for analysis. There was significant heterogeneity between studies within each modality, and covariates differed between modalities, necessitating adjustment. Adjusted 5-yr RFS ranged from 50% after cryotherapy to 60% after HDR brachytherapy and SBRT, with no significant differences between any modality and RP. Severe GU toxicity was significantly lower with all three forms of radiotherapeutic salvage than with RP (adjusted rates of 20% after RP vs 5.6%, 9.6%, and 9.1% after SBRT, HDR brachytherapy, and LDR brachytherapy, respectively; p ≤ 0.001 for all). Severe GI toxicity was significantly lower with HDR salvage than with RP (adjusted rates 1.8% vs 0.0%, p

Background: The Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate end point for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate end points exist in advanced prostate cancer. Methods: We searched for trials in advanced prostate cancer, defined as node-positive, metastatic castration-sensitive, nonmetastatic, or metastatic castration-resistant prostate cancer. Eligible randomized trials reported OS and one or more intermediate clinical end points, including biochemical failure (BF), clinical failure, biochemical failure-free survival (BFS), progression-free survival (PFS), and radiographic PFS. Candidacy for surrogacy was assessed by using the second condition of the meta-analytic approach; R² was weighted by the inverse variance of the log intermediate clinical end point hazard ratio and defined as R²>0.70. Results: A total of 143 randomized trials (n=75,601 patients) were included. No candidate end points met the criteria for surrogacy (R² BF [n=28,922], 0.42 [95% confidence interval (CI), 0.18 to 0.64]; BFS [n=25,741], 0.57 [95% CI, 0.37 to 0.73]; clinical failure [n=22,616], 0.31 [95% CI, 0.075 to 0.56]; PFS [n=52,639], 0.50 [95% CI, 0.35 to 0.63]; and radiographic PFS [n=52,548], 0.50 [95% CI, 0.35 to 0.63]). Within preplanned subgroups according to castration-sensitive or castration-resistant disease or according to treatment type, neither BFS nor PFS consistently met criteria for surrogacy. Sensitivity analyses showed that candidacy for surrogacy of all end points tested did not change over time. Conclusions: Our aggregate screening method for surrogate end points in advanced prostate cancer showed that commonly used clinical end points are not clear valid surrogate end points for OS. (Funded by the Prostate Cancer Foundation and the National Cancer Institute.) [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to determine the impact of prehabilitation exercise intervention with respect to (1) acceptability, feasibility, and safety; and (2) physical function, measured by 6‐minute‐walk test (6MWT). Data sources: PRISMA guidelines were used to systematically search PubMed, Embase, and CINAHL databases evaluating prehabilitation exercise interventions. Study selection: The inclusion criteria were studies investigating patients who underwent surgery for their cancer and underwent prehabilitation exercise. Data extraction and synthesis: Guidelines were applied by independent extraction by multiple observers. Data were pooled using a random‐effects model. Main outcome(s) and measure(s): Acceptability, feasibility, and safety rates were calculated. 6MWT (maximum distance a person can walk at their own pace on a hard, flat surface, measured in meters, with longer distance indicative of better performance status) was compared using two arms using the DerSimonian and Laird method. Results: Objective 1. Across 21 studies included in this review, 1564 patients were enrolled, 1371 (87.7%) accepted the trial; of 1371, 1230 (89.7% feasibility) completed the intervention. There was no grade 3+ toxicities. Objective 2. Meta‐analysis of five studies demonstrated a statistically significant decrease in 6MWT distance postoperatively in the control group (mean difference = +27.9 m; 95% confidence interval (CI): 9.3; 46.6) and a significant improvement postoperatively in the prehabilitation group (mean difference = −24.1 m; 95% CI: −45.7; −2.6). Meta‐analysis demonstrated improvements in 6MWT distance 4–8 weeks postoperatively in the prehabilitation group compared to the control group (mean difference = −58.0 m, 95% CI: −92.8; −23.3). Conclusions and relevance: Prehabilitation exercise for cancer patients undergoing surgery was found to be safe, acceptable, and feasible with a statistically significant improvement in the 6MWT, indicating that prehabilitation can improve postoperative functional capacity. [ABSTRACT FROM AUTHOR]

Background: The goal of this study was to characterize the efficacy and safety of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy with concurrent chemotherapy (CFRT) for the definitive treatment of locally advanced pancreatic cancer. The primary outcome measure was efficacy, defined by 2-year overall survival (OS). Secondary outcomes were incidence of any grade 3/4 toxicity and 1-year OS.Methods: A PICOS/PRISMA/MOOSE selection protocol was used to identify eligible studies. Inclusion criteria were: 1) patients diagnosed with locally advanced N0-1 M0 pancreatic cancer; 2) CFRT 1.8 to 2.0 Gy/fraction with chemotherapy per protocol or SBRT ≥5 Gy/fraction in ≤5 fractions; 3) either no control group or another definitive chemotherapy or radiation therapy arm; 4) at least 1 of the outcome measures reported; and 5) single or multi-arm phase 2/3 prospective study for CFRT and/or phase 1/2 or retrospective study for SBRT. Neoadjuvant and/or adjuvant chemotherapy was prescribed per protocol specifications. Weighted random effects meta-analyses were conducted using the DerSimonian and Laird method to characterize summary effect sizes for each outcome.Results: A total of 470 studies were initially screened; of these, 9 studies assessed SBRT and 11 studies assessed CFRT. For SBRT, the median dose was 30 Gy, and the most common regimen was 30 Gy/5 fractions. For CFRT, doses ranged from 45 to 54 Gy in 1.8- to 2.0-Gy fractions, with the majority of studies delivering 50.4 Gy in 28 fractions with concurrent gemcitabine. The random effects estimate for 2-year OS was 26.9% (95% CI, 20.6%-33.6%) for SBRT versus 13.7% (95% CI, 8.9%-19.3%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for 1-year OS was 53.7% (95% CI, 39.3%-67.9%) for SBRT versus 49.3% (95% CI, 39.3%-59.4%) for CFRT, and was not statistically significant. The random effects estimate for acute grade 3/4 toxicity was 5.6% (95% CI, 0.0%-20.0%) for SBRT versus 37.7% (95% CI, 24.0%-52.5%) for CFRT and was statistically significant in favor of SBRT. The random effects estimate for late grade 3/4 toxicity was 9.0% for SBRT (95% CI, 3.3%-17.1%) versus 10.1% (95% CI, 1.8%-23.8%) for CFRT, which was not statistically significant.Conclusion: These results suggest that SBRT for LAPC may result in a modest improvement in 2-year OS with decreased rates of acute grade 3/4 toxicity and no change in 1-year-OS or late toxicity. Further study into the use of stereotactic body radiation therapy for these patients is needed. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to compare the cosmesis and recurrence rates of conventional excision (CE), Mohs micrographic surgery (MMS), external-beam radiation therapy (EBRT), or brachytherapy (BT), for basal cell carcinoma and squamous cell carcinoma of the skin.Methods: Population, Intervention, Control, Outcome, Study Design (PICOS), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and Meta-Analyses of Observational Studies in Epidemiology (MOOSE) methods were used to identify studies on PubMed (from 1985 to 2018), including patients with American Joint Committee on Cancer (AJCC) T1-T2N0 basal cell carcinomas and squamous cell carcinomas and ≥10 months follow-up who received CE, MMS, EBRT, or BT. The primary endpoint was cosmesis, classified as "good," "fair," or "poor." The secondary endpoint was 1-year recurrence. Fixed-effects and random-effects meta-analyses were performed to evaluate primary and secondary outcomes with respect to treatment modality.Results: In total, 18,095 studies met initial search criteria. There were 24 CE, 13 MMS, 19 EBRT, and 7 BT studies included with a total of 21,371 patients. The summary effect size for "good" cosmesis was 81% (95% CI, 70.6%-89.6%), 74.6% (95% CI, 63%-84.6%), and 97.6% (95% CI, 91.3%-100%) for CE, EBRT, and BT, respectively. Good cosmesis was 96.0% in the only MMS study that reported cosmesis. BT had improved "good" cosmesis over EBRT (P = .0025) and was similar to CE and MMS. No significant differences were seen for "fair" or "poor" cosmesis. One-year recurrence rates were low throughout at 0.8% (95% CI, 0.3%-1.6%), 0.2% (95% CI, 0%-0.6%), 2% (95% CI, 1.3%-2.7%), and 0% (95% CI, 0%-0.5%) for CE, MMS, EBRT, and BT, respectively.Conclusions: For T1-T2N0 skin cancers, BT and MMS have improved cosmesis over EBRT and CE. It is unclear whether this is because of treatment superiority or selection and reporting bias. Local control is similar among all modalities at 1 year. [ABSTRACT FROM AUTHOR]

Background and purpose To compare cosmesis and local recurrence (LR) of definitive external beam radiation therapy (EBRT) vs brachytherapy (BT) for indolent basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin. Materials and methods Studies including patients with T1-2 N0 SCCs/BCCs treated with definitive EBRT/BT and ≥10 months follow-up were analyzed. The primary endpoint was post-treatment cosmesis, categorized as “good,” “fair,” or “poor.” The secondary endpoint was LR. Mixed effects regression models were used to estimate weighted linear relationships between biologically equivalent doses with α / β  = 3 (BED 3 ) and cosmetic outcomes. Results A total of 9965 patients received EBRT and 553 received BT across 24 studies. Mean age was 73 years, median follow-up was 36 months, and median dose was 45 Gy/10 fractions at 4.4 Gy/fraction. At BED 3 of 100 Gy, “good” cosmesis was more frequently observed in patients receiving BT, 95% (95% CI: 88–100%) vs 79% (95% CI: 60–82%), p  < 0.05. Similar results were found for “good” cosmesis at BED 3 >100 Gy. No difference in “poor” cosmesis was noted at any BED 3 . LR was <7% for both at one year. Conclusion BT has favorable cosmesis over EBRT for skin SCCs/BCCs at common fractionation regimens. Prospective studies comparing EBRT vs BT are warranted. [ABSTRACT FROM AUTHOR]

Purpose To characterize the cosmetic outcomes and local recurrence (LR) rates of various hypofractionated radiation therapy (RT) regimens for skin basal and squamous cell cancers (BCCs/SCCs). Methods A PICOS/PRISMA/MOOSE selection protocol was performed to identify 344 articles published between 1985–2016 evaluating patients with T1–2 N0 SCCs/BCCs treated with definitive RT. Biologically equivalent doses with α/β = 3 (BED 3 s) were calculated. The primary endpoint was post-treatment cosmesis. Mixed effects regression models were used to estimate weighted linear relationships between BED 3 and cosmetic outcomes. Results A total of 21 studies were identified detailing the treatment of 9729 skin BCC/SCC patients, across seven countries, with external beam RT (n = 9255) or brachytherapy (n = 474). Median follow-up was 36 months (range: 12–77). Median dose was 45 Gy/11 fractions (interquartile range: 37.5 Gy/6–55 Gy/18) at 4 Gy/fraction (interquartile range: 2.5–6 Gy); most hypofractionated 18.75 Gy/1. There was a trend to decreased “good” cosmesis with higher total dose: −3.4% “good” cosmesis/10 Gy BED 3 , p = 0.01. Similarly, there was a trend to increased “fair” cosmesis with higher dose: +3.8% “fair” cosmesis/10 Gy BED 3, p = 0.006. At a BED 3 of 100 Gy, the expected rate of “good” cosmesis is 79% (95% confidence interval: 70%, 88%). Hypofractionated schedules produced similar cosmesis to conventionally fractionated schedules, at the same BED 3 . Fewer than 8% of patients experienced “poor” cosmesis, independent of dose or fractionation regimen. Conclusion Hypofractionated RT has favorable cosmesis for patients with skin BCCs/SCCs. We recommend clinicians consider these commonly-used regimens, which all have BED 3 of ∼100 Gy: 50 Gy/15 fractions, 36.75 Gy/7 fractions, or 35 Gy/5 fractions, as they result in “good” cosmesis in 80% of patients. [ABSTRACT FROM AUTHOR]

Splenic irradiation (SI) is a palliative treatment option for symptomatic splenomegaly (i.e. for pain, early satiety, pancytopenia from sequestration) secondary to hematologic malignancies and disorders. The purpose of the current article is to review the literature on SI for hematologic malignancies and disorders, including: (1) patient selection and optimal technique; (2) efficacy of SI; and (3) toxicities of SI. PICOS/PRISMA methods are used to select 27 articles including 766 courses of SI for 486 patients from 1960 to 2016. The most common cancers treated included chronic lymphocytic leukemia and myeloproliferative disorders; the most common regimen was 10Gy in 1Gy fractions over two weeks, and 27% of patients received retreatment. A partial or complete response (for symptoms, lab abnormalities) was obtained in 85-90% of treated patients, and 30% were retreated within 6-12months. There was no correlation between biologically equivalent dose of radiation therapy and response duration, pain relief, spleen reduction, or cytopenia improvement (r2 all <0.4); therefore, lower doses (e.g. 5Gy in 5 fractions) may be as effective as higher doses. Grade 3-4 toxicity (typically leukopenia, infection) was noted in 22% of courses, with grade 5 toxicity in 0.7% of courses. All grade 5 toxicities were due to either thrombocytopenia with hemorrhage or leukopenia with sepsis (or a combination of both); they were sequelae of cancer and not directly caused by SI. In summary, SI is generally a safe and efficacious method for treating patients with symptomatic splenomegaly. [ABSTRACT FROM AUTHOR]

Purpose To determine if increasing the biologically equivalent dose (BED) via various radiation fractionation regimens is correlated with clinical outcomes or toxicities for prostate cancer. Methods and materials We performed a meta-analysis that included 12,756 prostate cancer patients from 55 studies published from 2003 to 2013 who were treated with non-dose-escalated conventionally fractionated external beam radiation therapy (non-DE-CFRT), DE-CFRT, hypofractionated RT, and high dose rate brachytherapy (HDR-BT; either mono or boost) with ⩾5-year actuarial follow-up. BEDs were calculated based on the following formula: ( nd [1 + d /( α / β )]), where n is the number of fractions, and d is dose per fraction; assuming an α / β of 1.5 for prostate cancer and 3.0 for late toxicities. Mixed effects meta-regression models were used to estimate weighted linear relationships between BED and the observed percentages of patients experiencing late toxicities or 5-year freedom from biochemical failure (FFBF). Results Increases in 10 Gy increments in BED (at α / β of 1.5) from 140 to 200 Gy were associated with 5-unit improvements in percent FFBF. Dose escalation of BED above 200 Gy was not correlated with FFBF. Increasing BED (at α / β of 3.0) from 98 to 133 Gy was associated with increased gastrointestinal toxicity. Dose escalation above 133 Gy was not correlated with toxicity. Conclusions An increase in the BED to 200 Gy (at α / β of 1.5) was associated with increased disease control. Doses above 200 Gy did not result in additional clinical benefit. [ABSTRACT FROM AUTHOR]

Purpose: Limited evidence is available on the utility of dose-escalated radiation therapy (DE-RT) with or without temozolomide (TMZ) versus standard-of-care radiation therapy (SoC-RT) for patients with newly diagnosed glioblastoma multiforme. We performed a systematic review/meta-analysis to compare overall survival (OS) and progression-free survival (PFS) between DE-RT and SoC-RT.Methods and Materials: We used a Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses/Meta-analysis of Observational Studies in Epidemiology selection criterion to identify studies. The primary and secondary outcomes were 1-year OS and 1-year PFS, respectively. Outcomes and comparisons were subdivided based on receipt of TMZ and MGMT status. DE-RT was defined based on equivalent dose calculations. Random effects meta-analyses using the Knapp-Hartung correction, arcsine transformation, and restricted maximum likelihood method were conducted. Meta-regression was used to compare therapeutic (eg, DE-RT or TMZ) and pathologic characteristics (eg, MGMT methylation status) using the Wald-type test.Results: Across 22 published studies, 2198 patients with glioblastoma multiforme were included; 507 received DE-RT. One-year OS after DE-RT alone was higher than SoC-RT alone (46.3% vs 23.4%; P = .02) as was 1-year PFS (17.9% vs 5.3%; P = .02). No significant difference in 1-year OS (73.2% vs 64.4%; P = .23) or 1-year PFS (44.5% vs 44.3%; P = .33) between DE-RT + TMZ and SoC-RT + TMZ was noted. No difference in 1-year OS was noted between DE-RT + TMZ and SoC-RT + TMZ in either MGMT methylated (83.2% vs 73.2%; P = .23) or MGMT unmethylated (72.6% vs 50.6%; P = .16) patients.Conclusions: DE-RT alone resulted in superior PFS and OS versus SoC-RT alone. DE-RT + TMZ did not lead to improved outcomes versus SoC-RT + TMZ. No differential benefit based on MGMT status was found. Future studies are warranted to define which subgroups benefit most from DE-RT. [ABSTRACT FROM AUTHOR]

• Few studies characterize combined immunotherapy and radiation. • Toxicities similar after adding radiation to immunotherapy. • Anti-CTLA-4 associated with more toxicity than anti-PD-1/PD-L1. • No significant difference based on timing of immunotherapy and radiation. Immune checkpoint inhibitor with radiation therapy (ICI + RT) is under investigation for improved patient outcome, so we performed a systematic review/meta-analysis of toxicities for ICI + RT compared to immune checkpoint inhibitor (ICI) therapy alone. A PRISMA-compliant systematic review of studies in MEDLINE (PubMed) and in the National Comprehensive Cancer Network guidelines was conducted, with primary outcome grade 3 + toxicity. Criteria for ICI alone were: phase III/IV trials that compared immunotherapy to placebo, chemotherapy, or alternative immunotherapy; and for ICI + RT: prospective/retrospective studies with an arm treated with ICI + RT. Meta-analysis was performed by random effects models using the DerSimonian and Laird method. The I 2 statistic and Cochran's Q test were used to assess heterogeneity, while funnel plots and Egger's test assessed publication bias. This meta-analysis included 51 studies (n = 15,398), with 35 ICI alone (n = 13,956) and 16 ICI + RT studies (n = 1,442). Our models showed comparable grade 3–4 toxicities in ICI + RT (16.3%; 95% CI, 11.1–22.3%) and ICI alone (22.3%; 95% CI, 18.1–26.9%). Stratification by timing of radiation and irradiated site showed no significant differences, but anti-CTLA-4 therapy and melanoma showed increased toxicity. The grade 5 toxicities were 1.1% and 1.9% for ICI alone and ICI + RT respectively. There was significant heterogeneity, but not publication bias. The random effects model showed comparable grade 3–4 toxicity in using ICI + RT compared to ICI alone in CNS melanoma metastases, NSCLC, and prostate cancer. ICI + RT is safe for future clinical trials in these cancers. [ABSTRACT FROM AUTHOR]

• UHRT is becoming a widely adopted treatment in localized prostate cancer. • UHRT offers similar rates of disease-free survival to CFRT and HFRT at 85%. • Grade 2+ late GI toxicity is approximately 12% across all modalities. • Grade 2+ late GU toxicity is approximately 20% across all modalities. To characterize the efficacy (5-year disease-free survival [DFS]) and safety (incidence of grade 2+ late gastrointestinal or genitourinary toxicity) of ultrahypofractionated radiation therapy (UHRT) versus hypofractionated radiation therapy (HFRT) and conventionally fractionated radiation therapy (CFRT) by comparing patients treated on phase III protocols. A PICOS/PRISMA/MOOSE protocol was used to identify eligible studies. Weighted random effects meta-analyses were conducted using the DerSimonian and Laird method. Wald-type tests were used to compare treatment modalities for each outcome, where the null hypothesis was rejected for p < 0.05. Seven studies were included that consisted of 6795 patients (2849 CFRT, 3357 HFRT, and 589 UHRT). Median age was 68 years. Summary effect sizes for 5-year DFS were 85.1% (95% CI: 82.1%–87.8%) for CFRT, 86% (95% CI: 83%–88.7%) for HFRT, and 85% (95% CI: 80%–87%) for UHRT (p = 0.66 and p = 0.8 for CFRT vs. HFRT and CFRT versus UHRT, respectively). Summary effect sizes for late grade 2+ gastrointestinal toxicity were 12.1% (95% CI: 9.2%–15.4%) for CFRT, 14.6% (95% CI: 9.9%–20%) for HFRT, and 10% (95% CI: 7%–13%) for UHRT (p = 0.41 and p = 0.09 for CFRT versus HFRT and CFRT versusus UHRT, respectively). Summary effect sizes for late grade 2+ genitourinary toxicity were 19.4% (95% CI: 10.7–29.9%) for CFRT, 20.4% (95% CI: 10.2%–32.9%) for HFRT, and 18% (95% CI: 15%–22%) for UHRT (p = 0.89 and p = 0.92 for CFRT versus HFRT and CFRT versus UHRT, respectively). Ultrahypofrationated regimens appear to offer similar levels of safety and efficacy to CFRT and HFRT. These findings are hypothesis-generating and require further validation by ongoing prospective trials. [ABSTRACT FROM AUTHOR]

• First meta-analysis comparing conventional RT to SRS for spinal metastases. • Single-fraction SRS resulted in improved LC compared to conventional RT. • BED 10 escalation of 10 Gy 10 via SRS resulted in roughly 5% LC benefit. • SRS was well-tolerated with <1% incidence of Grade 3–5 toxicities. • Single-fraction SRS with higher vertebral compression fracture rates than multiple-fraction SRS. To perform a systematic review/meta-analysis of outcomes for patients with spinal metastases treated with stereotactic radiosurgery (SRS) (either single-fraction (SF-SRS) or multiple-fraction (MF-SRS)) or conventional radiotherapy (RT). Thirty-seven studies were identified. Primary outcomes were 1-year local control (LC) and acute/late grade 3–5 toxicities (including vertebral compression fractures (VCF)). Weighted random effects meta-analyses using the DerSimonian and Laird methods and meta-regressions were conducted to characterize and compare effect sizes. Mixed effects regression models were used in dose analyses. A total of 3237 patients with 4911 lesions were included; 43.8%, 19.7%, and 36.5% of lesions received SF-SRS, MF-SRS, or RT, respectively. SF-SRS resulted in improved 1-year LC (92.9% (95% CI: 86.4–97.4%); p = 0.007) compared to RT (81.0% (95% CI: 69.2–90.5%)) with no difference between MF-SRS (82.1%; p = 0.86) and RT. On subgroup analysis of de novo metastases, superior 1-year LC following SF-SRS (95.5% (95% CI: 87.4–99.6%)) was maintained compared to RT (83.6% (95% CI: 70.4–93.5%); p = 0.007). A 4.7% increase in LC was noted for each 10 Gy 10 increase in biologically effective dose (BED 10 , assuming an alpha/beta = 10) with SRS (p < 0.001). No difference in toxicities were found between SF-SRS (0.4%), MF-SRS (0.2%), or RT (0%). Higher VCF rates were noted following SF-SRS (19.5%) vs. MF-SRS (9.6%; p = 0.039)) with no correlation between dose and VCF rates. SF-SRS resulted in superior LC with a roughly 5% LC benefit for every 10 Gy 10 increase in BED 10 with higher VCF rates compared to MF-SRS. If LC is the goal of treatment, then SRS may be a preferred treatment modality. However, these results are hypothesis-generating, and prospective randomized clinical trials are indicated to definitively address the question of whether SRS results in improved LC compared to RT. [ABSTRACT FROM AUTHOR]

• Meta-analysis of NSCLC patients with brain metastases with or without EGFR or ALK mutations. • 1st meta-analysis examining patients with brain metastases from NSCLC with confirmed EGFR or ALK mutations. • Examined outcomes following treatment with TKIs, RT, or multimodality approaches. • Patients with EGFR or ALK mutations have improved OS compared to wild-type patients. • No clinical benefit was noted from the addition of TKIs to RT, either WBRT or SRS. To analyze outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases harboring EGFR or ALK mutations and examine for differences between tyrosine kinase inhibitors (TKIs) alone, radiotherapy (RT) alone (either whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS)), or combined TKIs and RT. Thirty studies were identified. Patients: with brain metastases from NSCLC. Intervention: initial TKIs alone with optional salvage RT, RT alone, or TKIs and RT. Control: wild-type NSCLC and TKIs alone for mutational and treatment analysis, respectively. Outcomes: overall survival (OS) and intracranial progression-free survival (PFS). Setting: studies with mutation information. A total of 2649 patients were included. Patients with ALK and EGFR mutations had significantly higher median OS (48.5 months, p < 0.0001; and 20.9 months; p = 0.0006, respectively) compared to wild-type patients (9.9 months). Similar median OS was noted between TKIs and RT (28.3 months), RT alone (32.2 months; p = 0.22), or TKIs alone (23.9 months; p = 0.2). Patients treated with TKIs and RT had higher median PFS (18.6 months; p = 0.06) compared to TKIs alone (13.6 months) with no difference between TKIs and RT vs. RT alone (16.9 months; p = 0.72). No PFS difference was found between WBRT and TKI (23.2 months; p = 0.72) vs. WBRT alone (24 months) or SRS and TKI (16.7 months; p = 0.56) vs. SRS alone (13.6 months). NSCLC patients with brain metastases harboring EGFR or ALK mutations have superior OS compared to wild-type patients. No PFS or OS benefit was found with the addition of TKIs to RT. [ABSTRACT FROM AUTHOR]

• Collagen vascular disease and inflammatory bowel disease are "historically accepted" contraindications to radiotherapy. • In this meta-analysis of 621 patients with these disorders, grade 4 toxicity across both diseases was 1.5% and 4.5% for acute and late toxicities, respectively. • Thus, collagen vascular disease and inflammatory bowel disease are not absolute contraindications to radiotherapy. To investigate the incidence of radiotherapy-related acute and late toxicities among patients with pro-inflammatory comorbidities. PICOS/PRISMA/MOOSE methods were used to identify studies on PubMed and MEDLINE, 1970–2018. The following were extracted: location, cancer, sample size, age, follow-up duration, medical contraindication, treatment, and toxicity. A weighted random effects model with the DerSimonian and Laird method was used in the meta-analysis. The primary endpoint was the grade ≥ 3 acute toxicity, and the secondary endpoint was late toxicity. There were 1137 articles screened and 18 included, assessing 621 patients. Among the 18 articles, 10 had collagen vascular disease (n = 417) and 8 had inflammatory bowel disease (n = 204). Median follow-up was 52.8 months. 457 patients received radiotherapy alone, and 153 received concurrent chemo-radiotherapy. The random effects estimate for incidence of grade ≥ 3 toxicity in collagen vascular disease patients (95% confidence interval) was 11.7% (5.4–19.6%) and 6.1% (1.4–12.6%) for acute and late toxicities, respectively. Incidence of grade ≥ 3 toxicity in inflammatory bowel disease patients was 14.0% (7.1–22.4%) and 10.2% (3.2–19.7%) for acute and late toxicities, respectively. Average grade 4 toxicity across both diseases was 1.5% and 4.5% for acute and late toxicities, respectively. Average grade 5 toxicity across both diseases was negligible (<1%). Patients with historically accepted contraindications to radiation therapy have a 10–15% risk of any grade ≥ 3 toxicity, <5% risk of grade 4 toxicity, and <1% risk for grade 5 toxicity, suggesting that collagen vascular disease and inflammatory bowel disease are not absolute contraindications to radiotherapy. [ABSTRACT FROM AUTHOR]

Highlights • Immunotherapy and radiosurgery are utilized for brain metastases but data are limited. • In this metaanalysis, concurrent therapy improved 1-year survival and brain control. • The overall rate of radionecrosis was 5.3%. • Prospective trials are needed to more accurately inform on this clinical scenario. Abstract Background and purpose While the combination of stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) is becoming more widely used in the treatment of brain metastases (BM), there is a paucity of prospective data to validate both the safety and efficacy, as well as the optimal timing of these two therapies relative to one another. Methods A PICOS/PRISMA/MOOSE selection protocol was used to identify 17 studies across 15 institutions in 3 countries. Inclusion criteria were patients: diagnosed with BM; treated with SRS/ICI, either concurrently or non-concurrently; with at least one of the primary or secondary outcome measures reported. Weighted random effects meta-analyses using the DerSimonian and Laird method were performed. The primary outcome was 1-year overall survival (OS). Secondary outcomes were 1-year local control (LC), 1-year regional brain control (RBC), and radionecrosis incidence. Results A total of 534 patients with 1,570 BM were included. The 1-year OS was 64.6% and 51.6% for concurrent and non-concurrent therapy, respectively (p < 0.001). Local control at 1-year was 89.2% and 67.8% for concurrent and non-concurrent therapy, respectively (p = 0.09). The RBC at 1-year was 38.1% and 12.3% for concurrent and ICI administration prior to SRS, respectively (p = 0.049). The overall incidence of radionecrosis for all studies was 5.3%. Conclusions Concurrent administration of SRS/ICI may be associated with improved safety and efficacy versus sequential therapy. These findings, however, are hypothesis-generating and require further validation by ongoing and planned prospective trials. [ABSTRACT FROM AUTHOR]

Numerous trials have been launched over the prior decade examining the safety and efficacy of therapy de-escalation in human papillomavirus (HPV)-associated oropharyngeal cancer (OPC). Because no summative assessment of these prospective trials exists to date, we systematically reviewed the outcomes and toxicities associated with therapy de-intensification for this population. PRISMA-guided systematic PubMed searches (along with articles known to the authors and references thereof) were performed for prospective studies reporting clinical outcomes and/or toxicities of de-intensified RT and/or systemic therapy (with or without surgery), exclusively for HPV-associated OPC. Ten prospective studies were analyzed. Performing a meta-analysis was not entirely possible owing to the heterogeneity of treatment paradigms and the lack of >2 studies for most paradigms; however, because just one paradigm (induction chemotherapy followed by reduced-dose RT and/or systemic therapy) had 4 associated articles, an exploratory meta-analysis was conducted for that subset. Two trials of dose-reduced concurrent chemoradiotherapy (60 Gy/weekly cisplatin) demonstrated 3-year distant metastasis-free survival and overall survival (OS) ranging from 91 to 100% and 95%, respectively; acute grade 3+ mucositis and dysphagia occurred in 33-35% and 21-39%, respectively. In the four trials of induction chemotherapy (platinum/taxane-based) followed by dose-reduced RT, 2-year progression-free and OS ranged from 80 to 95% and 83 to 98%, respectively; acute grade 3+ dysphagia, dermatitis, and mucositis ranged from 9 to 15%, 7 to 20%, and 9 to 30% (excluding one outlier), respectively. For these four trials, the exploratory meta-analysis showed a pooled 2-year PFS and OS of 89% (95% confidence interval, 80-96%) and 96% (92-99%). The pooled rates of grade ≥3 dysphagia, dermatitis, and mucositis were 13% (7-19%), 9% (5-14%), and 28% (9-53%). However, there was significant heterogeneity in the 2-year PFS (I2 = 57%, p = 0.07) and grade ≥3 mucositis (I2 90%, p < 0.01). Next, both randomized trials which replaced concurrent tri-weekly cisplatin with weekly cetuximab illustrated superior outcomes with the former. Lastly, two remaining trials (one using functional imaging to guide reduced-dose RT, and another examining reduced-dose postoperative RT) also showed satisfactory outcomes and toxicities. Taken together, dose-reduced chemoradiotherapy (with or without induction chemotherapy for patient/biology selection purposes) seems to be a promising de-escalation strategy for HPV-associated OPC, although replacement of concurrent cisplatin by cetuximab is not recommended. Long-term follow-up is required for firmer conclusions. [ABSTRACT FROM AUTHOR]