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Background The objectives of this study were to characterize the risk of death (1) from the primary cancer vs competing cause of death; and (2) from various causes of death vs the general poplation. The relative risk of death after a pediatric cancer diagnosis versus the general population and the risk of death from a primary cancer diagnosis versus competing causes of death. Methods This retrospective, population‐based study used the Surveillance, Epidemiology, and End Results database (1980‐2015) and included patients aged 0 to 19 years at the time of diagnosis. Observed deaths were calculated; the risk of death versus the general population was assessed with standardized mortality ratios (SMRs). Competing risk models for the cause of death were performed. Results There were 58,356 patients who were diagnosed, and the mortality rate was 22.8%. To assess causes of death, 6996 patients who died during the study period were included (45,580 total person‐years at risk): 5128 (73%) died of their primary cancer, and 1868 (27%) died of a competing cause. Among all patients, the rate of death from the index cancer was higher than the rate of death from another cause within the first 5 years after diagnosis. The risk of death from a nonprimary cancer began to supersede the rate of death from the primary cancer 10 years after diagnosis for patients with germ cell tumors, lymphomas, and sarcomas. SMRs for the primary cancer were highest within the first 5 years after diagnosis for all cancers (SMRs, 100‐50,000; P < .0001). The risk of death from competing causes (heart disease, suicide, and sepsis) was elevated (SMR, >100; P < .001). The risk of dying of heart disease was high, especially for patients with astrocytomas (SMR, 47.84; 95% confidence interval [CI], 27.87‐76.59) and neuroblastomas (SMR, 98.59; 95% CI, 47.28‐181.32). The risk of dying of suicide was high in most patients, particularly for those with osteosarcomas (SMR, 111.40; 95% CI, 2.82‐620.69), Hodgkin lymphomas (SMR, 62.35; 95% CI, 34.89‐102.83), and gonadal germ cell tumors (SMR, 28.97; 95% CI, 12.51‐57.09). Conclusions The cause of death for patients with gonadal germ cell tumors, lymphomas, and sarcomas is more commonly a secondary cancer or noncancerous cause than the primary disease; their risk of death from competing causes (heart disease, suicide, and sepsis) rises throughout life.

Abstract The incidence of brain metastasis is increasing as improvements in systemic therapy lead to increased survival. This provides new and challenging clinical decisions for patients who are trying to balance the risk of recurrence or progression with treatment-related side effects, and it requires appropriate management strategies from multidisciplinary teams. Improvements in prognostic assessment and systemic therapy with increasing activity in the brain allow for individualized care to better guide the use of local therapies and/or systemic therapy. Here, we review the current landscape of brain-directed therapy for the treatment of brain metastasis in the context of recent improved systemic treatment options. We also discuss emerging treatment strategies including targeted therapies for patients with actionable mutations, immunotherapy, modern whole-brain radiation therapy, radiosurgery, surgery, and clinical trials.

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.

AbstractIntroduction Vestibular schwannomas (VS) are slow growing tumors. Although there are a wide variety of available treatment options, these tumors are often initially observed. We aimed to establish the presenting symptoms and outcomes of patients treated with initial observation at our institution.Methods The medical records of patients with radiographically diagnosed VS were reviewed from 1989 to 2018. Actuarial estimates of radiographic tumor control and freedom of local therapy were calculated and compared using Cox regression analyses.Results A total of 360 patients were diagnosed with VS at our institution from 1989 through 2018 with a median age of 59.9 years. After radiographic diagnosis, 243 patients (67.5%) opted for initial observation. Local control at 1, 5, and 10 years was 91, 67, and 58%, respectively. On multivariable analysis, factors associated with shorter time to radiographic tumor progression included younger patient age (p = 0.016) and tumors with an extracanalicular component (p = 0.032). Regarding time until definitive treatment only larger baseline American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) tumor size predicted for earlier initiation of therapy (p < 0.001), although this was restricted to tumors with an extracanalicular component (p = 0.004), as opposed to purely internal auditory canal tumors (p = 0.839).Conclusion Many patients who were initially observed continued to have satisfactory local control rates at 10 years. In patients with extracanalicular tumors, larger AAO-HNS tumor measurements were associated with earlier radiographic tumor progression and shorter time to local therapy, with 7 mm serving as a potential threshold value for extracanalicular tumors. Younger patients and tumors with primarily an extracanalicular portion may warrant closer observation.

OBJECTIVE The current standard initial therapy for pilocytic astrocytoma is maximal safe resection. Radiation therapy is considered for residual, recurrent, or unresectable pilocytic astrocytomas. However, the optimal radiation strategy has not yet been established. Here, the authors describe the outcomes of stereotactic radiosurgery (SRS) for pilocytic astrocytoma in a large multiinstitutional cohort. METHODS An institutional review board–approved multiinstitutional database of patients treated with Gamma Knife radiosurgery (GKRS) between 1990 and 2016 was queried. Data were gathered from 9 participating International Radiosurgery Research Foundation (IRRF) centers. Patients with a histological diagnosis of pilocytic astrocytoma treated using a single session of GKRS and with at least 6 months of follow-up were included in the analysis. RESULTS A total of 141 patients were analyzed in the study. The median patient age was 14 years (range 2–84 years) at the time of GKRS. The median follow-up was 67.3 months. Thirty-nine percent of patients underwent SRS as the initial therapy, whereas 61% underwent SRS as salvage treatment. The median tumor volume was 3.45 cm 3 . The tumor location was the brainstem in 30% of cases, with a nonbrainstem location in the remainder. Five- and 10-year overall survival rates at the last follow-up were 95.7% and 92.5%, respectively. Five- and 10-year progression-free survival (PFS) rates were 74.0% and 69.7%, respectively. On univariate analysis, an age < 18 years, tumor volumes < 4.5 cm 3 , and no prior radiotherapy or chemotherapy were identified as positive prognostic factors for improved PFS. On multivariate analysis, only prior radiotherapy was significant for worse PFS. CONCLUSIONS This represents the largest study of single-session GKRS for pilocytic astrocytoma to date. Favorable long-term PFS and overall survival were observed with GKRS. Further prospective studies should be performed to evaluate appropriate radiosurgery dosing, timing, and sequencing of treatment along with their impact on toxicity and the quality of life of patients with pilocytic astrocytoma.

Abstract Aims This observational study characterized cardiovascular disease (CVD) mortality risk for multiple cancer sites, with respect to the following: (i) continuous calendar year, (ii) age at diagnosis, and (iii) follow-up time after diagnosis. Methods and results The Surveillance, Epidemiology, and End Results program was used to compare the US general population to 3 234 256 US cancer survivors (1973–2012). Standardized mortality ratios (SMRs) were calculated using coded cause of death from CVDs (heart disease, hypertension, cerebrovascular disease, atherosclerosis, and aortic aneurysm/dissection). Analyses were adjusted by age, race, and sex. Among 28 cancer types, 1 228 328 patients (38.0%) died from cancer and 365 689 patients (11.3%) died from CVDs. Among CVDs, 76.3% of deaths were due to heart disease. In eight cancer sites, CVD mortality risk surpassed index-cancer mortality risk in at least one calendar year. Cardiovascular disease mortality risk was highest in survivors diagnosed at &lt;35 years of age. Further, CVD mortality risk is highest (SMR 3.93, 95% confidence interval 3.89–3.97) within the first year after cancer diagnosis, and CVD mortality risk remains elevated throughout follow-up compared to the general population. Conclusion The majority of deaths from CVD occur in patients diagnosed with breast, prostate, or bladder cancer. We observed that from the point of cancer diagnosis forward into survivorship cancer patients (all sites) are at elevated risk of dying from CVDs compared to the general US population. In endometrial cancer, the first year after diagnosis poses a very high risk of dying from CVDs, supporting early involvement of cardiologists in such patients.

Abstract BACKGROUND: It is well known that for patients with solitary metastatic disease in the brain, aggressive surgical treatment can prolong survival. However, there is a paucity of literature focusing on simultaneous resection of multiple metastatic brain tumors. METHODS: We analyzed 13 patients and 26 tumors between 2005–2019 who had simultaneous resection of at least 2 metastatic brain tumors via either one or two craniotomies. We independently analyzed those patients with simultaneous resection of metastatic disease in both the supra- and infratentorial compartments. RESULTS: Overall, 26 tumors were resected in a simultaneous fashion. There were 7 females (53.8%) and 6 males (46.2%) total. 5/13 (38.5%) patients had previously known brain metastases in which all 5 had previous adjuvant radiation. All 13 patients had 2 metastatic lesions resected during one operation. Gross total resection rate reached 88.5% with a median post-operative stay of 3 days. Complications presented in only 3 out of 13 cases (grade 2 and 3 according to CTCAE). Primary sites of metastatic disease were lung, breast, skin and renal. 12/13 (92.3%) had two distinct craniotomies and 23/26 (88.5%) tumors had gross total resection of both lesions. There were 11 frontal (42.3%), 7 parietal (26.9%), 2 temporal (7.7%), 1 occipital (3.8%) and 5 cerebellar (19.2%) tumors. There were three patients with both supra- and intratentorial tumors with simultaneous resection. All three patients had two craniotomies and two separate incisions. 1 of the 3 had pre-operative SRS. Overall, average local progression since surgery to at least one resected tumor bed was 88.3 days. CONCLUSIONS: Our results suggest that patients with multiple metastatic brain lesions have comparable outcomes and similar rates of surgical risk to those with solitary brain lesions. In patients with simultaneous supra- and infratentorial brain metastatic disease and indications for decompression, safe resection is feasible.

Abstract PURPOSE: Preoperative stereotactic radiosurgery (SRS) for symptomatic brain metastases has arisen as a therapeutic option for patients with brain lesions, potentially reducing radionecrosis risk, leptomeningeal disease risk, as well as delays in systemic therapy after craniotomy. The purpose of our work is to analyze the current evidence regarding 1-year local control (LC) and RN rates in the preoperative and postoperative settings. METHODS AND MATERIALS: Population, Intervention, Control, Outcomes, Study Design/Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were used to select articles in which patients had “large” brain metastases (&gt;4 cm3 or &gt;2 cm in diameter) solely treated with preoperative or postoperative SRS and 1-year LC and/or rates of RN reported. Radiosurgery was stratified by timing: preoperatively or postoperatively. Random effects meta-analyses using timing of SRS relative to surgery as covariates were conducted. Meta-regression and Wald-type tests were used to determine the effect of increasing tumor size on the summary estimate, where the null hypothesis was rejected for p &lt; 0.05. RESULTS: Fifteen studies were included (of 314 screened), published between 2012 and 2018 with 854 brain metastases. Preoperative SRS was delivered in 229 lesions. The 1-year LC random effects estimate was 79.1% (95% confidence interval [CI]: 55.9–95.0%; I 2 = 80%) for preoperative SRS and 80.5% (95% CI: 66.3–91.5%; I 2 = 93%) for postoperative SRS (p=0.9). Radionecrosis incidence random effects estimate was 2.1% (95% CI: 0.1–8.6%; I 2 = 36%) for preoperative SRS and 6.3% (95% CI: 1.1–15.4%; I 2 = 90%) for postoperative SRS (p=0.52). CONCLUSIONS: Rates of 1-year LC and RN incidence are similar after preoperative SRS as compared to postoperative SRS for large brain metastases. Results from ongoing prospective clinical trials studying preoperative SRS are important to further investigate these two techniques.

Purpose: We aim to systematically review and analyze the available literature on “exceptional responders” in oncology. We hypothesize that survival or patients with an exceptional response may be predicted based on clinical factors. Materials and Methods: A PICOS/PRISMA/MOOSE selection protocol was used to find studies that reported oncology patients with an exceptional response. A total of 333 initial articles were screened, and 76 articles were included, accounting for 85 patients. The primary outcome was survival after exceptional response therapy (ERT). The secondary outcome was survival since diagnosis. Univariate and multivariate analyses were conducted for both outcomes with 17 covariates. Results: The median age was 52 years (interquartile range, 35-66 y), 51.8% were male individuals, 18 (21.2%) had lung cancer, and 1 patient (1%) met all National Cancer Institute criteria for exceptional response. The most common treatment resulting in exceptional response was a form of chemotherapy (49.2%) followed by targeted therapy (26.8%) and radiation therapy (7.7%). The median time from diagnosis to initiation of ERT was 7.92 months (interquartile range, 0-24.72 mo). On multivariate analysis of survival after initiation of ERT, there were no predictors of exceptional response. On multivariate analysis of survival since diagnosis, predictors of prolonged survival included time between diagnosis and ERT initiation (hazard ratio, 0.52; 95% confidence interval, 0.32-0.87; P=0.0124) and single prior surgery versus none (0.08; 95% confidence interval, 0.01-0.98; P=0.04853). Conclusions: There were no clinically apparent patient or treatment factors that predicted favorable survival following ERT; instead, reporting of exceptional response appears to be biased.