Trifiletti, Daniel M

BACKGROUNDPatients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited.METHODSRN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN.RESULTSFifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow‐up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole‐brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06‐42.38 cm3); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27‐111.22 cm3). Any‐grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01‐1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99‐1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17‐2.30; P = .76), prior WBRT, and ICI agents were not statistically significant.CONCLUSIONSSymptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single‐fraction SRS.

Abstract Background We hypothesized that the addition of receptor tyrosine kinase inhibitors (RTKis, e.g., lapatinib, erlotinib, cetuximab, bevacizumab, panitumumab) to radiotherapy-based treatment for solid tumors does not increase overall survival but may increase toxicity. Methods Population, Intervention, Control, Outcome, Study Design; Preferred Reporting Items for Systematic Reviews and Meta-Analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify prospective randomized studies including patients with solid tumor cancers treated with radiotherapy with or without RTKis. Extracted variables included use of radiotherapy vs chemoradiotherapy, RTKi type (antibody vs small molecule), outcomes, and toxicities. The primary endpoint was overall survival; the secondary endpoint was grade 3+ toxicity. Random-effects meta-analyses were performed for each outcome measure. All statistical tests were 2-sided. Results A total of 405 studies met the initial search criteria, of which 13 prospective randomized trials of radiotherapy with or without RTKi met the inclusion criteria, encompassing 5678 patients. The trials included cancers of the head and neck (6 trials, 3295 patients), esophagus (3 trials, 762 patients), lung (2 trials, 550 patients), and brain (2 trials, 1542 patients). Three studies evaluated a small molecule and radiotherapy in 949 patients, and 10 studies evaluated antibodies and radiotherapy in 4729 patients. The addition of RTKis to radiotherapy-based treatment did not improve overall survival (hazard ratio = 1.02, 95% confidence interval = 0.90 to 1.15, P = .76) but increased grade 3+ toxicity (relative risk = 1.18, 95% confidence interval = 1.06 to 1.33, P = .009). Conclusions The addition of RTKis to radiotherapy does not improve survival and worsens toxicity.

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.

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.

AbstractPurposeLeverage the National Cancer Database (NCDB) to evaluate trends in management of nonmetastatic squamous cell cancer (SCC) of the rectum and their effect on survival for this uncommon tumor.Methods and MaterialsRetrospective data was obtained from the NCDB for patients diagnosed with SCC of the rectum between 2004 and 2014, including cT1‐4, cN0‐2, cM0 tumors (cohort A, n = 2296). A subgroup analysis was performed on locally advanced tumors (cT1‐T2, N+ or cT3, N any, subcohort B, n = 883), treated with chemoradiation (n = 706) or trimodality therapy (n = 177) including chemotherapy, radiation, and surgery. Pathological complete response rate following neoadjuvant therapy was obtained. Univariate and multivariate logistic regression analyses were performed to generate hazard ratios (HR) investigating factors associated with overall survival. Kaplan‐Meier (K‐M) method was used to estimate overall surviving proportion at 5 and 10 years.ResultsThe K‐M estimated 5 and 10 year overall survival for stage I disease was 71.3% and 57.8%, respectively; stage II disease was 57.0% and 38.9%, respectively; stage III disease was 57.8% and 41.5%, respectively. On multivariate analysis, higher cT category (P < 0.001) resulted in worse survival. For locally advanced tumors (subcohort B), there was no significant difference in survival between chemoradiation alone compared to trimodality therapy (P = 0.909 on multivariate analysis).ConclusionsMost providers manage locally advanced SCC of the rectum similar to anal cancer, which results in equivalent overall survival and spares patients from the additional morbidity associated with surgical resection.

In general, the role of whole‐brain radiation therapy (WBRT) in patients with cerebral metastases is evolving in favor of focused, radiosurgery‐alone approaches. Despite this, there still is a role for WBRT in many patients, and improvements in patient selection, advanced radiotherapy techniques, and novel medical and cellular therapies will continue to improve the therapeutic ratio of WBRT.

AbstractEarly‐stage nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) is associated with a favorable prognosis. Our aim was to evaluate the patterns of care of radiotherapy utilization in this disease and to define the relationship between treatment modality and survival. The National Cancer Database was queried for patients with stages I‐II NLPHL diagnosed from 2004 to 2012. Patients were compared based on primary therapy into four categories: radiotherapy, chemotherapy, both, or neither. Covariate‐adjusted and propensity score‐weighted (PS) Cox proportional hazards models were used, adjusting for potential factors confounding survival. After exclusions, 1420 patients were evaluated, 571 (40%) received radiotherapy alone, 318 (22%) received chemotherapy alone, 351 (25%) received both, and 180 (13%) received neither. Younger patient age (P = 0.001), female gender (P = 0.019), and chemotherapy use (P < 0.001) were associated with decreased radiotherapy utilization. On PS, radiation alone (HR = 0.298, P < 0.001) and chemoradiotherapy (HR = 0.258, P < 0.001) were associated with improved survival compared to no upfront therapy, but the use of chemotherapy alone did not statistically differ compared to no initial therapy (HR = 0.784, P = 0.078). In this large database analysis, over one‐third of patients with early‐stage NLPHL did not receive radiotherapy as a component of initial therapy. The omission of upfront radiotherapy was associated with inferior survival.