The impact of adjuvant therapy for patients with high-risk diffuse WHO grade II glioma.

Despite recent randomized, prospective evidence supporting use of RT and chemotherapy (CRT) for high-risk low-grade gliomas (LGG), many patients have historically received RT alone, chemotherapy alone or observation postoperatively. The purpose of this study is to evaluate outcomes for historical treatments in comparison to CRT for high-risk diffuse WHO grade II glioma patients. Records from 309 adults with WHO grade II glioma (1997-2008) eligible for RTOG 9802 (incomplete resection/biopsy or age ≥40 years) were retrospectively reviewed. Kaplan-Meier estimates were used for progression-free survival (PFS) and overall survival (OS). The Cox proportional hazards model was used for estimates of risk ratios for univariate and multivariate analyses. Median follow-up was 10.6 years. Adjuvant treatments included radiotherapy (RT) alone (45%), observation (31%), CRT (21%) and chemotherapy alone (3%). Non-astrocytic histology, TERT promoter mutation, 1p/19q codeletion and extensive resections were associated with improved PFS and OS on univariate analysis (all p < 0.05). IDH mutations and adjuvant CRT was associated with improved PFS (all p < 0.05). On multivariate analysis, histology, molecular grouping and extent of resection were significantly associated with PFS and OS. In addition, multivariate analysis revealed that CRT was associated with improved PFS and OS compared with RT alone, and improved PFS compared with observation. This study confirms the benefit of adding chemotherapy to RT compared with RT alone or observation. These findings emphasize the need for aggressive treatment in patients with high-risk LGG.

Outcomes and Profiles of Older Patients Receiving Definitive Radiation Therapy for Muscle-Invasive Bladder Cancer at a Tertiary Medical Center.

PURPOSE: Our purpose was to evaluate the outcomes and profiles of older patients with muscle-invasive bladder cancer (MIBC) treated with definitive radiation therapy (RT) with or without chemotherapy (CHT) at a tertiary medical center. METHODS AND MATERIALS: A retrospective study was conducted for older patients with MIBC who were ≥70 years old and underwent RT with or without CHT between 2000 and 2016. Overall survival (OS) was estimated using the Kaplan-Meier method. Disease-specific survival (DSS), cumulative incidence of progression, patterns of recurrence, and toxicities were examined. Univariate analyses were performed to identify variables associated with OS, DSS, and cumulative incidence of progression, using the Cox proportional hazards model. RESULTS: A total of 84 patients underwent definitive RT with or without CHT. Of these, only 29% were deemed medically fit to undergo radical cystectomy, and the remainder were medically unfit or had surgically unresectable disease. Median age was 81 years. Sixty-one percent, 29%, and 11% had clinical stage II, III, and IV disease, respectively. Eighty-six percent had maximal transurethral resection of bladder tumor before RT. Seventy-three percent received CHT with RT, and 27% had RT alone. Median follow-up was 5.7 years. Median OS was 1.9 years. OS was 42% and 25%, and DSS was 64% and 54% at 3 and 5 years, respectively. On univariate analysis, medical fitness to undergo radical cystectomy, receipt of CHT, lower T stage, and maximal transurethral resection of bladder tumor were associated with better OS; lower T stage was associated with better DSS. The cumulative incidence of progression was 44% and 49% at 3 and 5 years, respectively. Late grade 3 genitourinary and gastrointestinal toxicity were 15% and 4%, respectively. None had grade 4 or 5 toxicity. CONCLUSIONS: Older patients with MIBC referred for RT were often medically unfit or had a surgically unresectable tumor. In these medically compromised patients, definitive RT with or without CHT was well tolerated and yielded encouraging treatment outcomes.

Modern reirradiation for recurrent gliomas can safely delay tumor progression.

BACKGROUND: Despite advances in modern therapy, high-grade gliomas continue to portend a dismal prognosis and nearly all patients will experience relapse. Unfortunately, salvage options remain limited. In this study, we assessed outcomes for patients with recurrent gliomas treated with reirradiation. METHODS: We retrospectively identified 48 glioma patients treated with reirradiation between 2013 and 2016. All had radiographic or pathologic evidence of recurrence. Prognostic factors were abstracted from the electronic medical record. RESULTS: Initial surgery included biopsy in 15, subtotal resection in 21, and gross total resection in 12. Initial chemotherapy included temozolomide (TMZ) in 31, TMZ+dasatinib in 7, TMZ+vorinostat in 3, and procarbazine, lomustine, and vincristine in 2. The median dose of primary radiotherapy was 60 Gy delivered in 30 fractions. Median overall survival (OS) and progression-free survival (PFS) from initial diagnosis were 3.2 and 1.7 years, respectively. A total of 36 patients failed salvage bevacizumab before reirradiation. Salvage surgery was performed before reirradiation in 21 patients. Median time to reirradiation was 1.7 years. Median follow-up was 13.7 months from reirradiation. Concurrent systemic therapy was given in 33 patients (bevacizumab in 27, TMZ in 8, and lomustine in 2). Median PFS and OS after reirradiation were 3.2 and 6.3 months, respectively. Radionecrosis occurred in 4 patients and no radionecrosis was seen in patients receiving concurrent bevacizumab with reirradiation (0% vs 19%, P = .03). CONCLUSIONS: Reirradiation may result in delayed tumor progression with acceptable toxicity. Prospective trials are needed to determine the impact of reirradiation on tumor progression and quality of life.

Clinically Applicable Monte Carlo-based Biological Dose Optimization for the Treatment of Head and Neck Cancers With Spot-Scanning Proton Therapy.

PURPOSE: Our aim is to demonstrate the feasibility of fast Monte Carlo (MC)-based inverse biological planning for the treatment of head and neck tumors in spot-scanning proton therapy. METHODS AND MATERIALS: Recently, a fast and accurate graphics processor unit (GPU)-based MC simulation of proton transport was developed and used as the dose-calculation engine in a GPU-accelerated intensity modulated proton therapy (IMPT) optimizer. Besides dose, the MC can simultaneously score the dose-averaged linear energy transfer (LETd), which makes biological dose (BD) optimization possible. To convert from LETd to BD, a simple linear relation was assumed. By use of this novel optimizer, inverse biological planning was applied to 4 patients, including 2 small and 1 large thyroid tumor targets, as well as 1 glioma case. To create these plans, constraints were placed to maintain the physical dose (PD) within 1.25 times the prescription while maximizing target BD. For comparison, conventional intensity modulated radiation therapy (IMRT) and IMPT plans were also created using Eclipse (Varian Medical Systems) in each case. The same critical-structure PD constraints were used for the IMRT, IMPT, and biologically optimized plans. The BD distributions for the IMPT plans were obtained through MC recalculations. RESULTS: Compared with standard IMPT, the biologically optimal plans for patients with small tumor targets displayed a BD escalation that was around twice the PD increase. Dose sparing to critical structures was improved compared with both IMRT and IMPT. No significant BD increase could be achieved for the large thyroid tumor case and when the presence of critical structures mitigated the contribution of additional fields. The calculation of the biologically optimized plans can be completed in a clinically viable time (<30 minutes) on a small 24-GPU system. CONCLUSIONS: By exploiting GPU acceleration, MC-based, biologically optimized plans were created for small-tumor target patients. This optimizer will be used in an upcoming feasibility trial on LETd painting for radioresistant tumors.

Myofibroblast cells are preferentially expressed early in a rabbit model of joint contracture.

Studies have demonstrated increased myofibroblasts in contractures. However, the timeline is largely unknown. The aim of this study was to determine the number of myofibroblasts in contracting joint capsules at 3-time points over a 24-week period. Eighteen rabbits subjected to a surgical procedure designed to elicit a knee joint contracture were divided into three groups of six. Rabbits were sacrificed at each respective time point and myofibroblasts in the joint capsules were quantified using immunohistochemistry. The percent of myofibroblasts was significantly elevated in the operated limbs compared to the control limbs at 2 weeks (20% vs. 7%, respectively; p = 0.014). There was no difference in the percent of myofibroblasts between the operated and control limbs at 8 or 24 weeks (p = 0.96 and 0.07, respectively). The percent of myofibroblasts dropped from 20% at 2 weeks to 3.0% at 8 weeks (p < 0.001). The decrease from 8 to 24 weeks was not significant (p = 0.19). A large proportion of myofibroblasts are present in contracted joints at 2 weeks. By week 8, the proportion of myofibroblasts seem to return to normal. Interventions aimed at affecting the myofibroblast cell in order to prevent fibrosis should be instituted early.

Treatment of medulloblastoma with a modified measles virus.

Although treatment of medulloblastoma has improved, at least 30% of patients with this tumor die of progressive disease. Unfortunately, many of the children who survive suffer long-term treatment-related morbidity. Previous studies have demonstrated the efficacy of using oncolytic viruses to eradicate brain tumors. The objective of this study was to test the efficacy of measles virus in treating medulloblastoma. To determine whether medulloblastoma cells are susceptible, 5 different human medulloblastoma cell lines were analyzed for the expression of the measles virus receptor CD46. Fluorescence-activated cell-sorting analysis confirmed expression of CD46 on all cell lines tested, with UW288-1 having the most prominent expression and D283med displaying the lowest expression. CD46 expression was also demonstrated, using immunohistochemistry, in 13 of 13 medulloblastoma tissue specimens. All 5 medulloblastoma cell lines were examined for their susceptibility to measles virus killing in vitro. A measles virus containing the green fluorescent protein (GFP) gene as a marker for infection (MV-GFP) was used. All cell lines exhibited significant killing when infected with MV-GFP, all formed syncytia with infection, all showed fluorescence, and all allowed viral replicaton after infection. In an intracerebral murine xenograft model, a statistically significant increase in survival was seen in animals treated with the active measles virus compared with those treated with inactivated virus. These data demonstrate that medulloblastoma is susceptible to measles virus killing and that the virus may have a role in treating this tumor in the clinical setting.