Consensus Statement Supporting the Presence of Onsite Radiation Oncology Departments at VHA Medical Centers.

Background: Although multiple studies demonstrate that radiotherapy is underused worldwide, the impact that onsite radiation oncology at medical centers has on the use of radiotherapy is poorly studied. The Veterans Health Administration (VHA) Palliative Radiotherapy Taskforce has evaluated the impact of onsite radiation therapy on the use of palliative radiation and has made recommendations based on these findings. Observations: Radiation consults and treatment occur in a more timely manner at VHA centers with onsite radiation therapy compared with VHA centers without onsite radiation oncology. Referring practitioners with onsite radiation oncology less frequently report difficulty contacting a radiation oncologist (0% vs 20%, respectively; P = .006) and patient travel (28% vs 71%, respectively; P < .001) as barriers to referral for palliative radiotherapy. Facilities with onsite radiation oncology are more likely to have multidisciplinary tumor boards (31% vs 3%, respectively; P = .11) and are more likely to be influenced by radiation oncology recommendations at tumor boards (69% vs 44%, respectively; P = .02). Conclusions: The VHA Palliative Radiotherapy Taskforce recommends the optimization of the use of radiotherapy within the VHA. Radiation oncology services should be maintained where present in the VHA, with consideration for expansion of services to additional facilities. Telehealth should be used to expedite consults and treatment. Hypofractionation should be used, when appropriate, to ease travel burden. Options for transportation services and onsite housing or hospitalization should be understood by treating physicians and offered to patients to mitigate barriers related to travel.

Palliative Radiotherapy Within the Veterans Health Administration: Barriers to Referral and Timeliness of Treatment.

PURPOSE: Most Veterans Health Administration hospitals do not have radiation oncology (RO) departments on-site. The purpose of this study is to determine the impact of on-site RO on referral patterns and timeliness of palliative radiation therapy (PRT). MATERIALS AND METHODS: A survey was sent to medical directors at 149 Veterans Health Administration centers. Questions evaluated frequency of referral for PRT, timeliness of RO consults and treatment, and barriers to referral for PRT. Chi-square analysis was used to evaluate differences between centers that have on-site RO and centers that refer to outside facilities. RESULTS: Of 108 respondents, 33 (31%) have on-site RO. Chi-square analysis revealed that RO consult within 1 week is more likely at centers with on-site RO (68% v 31%; P = .01). Centers with on-site RO more frequently deliver PRT for spinal cord compression within 24 hours (94% v 70%; P = .01). Those without on-site RO were more likely to want increased radiation oncologist involvement (64% v 26%; P < .001). Barriers to referral for PRT included patient ability to travel (81%), patient noncompliance (31%), delays in consult and/or treatment (31%), difficulty contacting a radiation oncologist (14%), and concern regarding excessive number of treatments (13%). Respondents with on-site RO less frequently reported delays in consult and/or treatment (6% v 41%; P < .0001) and difficulty contacting a radiation oncologist (0% v 20%; P = .0056) as barriers. CONCLUSION: Respondents with on-site RO reported improved communication with radiation oncologists and more timely consultation and treatment initiation. Methods to improve timeliness of PRT for veterans at centers without on-site RO should be considered.

Risk factors for symptomatic radiation pneumonitis after stereotactic body radiation therapy (SBRT) in patients with non-small cell lung cancer.

BACKGROUND AND PURPOSE: Radiation pneumonitis (RP) can be a potential fatal toxicity of stereotactic body radiation therapy (SBRT) for medically inoperable non-small cell lung cancer (NSCLC). This study aimed to examine the risk factors that predict RP and explore dosimetric tolerance for safe practice in a large institutional series of NSCLC patients. MATERIALS AND METHODS: Patients with early-stage and locally recurrent NSCLC who received lung SBRT between 2002 and 2015 formed the study population. The primary endpoint was grade 2 or above radiation pneumonitis (RP2). Lungs were re-contoured consistently by one radiation oncologist according to the RTOG atlas for organs at risk. Dosimetric factors were computed consistently with exclusion of gross tumor volume of either ipsilateral, contralateral, or total lungs. RESULTS: A total of 339 patients were eligible. With a median follow-up of 47 months, RP2 was recorded in 10% patients. History of respiratory comorbidity, previous thoracic radiation, right lung location, mean lung doses of total or ipsilateral lung, and total lung volume receiving 20 Gy were all significantly associated with the risk of RP2. The dosimetric parameters of contralateral lung, including mean dose and volume receiving more than 5, 10, and 20 Gy, were not significantly associated with RP2 (ps > 0.05). A model of combining significant clinical and dosimetric factors had a predictive accuracy AUC of 0.76. According to this model, RP2 can be limited to <10% should the patient have no previous lung radiation and the mean dose of total and ipsilateral lungs be kept less than 6 Gy and 20 Gy, respectively. CONCLUSION: Dosimetric factors of total or ipsilateral lung together with important clinical factors were significant risk factors for symptomatic radiation pneumonitis after SBRT. Constraining mean lung dose can limit clinically significant lung toxicity.

DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo.

Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide can inhibit NF-κB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with dimethylaminoparthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-κB binding activity and slows prostate cancer cell growth. We also show that DMAPT increases single and fractionated X-ray-induced killing of prostate cancer cells through inhibition of DNA double strand break repair and also that DMAPT-induced radiosensitization is, at least partially, dependent upon the alteration of intracellular thiol reduction-oxidation chemistry. Finally, we demonstrate that the treatment of PC-3 prostate tumor xenografts with oral DMAPT in addition to radiation therapy significantly decreases tumor growth and results in significantly smaller tumor volumes compared to xenografts treated with either DMAPT or radiation therapy alone, suggesting that DMAPT might have a potential clinical role as a radiosensitizing agent in the treatment of prostate cancer.

Irradiated human endothelial progenitor cells induce bystander killing in human non-small cell lung and pancreatic cancer cells.

Purpose To investigate whether irradiated human endothelial progenitor cells (hEPC) could induce bystander killing in the A549 non-small cell lung cancer (NSCLC) cells and help explain the improved radiation-induced tumor cures observed in A549 tumor xenografts co-injected with hEPC. Materials and methods We investigated whether co-injection of CBM3 hEPC with A549 NSCLC cells would alter tumor xenograft growth rate or tumor cure after a single dose of 0 or 5 Gy of X-rays. We then utilized dual chamber Transwell dishes, to test whether medium from irradiated CBM3 and CBM4 hEPC would induce bystander cell killing in A549 cells, and as an additional control, in human pancreatic cancer MIA PaCa-2 cells. The CBM3 and CBM4 hEPC were plated into the upper Transwell chamber and the A549 or MIA PaCa-2 cells were plated in the lower Transwell chamber. The top inserts with the CBM3 or CBM4 hEPC cells were subsequently removed, irradiated, and then placed back into the Transwell dish for 3 h to allow for diffusion of any potential bystander factors from the irradiated hEPC in the upper chamber through the permeable membrane to the unirradiated cancer cells in the lower chamber. After the 3 h incubation, the cancer cells were re-plated for clonogenic survival. Results We found that co-injection of CBM3 hEPC with A549 NSCLC cells significantly increased the tumor growth rate compared to A549 cells alone, but paradoxically also increased A549 tumor cure after a single dose of 5 Gy of X-rays (p < 0.05). We hypothesized that irradiated hEPC may be inducing bystander killing in the A549 NSCLC cells in tumor xenografts, thus improving tumor cure. Bystander studies clearly showed that exposure to the medium from irradiated CBM3 and CBM4 hEPC induced significant bystander killing and decreased the surviving fraction of A549 and MIA PaCa-2 cells to 0.46 (46%) ± 0.22 and 0.74 ± 0.07 (74%) respectively (p < 0.005, p < 0.0001). In addition, antibody depletion studies demonstrated that the bystander killing induced in both A549 and MIA PaCa-2 cells was mediated by the cytokines TNF-α and TGF-ß (p < 0.05). Conclusions These data provide evidence that irradiated hEPC can induce strong bystander killing in A549 and MIA PaCa-2 human cancer cells and that this bystander killing is mediated by the cytokines TNF-α and TGF-ß.

Risk of Gleason grade inaccuracies in prostate cancer patients eligible for active surveillance.

OBJECTIVE: To evaluate increases in Gleason grade because of sample bias after immediate rebiopsy or prostatectomy for patients considered active surveillance candidates by institutional protocol. METHODS: A contemporary medical literature search was performed using PubMed. Series were included if the patients had no more than Gleason 6 prostate cancer score on initial biopsy and underwent a prostatectomy or rebiopsy within 6 months. Patient sets using neoadjuvant hormonal therapy or focal prostate treatment were excluded. RESULTS: In patients who would have fallen into the D'Amico low-risk prostate cancer group, 42% were found to have an increase in the Gleason score: 32% resulting in grade ≥ 7 disease and 3% grade ≥ 8. For series that limited patients to the Epstein criteria, Gleason upgrades were 34%, 29%, and 2%, respectively. Of the 139 patients whose second tissue specimens were from a rebiopsy, 17% were found to have grade ≥ 7 disease, whereas only 1 patient had grade ≥ 8. There were no consistent multivariate analysis variables among the series to predict for an increase in Gleason score. CONCLUSION: More than one third of the patients were found to have been undergraded based on their initial prostate biopsy. Therefore, 1 biopsy alone may not be sufficient to offer active surveillance as an option. Further exploration is necessary to better ensure low-risk disease before active surveillance.

A dose-volume analysis of radiation pneumonitis in non-small cell lung cancer patients treated with stereotactic body radiation therapy.

PURPOSE: To examine the rates and risk factors of radiation pneumonitis (RP) in non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: Dosimetry records for 251 patients with lymph node-negative Stage I-IIB NSCLC and no prior chest radiation therapy (RT) treated with SBRT were reviewed. Patients were coded on the basis of the presence of at least Grade (G) 2 RP using the Common Toxicity Criteria version 2 criteria. Radiation doses, V5, V10, V20, and mean lung dose (MLD) data points were extracted from the dose-volume histogram (DVH). RESULTS: Median PTV volume was 48 cc. Median prescribed radiation dose was 60 Gy delivered in three fractions to the 80% isodose line. Median age at treatment was 74 years. Median follow-up was 17 months. RP was reported after treatment of 42 lesions: G1 in 19 (8%), G2 in 17 (7%), G3 in 5 (2%), and G4 in 1 (0.4%). Total lung DVHs were available for 143 patients. For evaluable patients, median MLD, V5, V10, and V20 were 4.1 Gy, 20%, 12%, and 4%, respectively. Median MLDs were 4 Gy and 5 Gy for G0-1 and G2-4 groups, respectively (p = 0.14); median V5 was 20% for G0-1 and 24% for G2-4 (p = 0.70); median V10 was 12% in G0-1 and 16% in G2-4 (p = 0.08), and median V20 was 4% in G0-1 and 6.6% in G2-4 (p = 0.05). G2-4 RP was noted in 4.3% of patients with MLD ≤4 Gy compared with 17.6% of patients with MLD >4 Gy (p = 0.02), and in 4.3% of patients with V20 ≤4% compared with 16.4% of patients with V20 >4% (p = 0.03). CONCLUSION: Overall rate of G2-4 RP in our population treated with SBRT was 9.4%. Development of symptomatic RP in this series correlated with MLD and V20.

Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays.

We investigated the efficacy and mechanism of dimethylaminoparthenolide (DMAPT), an NF-κB inhibitor, to sensitize human lung cancer cells to X-ray killing in vitro and in vivo. We tested whether DMAPT increased the effectiveness of single and fractionated X-ray treatment through inhibition of NF-κB and/or DNA double-strand break (DSB) repair. Treatment with DMAPT decreased plating efficiency, inhibited constitutive and radiation-induced NF-κB binding activity, and enhanced radiation-induced cell killing by dose modification factors of 1.8 and 1.4 in vitro. X-ray fractionation demonstrated that DMAPT inhibited split-dose recovery/repair, and neutral DNA comet assays confirmed that DMAPT altered the fast and slow components of X-ray-induced DNA DSB repair. Knockdown of the NF-κB family member p65 by siRNA increased radiation sensitivity and completely inhibited split-dose recovery in a manner very similar to DMAPT treatment. The data suggest a link between inhibition of NF-κB and inhibition of DSB repair by DMAPT that leads to enhancement of X-ray-induced cell killing in vitro in non-small-cell lung cancer cells. Studies of A549 tumor xenografts in nude mice demonstrated that DMAPT enhanced X-ray-induced tumor growth delay in vivo.

Urgent radiotherapy is effective in the treatment of metastatic medulloblastoma causing symptomatic brainstem edema.

A 3-year-old male who presented with hydrocephalus symptoms was found to have metastatic medulloblastoma with diffuse spinal disease. Thirteen days following surgical resection of his primary tumor, he clinically deteriorated due to worsening brainstem edema. Following intubation, stress-dose steroids, and mannitol, urgent radiotherapy was initiated to the whole brain and cervical cord. The patient improved clinically with a repeat MRI showing decreased leptomeningeal enhancement in the radiation fields. In the literature, there are no reports of successful urgent radiotherapy in medulloblastoma, but in this instance, it proved to be a viable option.

Chest wall toxicity after stereotactic body radiotherapy for malignant lesions of the lung and liver.

PURPOSE: To quantify the frequency of rib fracture and chest wall (CW) pain and identify the dose-volume parameters that predict CW toxicity after stereotactic body radiotherapy (SBRT). METHODS AND MATERIALS: The records of patients treated with SBRT between 2000 and 2008 were reviewed, and toxicity was scored according to Common Terminology Criteria for Adverse Events v3.0 for pain and rib fracture. Dosimetric data for CW and rib were analyzed and related to the frequency of toxicity. The risks of CW toxicity were then further characterized according to the median effective concentration (EC(50)) dose-response model. RESULTS: A total of 347 lesions were treated with a median follow-up of 19 months. Frequency of Grade I and higher CW pain and/or fracture for CW vs. non-CW lesions was 21% vs. 4%, respectively (p < 0.0001). A dose of 50 Gy was the cutoff for maximum dose (Dmax) to CW and rib above which there was a significant increase in the frequency of any grade pain and fracture (p = 0.03 and p = 0.025, respectively). Volume of CW receiving 15 Gy - 40 Gy was highly predictive of toxicity (R(2) > 0.9). According to the EC(50) model, 5 cc and 15 cc of CW receiving 40 Gy predict a 10% and 30% risk of CW toxicity, respectively. CONCLUSION: Adequate tumor coverage remains the primary objective when treating lung or liver lesions with SBRT. To minimize toxicity when treating lesions in close proximity to the CW, Dmax of the CW and/or ribs should remain <50 Gy, and <5 cc of CW should receive ≥ 40 Gy.