NRG brain tumor specialists consensus guidelines for glioblastoma contouring.

INTRODUCTION: NRG protocols for glioblastoma allow for clinical target volume (CTV) reductions at natural barriers; however, literature examining CTV contouring and the relevant white matter pathways is lacking. This study proposes consensus CTV guidelines, with a focus on areas of controversy while highlighting common errors in glioblastoma target delineation. METHODS: Ten academic radiation oncologists specializing in brain tumor treatment contoured CTVs on four glioblastoma cases. CTV expansions were based on NRG trial guidelines. Contour consensus was assessed and summarized by kappa statistics. A meeting was held to discuss the mathematically averaged contours and form consensus contours and recommendations. RESULTS: Contours of the cavity plus enhancement (mean kappa 0.69) and T2-FLAIR signal (mean kappa 0.74) showed moderate to substantial agreement. Experts were asked to trim off anatomic barriers while respecting pathways of spread to develop their CTVs. Submitted CTV_4600 (mean kappa 0.80) and CTV_6000 (mean kappa 0.81) contours showed substantial to near perfect agreement. Simultaneous truth and performance level estimation (STAPLE) contours were then reviewed and modified by group consensus. Anatomic trimming reduced the amount of total brain tissue planned for radiation targeting by a 13.6% (range 8.7-17.9%) mean proportional reduction. Areas for close scrutiny of target delineation were described, with accompanying recommendations. CONCLUSIONS: Consensus contouring guidelines were established based on expert contours. Careful delineation of anatomic pathways and barriers to spread can spare radiation to uninvolved tissue without compromising target coverage. Further study is necessary to accurately define optimal target volumes beyond isometric expansion techniques for individual patients.

Extended Volumetric Follow-up of Juvenile Pilocytic Astrocytomas Treated with Proton Beam Therapy.

PURPOSE: To describe volume changes following proton beam therapy (PBT) for juvenile pilocytic astrocytoma (JPA), we analyzed post-PBT magnetic resonance imaging (MRI) to clarify survivorship, response rate, and the concept of pseudoprogression. MATERIALS AND METHODS: Pediatric patients with a histologic diagnosis of JPA after a biopsy or subtotal resection and at least 4 post-PBT MRIs were retrospectively reviewed. After PBT, tumors were contoured on follow-up T1-contrasted MRIs, and 3-dimensional volumes were plotted against time, with thresholds for progressive disease and partial response. Patterns of response, pseudoprogression, and progression were uncovered. Post-PBT clinical course was described by the need for further intervention and survivorship. RESULTS: Fifteen patients with a median of 10 follow-up MRIs made up this report: 60% were heavily pretreated with multiple lines of chemotherapy, and 67% had undergone subtotal resection. With a median follow-up of 55.3 months after a median of 5400 centigray equivalents PBT, estimates of 5-year overall survival and intervention-free survival were 93% and 72%, respectively. The crude response rate of 73% included pseudoprogressing patients, who comprised 20% of the entire cohort; the phenomenon peaked between 3 and 8 months and resolved by 18 months. One nonresponder expired from progression. Post-PBT intervention was required in 53% of patients, with 1 patient resuming chemotherapy. There were no further resections or radiotherapy. One patient developed acute lymphoblastic leukemia, and another developed biopsy-proven radionecrosis. CONCLUSION: The PBT for inoperable/progressive JPA provided 72% 5-year intervention-free survival in heavily pretreated patients. Although most patients responded, 20% demonstrated pseudoprogression. The need for post-PBT surveillance for progression and treatment-induced sequelae should not be underestimated in this extended survivorship cohort.

Parameters of anesthesia/sedation in children receiving radiotherapy.

BACKGROUND: Previous reports establish low risk of complications in pediatric treatments under anesthesia/sedation (A/S) in the outpatient setting. Here, we present our institutional experience with A/S by age and gender in children receiving daily proton RT. METHODS: After Institutional Review Board approval, we reviewed our center's records between 9/9/2004 and 6/30/2013 with respect to age and gender of A/S requirement in our pediatric patients (defined as patients ≤18 years of age). RESULTS: Of 390 patients treated in this era, 182 were girls. Children aged ≤3 invariably required A/S; and by age 7-8, approximately half of patients do not. For pediatric patients ≥ 12 years of age, approximately 10% may require A/S for different reasons. There was no difference by gender. CONCLUSIONS: Beyond age 3, the requirement for A/S decreases in an age-dependent fashion, with a small cadre of older children having difficulty enough with sustained immobilization that A/S is necessary. In our experience, there is no difference in A/S requirement by gender.

Proton therapy for atypical meningiomas.

We report clinical outcomes of proton therapy in patients with World Health Organization grade 2 (atypical) meningiomas. Between 2005 and 2013, 22 patients with atypical meningiomas were treated to a median dose of 63 Gy (RBE) using proton therapy, as an adjuvant therapy after surgery (n = 12) or for recurrence or progression of residual tumor (n = 10). Six patients had presumed radiation-induced meningiomas, but none had received prior radiotherapy for their meningioma. The median follow-up time after radiation was 39 months (range 7-104) and all patients remain alive at last follow-up. The 5-year estimate of local control was 71.1% (95% CI 49.3-92.9%). The 5-year estimate of local control was 87.5% following a radiation dose >60 Gy (RBE), compared to 50.0% for ≤ 60 Gy (RBE) (p = 0.038). The 5-year estimate of neuraxis dissemination was 5% (95% CI 0-14.6%) and 6.2% (95% CI 0-18.2%) for metastases outside of the central nervous system. Radiation necrosis was observed in one patient with a history of prior cranial irradiation. Fractionated proton therapy was associated with favorable tumor control rates for grade 2 meningiomas. Prospective studies are needed to define the optimal radiation dose for high-grade meningiomas.

Proton Radiotherapy for Midline Central Nervous System Lesions: A Class Solution.

OBJECTIVE: Midline and central lesions of the brain requiring conventional radiotherapy (RT) present complex difficulties in dose avoidance to organs at risk (OAR). In either definitive or adjuvant settings, proper RT coverage of these lesions involves unnecessary treatment of large volumes of normal brain. We propose a class solution for these lesions using proton radiotherapy (PrT). MATERIALS AND METHODS: The records of the Indiana University Health Proton Therapy Center were reviewed for patients presenting between January 1, 2005 and October 1, 2013 with midline central nervous system (CNS) lesions. Twenty-four patients were identified. After Institutional Review Board approval was granted, their dosimetry was reviewed for target volume doses and OAR dose avoidance. RESULTS: For these cases, meningiomas were the most common histology (8 cases), and next most prevalent were craniopharyngiomas (6 cases). The others were various different deep midline brain tumors (10 cases). In all cases, fields formed by vertex and/or anterior/posterior superior oblique PrT beams along the midsagittal plane were used to provide coverage with minimal dose to the brain stem or to the cerebral hemispheres. The median prescribed dose to the planning target volume for treating these patients was 54.0 Gy RBE (range 48.6-62.5) with a mean dose of 53.5 Gy RBE. The average of the mean doses to the brain stems using these fields in the 24 plans was 18.4 Gy RBE (range 0.0-44.7). Similarly, the average of the mean doses to the hippocampi was 15.8 Gy RBE (range 0.0-52.6). CONCLUSIONS: We consider these patients to be optimally treated with PrT. The use of modified midsagittal PrT schemas allows for the treatment of midline CNS lesions with sparing of most of the uninvolved brain.

Radiation therapy at end of life in children.

OBJECTIVE: Few data exist on evaluating utilization patterns of radiotherapy (RT) at the end of life (EOL) in children. Metastatic disease in pediatric patients is not pathognomonic for palliative treatment intent; further complicating the issue are complexities surrounding the very select population of children receiving proton therapy (PrT). We compared data for RT and PrT in terms of death rate within 30 days. METHODS: We performed chart reviews for patients receiving radiation therapy at age ≤21 years treated at Indiana University Health Proton Therapy Center (IUHPTC) between June 2008 and June 2013 and University of Miami Radiation Oncology Department (UM) between June 2000 and June 2013. Included were patients not completing prescribed courses of RT, and those dying within 30 days of therapy. Comparison was made of differences between practice data for PrT and conventional RT. RESULTS: At IUHPTC, 2 children of 272 did not complete their courses and died within 30 days (0.7%). At UM, data are available for 425 children; 9 did not complete their courses and 7 died within 30 days (1.6%). Neither the number of patients who did not complete treatment nor the 30-day death rates (P=.21) for PrT and RT were significantly different. CONCLUSIONS: Delivery of RT for children at EOL is complex. Frequency of RT at EOL in children occurs in is <2% of cases, and is not significantly less frequent in the proton milieu. This appears to be about an order of magnitude less than in adults.

Practical aspects of pediatric proton radiation therapy.

Many radiotherapy centers desire proton therapy (PrT) because the unique physical dosimetry allows for improved dose distribution in some clinical situations. These benefits are best described in skull base and many pediatric lesions. However, there are significant challenges to PrT that are overlooked or simply ignored when centers embark on the PrT journey particularly as it applies to pediatric patients.In this review, we review the Indiana University Health Proton Therapy Center experience regarding benefits and drawbacks of PrT for pediatric patients. In conclusion, centers aspiring to PrT capacity should be aware not only of the well-described benefits in some clinical scenarios, but also the significant challenges to the modality in its practical clinical application.

Oral and dental late effects in survivors of childhood cancer: a Children's Oncology Group report.

PURPOSE: Multi-modality therapy has resulted in improved survival for childhood malignancies. The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers provide practitioners with exposure- and risk-based recommendations for the surveillance and management of asymptomatic survivors who are at least 2 years from completion of therapy. This review outlines the pathophysiology and risks for oral and dental late effects in pediatric cancer survivors and the rationale for oral and dental screening recommended by the Children's Oncology Group. METHODS: An English literature search for oral and dental complications of childhood cancer treatment was undertaken via MEDLINE and encompassed January 1975 to January 2013. Proposed guideline content based on the literature review was approved by a multi-disciplinary panel of survivorship experts and scored according to a modified version of the National Comprehensive Cancer Network "Categories of Consensus" system. RESULTS: The Children's Oncology Group oral-dental panel selected 85 relevant citations. Childhood cancer therapy may impact tooth development, salivary function, craniofacial development, and temporomandibular joint function placing some childhood cancer survivors at an increased risk for poor oral and dental health. Additionally, head and neck radiation and hematopoietic stem cell transplantation increase the risk of subsequent malignant neoplasms in the oral cavity. Survivors require routine dental care to evaluate for potential side effects and initiate early treatment. CONCLUSIONS: Certain childhood cancer survivors are at an increased risk for poor oral and dental health. Early identification of oral and dental morbidity and early interventions can optimize health and quality of life.

Local control and toxicity outcomes in brainstem metastases treated with single fraction radiosurgery: is there a volume threshold for toxicity?

Gamma Knife Radiosurgery (GKRS) has been reported in the treatment of brainstem metastases while dose volume toxicity thresholds remain mostly undefined. A retrospective review of 52 brainstem metastases in 44 patients treated with GKRS was completed. A median dose of 18 Gy (range 10-22 Gy) was prescribed to the tumor margin (median 50 % isodose). 25 patients had undergone previous whole brain radiation therapy. Toxicity was graded by the LENT-SOMA scale. Mean and median follow-up was 10 and 6 months. Only 3 of the 44 patients are living. Multiple brain metastases were treated in 75 % of patients. Median size of lesions was 0.134 cc, (range 0.013-6.600 cc). Overall survival rate at 1 year was 32 % (95 % CI 51.0-20.1 %) with a median survival time of 6 months (95 % CI 5.0-16.5). Local control rate at 6 months and 1 year was 88 % (95 % CI 70-95 %) and 74 % (95 % CI 52-87 %). Cause of death was neurologic in 17 patients, non-neurologic in 20 patients, and unknown in four. Four patients experienced treatment related toxicities. Univariate analysis of tumor volume revealed that volume greater than 1.0 cc predicted for toxicity. A strategy of using lower marginal doses with GKRS to brain stem metastases appears to lead to a lower local control rate than seen with lesions treated within the standard dose range in other locations. Tumor size greater than 1.0 cc predicted for treatment-related toxicity.

Range modulation in proton therapy planning: a simple method for mitigating effects of increased relative biological effectiveness at the end-of-range of clinical proton beams.

BACKGROUND: The increase in relative biological effectiveness (RBE) of proton beams at the distal edge of the spread out Bragg peak (SOBP) is a well-known phenomenon that is difficult to quantify accurately in vivo. For purposes of treatment planning, disallowing the distal SOBP to fall within vulnerable tissues hampers sparing to the extent possible with proton beam therapy (PBT). We propose the distal RBE uncertainty may be straightforwardly mitigated with a technique we call "range modulation". With range modulation, the distal falloff is smeared, reducing both the dose and average RBE over the terminal few millimeters of the SOBP. METHODS: One patient plan was selected to serve as an example for direct comparison of image-guided radiotherapy plans using non-range modulation PBT (NRMPBT), and range-modulation PBT (RMPBT). An additional plan using RMPBT was created to represent a re-treatment scenario (RMPBTrt) using a vertex beam. Planning statistics regarding dose, volume of the planning targets, and color images of the plans are shown. RESULTS: The three plans generated for this patient reveal that in all cases dosimetric and device manufacturing advantages are able to be achieved using RMPBT. Organ at risk (OAR) doses to critical structures such as the cochleae, optic apparatus, hypothalamus, and temporal lobes can be selectively spared using this method. Concerns about the location of the RBE that did significantly impact beam selection and treatment planning no longer have the same impact on the process, allowing these structures to be spared dose and subsequent associated issues. CONCLUSIONS: This present study has illustrated that RMPBT can improve OAR sparing while giving equivalent coverage to target volumes relative to traditional PBT methods while avoiding the increased RBE at the end of the beam. It has proven easy to design and implement and robust in our planning process. The method underscores the need to optimize treatment plans in PBT for both traditional energy dose in gray (Gy) and biologic dose (RBE).

Limited margins using modern radiotherapy techniques does not increase marginal failure rate of glioblastoma.

OBJECTIVE: We investigate the patterns of failure in the treatment of glioblastoma (GBM) based on clinical target volume (CTV) margin size, dose delivered to the site of initial failure, and the use of temozolomide and intensity-modulated radiotherapy (IMRT). METHODS: Between August 2000 and May 2010, 161 patients with GBM were treated with radiotherapy with or without concurrent temozolomide. Patients were treated with CTV expansions that ranged from 5 to 20 mm using a shrinking field technique. Patterns of failure and time to progression and overall survival were compared based on CTV margin, use of temozolomide, and use of IMRT. Kaplan Meier analysis was used to estimate survival times, and χ test was used for comparison of cohorts. RESULTS: For patients treated with 5-, 10-, and 15- to 20-mm CTV, 79%, 77%, and 86% experienced failures in the 60 Gy volume, respectively. Forty-eight percent, 55%, and 66% of patients with 5-, 10-, and 15- to 20-mm CTV experienced failures in the 46 Gy volume, respectively. There was no statistical difference between patients treated with 5-, 10-, 15- to 20-mm margins with regard to 60 Gy failure (P=0.76), 46 Gy failure (P=0.51), or marginal failure (P=0.73). Eighty percent of patients receiving temozolomide experienced failures in the 60 Gy volume. There was no increased likelihood of marginal failures in patients receiving IMRT (P=0.97). CONCLUSIONS: Modern treatment techniques including use of concurrent temozolmide, limited CTV margin size, and IMRT have not greatly changed the patterns of failure of GBM.

Definitive treatment of vein of Galen aneurysmal malformation with stereotactic radiosurgery.

Vein of Galen aneurysmal malformations (VGAMs) are uncommon congenital malformations arising from fistulous communication with the median vein of the prosencephalon, a primitive precursor of midline cerebral venous structures. Angiographic embolization is the primary modality for treatment given historically poor microsurgical outcomes. Only a few reports of treatment by Gamma Knife radiosurgery (GKRS) exist in the literature, and the results are variable. The authors present 2 cases of VGAM in which GKRS provided definitive treatment with good outcome: one case involving antenatal presentation of a high-output, mural-type VGAM with complex clinical course refractory to multiple embolic procedures, and the other a choroidal-type VGAM presenting with hemorrhage in an adult and without a feasible embolic approach. With discussion of these cases and review of the literature, the authors advocate inclusion of GKRS as a therapeutic option for treatment of these complex lesions.

Outpatient management of vascular access devices in children receiving radiotherapy: complications and morbidity.

BACKGROUND: When treating children with cancer, long-term venous access is critical. This is especially true in the context of children receiving daily radiation therapy (RT) under general anesthesia. We have previously reported <0.1% risk of complications in complications in over 4,040 pediatric treatments under general anesthesia in our outpatient facility. Here, we present our experience with venous catheter access techniques in children receiving daily proton RT. PROCEDURE: After Institutional Review Board approval, we reviewed our center's records between September 9, 2004 and October 23, 2012 with respect to complications and morbidity of indwelling catheters in our pediatric patients. RESULTS: Vascular access device (VAD) types included: 110 patients with indwelling port-a-cath (PAC), 34 PICC line devices, and 34 central venous catheter (CVC) devices in 170 patients. Median catheter life during RT was 43 days (range 1-86 days) with a total of 7,169 total catheter days while patients received RT. A 14% PAC complication rate included negative blood return (6.3%) and infection (3.6%). Complication rates for PICC and CVC access devices were 38% and 20.5%, respectively (χ(2) P = 0.007 when compared with PAC). Most frequent complications for PICC lines were no blood return (11.7%), and infection or occlusion (8.8% each). CVC complications were breakage (8.8%) and infection (8.8%). Access device replacement rates were 3.6% (PAC), 14.7% (PICC), and 8.8% (CVC). CONCLUSIONS: In the outpatient delivery of RT to children, indwelling ports provide greater convenience, less likelihood of infection or complication, and greater durability than PICC or CVC devices.

Tumor histology predicts patterns of failure and survival in patients with brain metastases from lung cancer treated with gamma knife radiosurgery.

BACKGROUND: We review our experience with lung cancer patients with newly diagnosed brain metastases treated with Gamma Knife radiosurgery (GKRS). OBJECTIVE: To determine whether tumor histology predicts patient outcomes. METHODS: Between July 1, 2000, and December 31, 2010, 271 patients with brain metastases from primary lung cancer were treated with GKRS at our institution. Included in our study were 44 squamous cell carcinoma (SCC), 31 small cell carcinoma (SCLC), and 138 adenocarcinoma (ACA) patients; 47 patients with insufficient pathology to determine subtype were excluded. No non-small cell lung cancer (NSCLC) patients received whole-brain radiation therapy (WBRT) before their GKRS, and SCLC patients were allowed to have prophylactic cranial irradiation, but no previously known brain metastases. A median of 2 lesions were treated per patient with median marginal dose of 20 Gy. RESULTS: Median survival was 10.2 months for ACA, 5.9 months for SCLC, and 5.3 months for SCC patients (P = .008). The 1-year local control rates were 86%, 86%, and 54% for ACA, SCC, and SCLC, respectively (P = .027). The 1-year distant failure rates were 35%, 63%, and 65% for ACA, SCC, and SCLC, respectively (P = .057). The likelihood of dying of neurological death was 29%, 36%, and 55% for ACA, SCC, and SCLC, respectively (P = .027). The median time to WBRT was 11 months for SCC and 24 months for ACA patients (P = .04). Multivariate analysis confirmed SCLC histology as a significant predictor of worsened local control (hazard ratio [HR]: 6.46, P = .025) and distant failure (HR: 3.32, P = .0027). For NSCLC histologies, SCC predicted for earlier time to salvage WBRT (HR: 2.552, P = .01) and worsened overall survival (HR: 1.77, P < .0121). CONCLUSION: Histological subtype of lung cancer appears to predict outcomes. Future trials and prognostic indices should take these histology-specific patterns into account.

Definitive treatment of leptomeningeal spinal metastases in children.

BACKGROUND: Uniquely in children, the existence of leptomeningeal spinal metastases does not confer a uniformly grave prognosis. Although the radiation tolerance of the spinal cord is of significant concern in these cases, the chemo- and radiosensitivity of these lesions argues for an aggressive approach where possible. METHODS: The records of the Indiana University Health Proton Therapy Center were reviewed for patients undergoing proton beam therapy with curative intent for LSM between January 1, 2004 and July 7, 2012. Patients with microscopic disease only on LP were not included. Particulars of therapy, including dose, field sizes, toxicities, and outcomes were collated. RESULTS: Twenty-two children received therapy as described, of median age 5 years (range 1.1-17.1). Patients had medulloblastoma (n = 9), ATRT (n = 4), ependymoma, and PNET (n = 3 each). Five lesions (23%) were chemo-recurrent, though no patient had prior radiation to the spine. Median follow-up was 14 months (range 4-33) for all living patients. Fifteen (68%) children continued to have local control at last follow-up visit. Median dose was 37.8 Gy (range 21.6-54 Gy). Eight patients with chemo-recurrent disease or diffuse cord seeding did poorly, with local control and overall survival achieved in four. The 12-month overall survival was 68% with grade 1 skin erythema as the most frequent toxicity. CONCLUSIONS: We describe a cohort of LSM patients treated with RT with definitive intent, and the only available data from the proton environment. Durable response is possible for these children in over two-thirds of cases. Significant toxicity was infrequent using proton radiotherapy and these fractionation schemes.

Patterns of patient specific dosimetry in total body irradiation.

PURPOSE: Total body irradiation (TBI) has been used for bone marrow transplant for hematologic and immune deficiency conditions. The goal of TBI is to deliver a homogeneous dose to the entire body, with a generally accepted range of dose uniformity being within ± 10% of the prescribed dose. The moving table technique for TBI could make dose uniform in whole body by adjusting couch speed. However, it is difficult to accurately estimate the actual dose by calculation and hence in vivo dosimetry (IVD) is routinely performed. Here, the authors present patterns of patient-specific IVD in 161 TBI patients treated at our institution. METHODS: Cobalt-60 teletherapy unit (Model C9 Cobalt-60 teletherapy unit, Picker X-ray Corporation) with customized moving bed (SITI Industrial Products, Inc., Fishers, IN) were used for TBI treatment. During treatment, OneDose(TM) (Sicel Technology, NC) Metal Oxide-silicon Semiconductor Field Effect Transistor detectors were placed at patient body surface; both entrance and exit side of the beam at patient head, neck, mediastinum, umbilicus, and knee to estimate midplane dose. When large differences (>10%) between the prescribed and measured dose were observed, dose delivery was corrected for subsequent fractions by the adjustment of couch speed and/or bolus placement. Under IRB exempt status, the authors retrospectively analyzed the treatment records of 161 patients who received TBI treatment between 2006 and 2011. RESULTS: Across the entire cohort, the median ± SD (range) percent variance between calculated and measured dose for head, neck, mediastinum, umbilicus, and knee was -2.3 ± 10.2% (-66.2 to +35.3), 1.1 ± 11.5% (-62.2 to +40.3), -1.9 ± 9.5% (-66.4 to +46.6), -1.1 ± 7.2% (-35.2 to +42.9), and 3.4 ± 12.2% (-47.9 to +108.5), respectively. More than half of treatments were within ± 10% of the prescribed dose for all anatomical regions. For 80% of treatments (10%-90%), dose at the umbilicus was within ± 10%. However, some large differences greater than 35% were also found at several points. For one case, the knee received double the prescribed dose. When the dose differences for multiple fractions were averaged, compliance (± 1 0%) between the prescription and measured dose was improved compared to the dose difference of the first single fraction, for example, as at umbilicus, which improved from 83.9% to 98.5%. CONCLUSIONS: Actual dose measurement analysis of TBI patients revealed a potentially wide variance from the calculated dose. Based from their IVD method for TBI using Cobalt-60 irradiator and moving table, ± 10% over entire body is hard to achieve. However, it can be significantly improved with immediate feedback after the first fraction prior to subsequent treatments.