Christopher Tinkle

Late toxicity and outcomes following radiation therapy for chest wall sarcomas in pediatric patients

PURPOSE To investigate the contribution of radiation therapy to acute and late toxicity in pediatric chest wall sarcoma patients and evaluate dosimetric correlates of higher incidence toxicities such as scoliosis and pneumonitis. METHODS AND MATERIALS The data from 23 consecutively treated pediatric patients with chest wall sarcomas of various histologies (desmoid, Ewing, rhabdomyosarcoma, nonrhabdomyosarcoma-soft tissue sarcomas) were reviewed to evaluate the relationship between end-organ radiation dose, clinical factors, and the risk of subsequent late effects (scoliosis, pneumonitis). Cobb angles were used to quantify the extent of scoliosis. Doses to the spine and lung were calculated from the radiation treatment plan. RESULTS The range of scoliosis identified on follow-up imaging ranged from -47.6 to 64° (median, 2.95°). No relationship was identified between either radiation dose to the ipsilateral or contralateral vertebral body or tumor size and the degree or direction of scoliosis. The extent of surgical resection and number and location of resected ribs affected the extent of scoliosis. The dominant predictor of extent of scoliosis at long-term follow-up was the extent of scoliosis following surgical resection. Radiation pneumonitis was uncommon and was not correlated with mean dose or volume of lung receiving 24 Gy; however, 1 of 3 surviving patients who received whole pleural surface radiation therapy developed significant restrictive lung disease. CONCLUSIONS Acute and late radiation therapy-associated toxicities in pediatric chest wall sarcoma patients are modest. The degree of scoliosis following resection is a function of the extent of resection and of the number and location of ribs resected, and the degree of scoliosis at the last follow-up visit is a function of the extent of scoliosis following surgery. Differential radiation therapy dose across the vertebral body does not increase the degree of scoliosis. Severe restrictive pulmonary disease is a late complication of survivors after whole pleural surface radiation therapy.

Radiomics Features Differentiate Between Normal and Tumoral High-Fdg Uptake.

Identification of FDGavid- neoplasms may be obscured by high-uptake normal tissues, thus limiting inferences about the natural history of disease. We introduce a FDG-PET radiomics tissue classifier for differentiating FDGavid- normal tissues from tumor. Thirty-three scans from 15 patients with Hodgkin lymphoma and 68 scans from 23 patients with Ewing sarcoma treated on two prospective clinical trials were retrospectively analyzed. Disease volumes were manually segmented on FDG-PET and CT scans. Brain, heart, kidneys and bladder and tumor volumes were automatically segmented on PET images. Standard-uptake-value (SUV) derived shape and first order radiomics features were computed to build a random forest classifier. Manually segmented volumes were compared to automatically segmented tumor volumes. Classifier accuracy for normal tissues was 90%. Classifier performance was varied across normal tissue types (brain, left kidney and bladder, hear and right kidney were 100%, 96%, 97%, 83% and 87% respectively). Automatically segmented tumor volumes showed high concordance with the manually segmented tumor volumes (R2 = 0.97). Inclusion of texture-based radiomics features minimally contributed to classifier performance. Accurate normal tissue segmentation and classification facilitates accurate identification of FDGavid tissues and classification of those tissues as either tumor or normal tissue.

Evaluation of 11C-methionine PET and anatomic MRI associations in diffuse intrinsic pontine glioma

The role of metabolic imaging in the diagnosis, treatment, and response assessment of diffuse intrinsic pontine glioma (DIPG) is poorly defined. We investigated the uptake of 11C-methionine in pediatric patients with newly diagnosed DIPG and evaluated the associations of 11C-methionine PET metrics with conventional MRI indices and survival outcomes. Methods: Twenty-two patients with newly diagnosed DIPG were prospectively enrolled on an institutional review board–approved investigational study of 11C-methionine PET. All patients underwent baseline 11C-methionine PET/CT, and initial treatment-response scans after chemotherapy or radiation therapy were obtained for 17 patients. Typical and atypical DIPGs were assessed clinically and radiographically and defined by multidisciplinary consensus. Three-dimensional regions of interest, reviewed by consensus between a nuclear medicine physician and a radiation oncologist, were delineated after coregistration of PET and MR images. Associations of 11C-methionine uptake intensity and uniformity with survival, along with associations between 11C-methionine uptake and conventional MRI tumor indices over time, were evaluated. 11C-methionine PET voxel values within regions of interest were assessed as threshold values across proportions of the study population, and 11C-methionine uptake at baseline was assessed relative to MRI-defined tumor progression. Results: 11C-methionine uptake above that of uninvolved brain tissue was observed in 18 of 22 baseline scans (82%) and 15 of 17 initial response scans (88%). 11C-methionine avidity within MRI-defined tumor was limited in extent, with 11 of 18 positive baseline 11C-methionine PET scans (61%) showing less than 25% 11C-methionine–avid tumor. The increase in total tumor volume with 11C-methionine PET was relatively limited (17.2%; interquartile range, 6.53%–38.90%), as was the extent of 11C-methionine uptake beyond the MRI-defined tumor (2.2%; interquartile range, 0.55%–10.88%). Although baseline 11C-methionine PET intensity and uniformity metrics did not correlate with survival outcomes, initial 11C-methionine avidity overlapped with recurrent tumor in 100% of cases. A clinical diagnosis of atypical DIPG was associated with borderline significantly prolonged progression-free survival (P  =  0.07), yet 11C-methionine PET indices at diagnosis did not differ significantly between atypical and typical DIPGs. Conclusion: Most newly diagnosed DIPGs are successfully visualized by 11C-methionine PET. Baseline 11C-methionine uptake delineates regions at increased risk for recurrence, yet intensity and uniformity metrics did not correlate with treatment outcomes in children with DIPG in this study.

The Non-rhabdomyosarcoma Soft Tissue Sarcomas, Desmoid Tumor and Osteosarcoma

Soft-tissue sarcoma (STS) are a group of rare tumors diagnosed in children and adults that require multi-modality specialty care. The etiology of STS in children is largely unknown although they are among the tumor types associated with cancer predisposition syndromes and included in the differential of radiation-induced malignancies. STS include a broad variety of histologic subtypes, diverse presentations, and wide-ranging lethality. Evaluation and management of STS in pediatric patients has evolved based on knowledge derived from clinical trials performed in adults and more recently prospective studies performed exclusively with children. Surgery, irradiation modalities, and conventional chemotherapy have identified roles in the treatment of pediatric patients with current studies focused on toxicity reduction in low-risk patients, optimal sequencing of therapy and new agent testing in intermediate and high-risk patients, and systematic salvage strategies for patients that do not respond to front-line therapy.

Atypical Teratoid/Rhabdoid Tumor (AT/RT)

Atypical Teratoid/Rhabdoid Tumor (AT/RT) is a rare and aggressive tumor of the Pediatric Central Nervous System (CNS) that was first described in 1987 (Biggs et al. 1987). Its aggressive behavior and predilection for infants who are less than 2 years of age enticed further study and pathological characterization over the 1990s (Burger et al. 1998; Rorke et al. 1996b). AT/RT histopathology is characterized by complex rhabdoid, epithelial, and mesenchymal cellular morphology and is genetically defined by loss of SMARCB1. Despite this early observation, AT/RT remains a challenging disease, with high mortality rates despite aggressive multimodality therapy including surgery, various chemotherapy regimens with or without stem cell transplant, intrathecal chemotherapy, and radiotherapy. The challenge is due in part to the very young age of presentation for most patients which can limit aggressive treatment particularly radiotherapy, as well as the relatively high rate of disseminated disease at diagnosis. Retrospective series, reported across multiple institutions, helped guide the development of a Children Oncology Group (COG) study designed for AT/RT (ACNS0333) that closed for accrual in February 2014. This was the first cooperative group prospective study dedicated for ATRT patients in an attempt to standardize the approach to treat AT/RT based on best available data from previous published experiences This chapter discusses the epidemiology of AT/RT, clinical features and evaluation, pathology and genetic abnormalities, and current treatment approaches. In addition, experimental therapies under investigation, as well as salvage treatment options, are reviewed.

Late Infection-Related Mortality in Asplenic Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study

Purpose Infection-related outcomes associated with asplenia or impaired splenic function in survivors of childhood cancer remains understudied. Methods Late infection-related mortality was evaluated in 20,026 5-year survivors of childhood cancer (diagnosed < 21 years of age from 1970 to 1999; median age at diagnosis, 7.0 years [range, 0 to 20 years]; median follow-up, 26 years [range, 5 to 44 years]) using cumulative incidence and piecewise-exponential regression models to estimate adjusted relative rates (RRs). Splenic radiation was approximated using average dose (direct and/or indirect) to the left upper quadrant of the abdomen (hereafter, referred to as splenic radiation). Results Within 5 years of diagnosis, 1,354 survivors (6.8%) had a splenectomy and 9,442 (46%) had splenic radiation without splenectomy. With 62 deaths, the cumulative incidence of infection-related late mortality was 1.5% (95% CI, 0.7% to 2.2%) at 35 years after splenectomy and 0.6% (95% CI, 0.4% to 0.8%) after splenic radiation. Splenectomy (RR, 7.7; 95% CI, 3.1 to 19.1) was independently associated with late infection-related mortality. Splenic radiation was associated with increasing risk for late infection-related mortality in a dose-response relationship (0.1 to 9.9 Gy: RR, 2.0; 95% CI, 0.9 to 4.5; 10 to 19.9 Gy: RR, 5.5; 95% CI, 1.9 to 15.4; ≥ 20 Gy: RR, 6.0; 95% CI, 1.8 to 20.2). High-dose alkylator chemotherapy exposure was also independently associated with an increased risk of infection-related mortality (RR, 1.9; 95% CI, 1.1 to 3.4). Conclusion Splenectomy and splenic radiation significantly increase risk for late infection-related mortality. Even low- to intermediate-dose radiation exposure confers increased risk, suggesting that the spleen is highly radiosensitive. These findings should inform long-term follow-up guidelines for survivors of childhood cancer and should lead clinicians to avoid or reduce radiation exposure involving the spleen whenever possible.

Rapid and fulminant leptomeningeal spread following radiotherapy in diffuse intrinsic pontine glioma

A 4‐year‐old male presented with rapid‐onset cranial nerve palsy and ataxia. Brain magnetic resonance imaging (MRI) revealed a pontine mass lesion with discordant conventional and advanced imaging. A stereotactic core biopsy revealed glioblastoma with immunostaining suggestive of histone H3K27M and TP53 mutation, consistent with diffuse intrinsic pontine glioma. MRI 3 months after radiotherapy revealed extensive new leptomeningeal metastatic disease involving both the supra‐ and infratentorial brain, as well as the imaged portion of the spine. Tissue procured at the time of needle biopsy has undergone striking in vivo expansion as an orthotopic xenograft.

Nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) in pediatric and young adult patients: Results from a prospective study using limited-margin radiotherapy

Indications for and delivery of adjuvant therapies for pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) have been derived largely from adult studies; therefore, significant concern remains regarding radiation exposure to normal tissue. The authors report long‐term treatment outcomes and toxicities for pediatric and young adult patients with high‐grade NRSTS who were treated on a prospective trial using limited‐margin radiotherapy.

SU-D-207A-06: Pediatric Abdominal Organ Motion Quantified Via a Novel 4D MRI Method

PURPOSE To develop a 4D MRI method for assessing respiration-induced abdominal organ motion in children receiving radiation therapy. METHODS A 4D MRI using internal image-based respiratory surrogate has been developed and implemented on a clinical scanner (1.5T Siemens Avanto). Ten patients (younger group: N=6, 2-5 years, anesthetized; older group: N=4, 11-15 years) with neuroblastoma, Wilms tumor rhabdomyosarcoma, or desmoplastic small round cell tumor received free breathing 4D MRI scans for treatment planning. Coronal image slices of the entire abdomen were retrospectively constructed in 10 respiratory phases. A B-spline deformable registration (Metz et al. 2011) was performed on 4D datasets to automatically derive motion trajectories of selected anatomical landmarks, including the dome and the center of the liver, and the superior edges of kidneys and spleen. The extents of the motion in three dimensions (anteroposterior, AP; mediolateral, ML; superoinferior, SI) and the correlations between organ motion trajectories were quantified. RESULTS The 4D MRI scans were successfully performed in <20 minutes for all patients without the use of any external device. Organ motion extents were larger in adolescents (kidneys: 3-13 mm SI, liver and spleen: 6-18 mm SI) than in younger children (kidneys:<3mm in all directions; liver and spleen: 1-8 mm SI, 1-5 mm ML and AP). The magnitude of respiratory motion in some adolescents may warrant special motion management. Motion trajectories were not synchronized across selected anatomical landmarks, particularly in the ML and AP directions, indicating inter- and intra-organ variations of the respiratory-induced motion. CONCLUSION The developed 4D MRI acquisition and motion analysis methods provide a non-ionizing, non-invasive approach to automatically measure the organ motion trajectory in the pediatric abdomen. It is useful for defining ITV and PRV, monitoring changes in target motion patterns during the treatment course, and studying interplay effects in proton scanning.