Chris Beltran

ON THE BENEFITS AND RISKS OF PROTON THERAPY IN PEDIATRIC CRANIOPHARYNGIOMA

PURPOSE Craniopharyngioma is a pediatric brain tumor whose volume is prone to change during radiation therapy. We compared photon- and proton-based irradiation methods to determine the effect of tumor volume change on target coverage and normal tissue irradiation in these patients. METHODS AND MATERIALS For this retrospective study, we acquired imaging and treatment-planning data from 14 children with craniopharyngioma (mean age, 5.1 years) irradiated with photons (54 Gy) and monitored by weekly magnetic resonance imaging (MRI) examinations during radiation therapy. Photon intensity-modulated radiation therapy (IMRT), double-scatter proton (DSP) therapy, and intensity-modulated proton therapy (IMPT) plans were created for each patient based on his or her pre-irradiation MRI. Target volumes were contoured on each weekly MRI scan for adaptive modeling. The measured differences in conformity index (CI) and normal tissue doses, including functional sub-volumes of the brain, were compared across the planning methods, as was target coverage based on changes in target volumes during treatment. RESULTS CI and normal tissue dose values of IMPT plans were significantly better than those of the IMRT and DSP plans (p < 0.01). Although IMRT plans had a higher CI and lower optic nerve doses (p < 0.01) than did DSP plans, DSP plans had lower cochlear, optic chiasm, brain, and scanned body doses (p < 0.01). The mean planning target volume (PTV) at baseline was 54.8 cm(3), and the mean increase in PTV was 11.3% over the course of treatment. The dose to 95% of the PTV was correlated with a change in the PTV; the R(2) values for all models, 0.73 (IMRT), 0.38 (DSP), and 0.62 (IMPT), were significant (p < 0.01). CONCLUSIONS Compared with photon IMRT, proton therapy has the potential to significantly reduce whole-brain and -body irradiation in pediatric patients with craniopharyngioma. IMPT is the most conformal method and spares the most normal tissue; however, it is highly sensitive to target volume changes, whereas the DSP method is not.

Sequencing of Local Therapy Affects the Pattern of Treatment Failure and Survival in Children With Atypical Teratoid Rhabdoid Tumors of the Central Nervous System

PURPOSE To assess the pattern of treatment failure associated with current therapeutic paradigms for childhood atypical teratoid rhabdoid tumors (AT/RT). METHODS AND MATERIALS Pediatric patients with AT/RT of the central nervous system treated at our institution between 1987 and 2007 were retrospectively evaluated. Overall survival (OS), progression-free survival, and cumulative incidence of local failure were correlated with age, sex, tumor location, extent of disease, and extent of surgical resection. Radiotherapy (RT) sequencing, chemotherapy, dose, timing, and volume administered after resection were also evaluated. RESULTS Thirty-one patients at a median age of 2.3 years at diagnosis (range, 0.45-16.87 years) were enrolled into protocols that included risk- and age-stratified RT. Craniospinal irradiation with focal tumor bed boost (median dose, 54 Gy) was administered to 18 patients. Gross total resection was achieved in 16. Ten patients presented with metastases at diagnosis. RT was delayed more than 3 months in 20 patients and between 1 and 3 months in 4; 7 patients received immediate postoperative irradiation preceding high-dose alkylator-based chemotherapy. At a median follow-up of 48 months, the cumulative incidence of local treatment failure was 37.5% ± 9%; progression-free survival was 33.2% ± 10%; and OS was 53.5% ± 10%. Children receiving delayed RT (≥1 month postoperatively) were more likely to experience local failure (hazard ratio [HR] 1.23, p = 0.007); the development of distant metastases before RT increased the risk of progression (HR 3.49, p = 0.006); and any evidence of disease progressionbefore RT decreased OS (HR 20.78, p = 0.004). Disease progression occurred in 52% (11/21) of children with initially localized tumors who underwent gross total resection, and the progression rate increased proportionally with increasing delay from surgery to RT. CONCLUSIONS Delayed RT is associated with a higher rate of local and metastatic disease progression in children with AT/RT. Current treatment regimens for pediatric patients with AT/RT are distinctly age stratified; novel protocols investigating RT volumes and sequencing are needed.

Dosimetric effect of target expansion and setup uncertainty during radiation therapy in pediatric craniopharyngioma.

PURPOSE Investigate the effect of tumor change and setup uncertainties on target coverage for pediatric craniopharyngioma during RT. METHODS AND MATERIALS Fifteen pediatric patients with craniopharyngioma (mean 5.1 years) were included in this study. MRI was performed before and a median of six times during RT to monitor changes in the tumor volume. IMRT plans were created and compared to the CRT plan used for treatment. The role of adaptive therapy based on GTV changes was investigated. Dosimetric effects of interfraction and intrafraction motion were examined. RESULTS The mean of the maximal change in the GTV was 28.5% [-20.7% to 82.0%]. For the standard margin IMRT plans, the mean D(95) of the base plan on the base target was 53.6 Gy [53.1-54.1]. The mean D(95) of the base plans on the adaptive targets was 52.1 Gy [47.9-54.1]. The D(95) for the adaptive plan on the adaptive target was 53.8 Gy [53.4-54.3]. A linear regression equation of y=-0.12x , r(2)=0.70, was found for the percent change in D(95) of the PTV (y) vs. the percent change in the GTV (x). Inter and intrafraction motion did not affect the target coverage for standard and reduced margin plans. CONCLUSIONS The GTV of pediatric craniopharyngioma patients change size during therapy and adaptive planning is critical for conformal plans; therefore early and regular surveillance imaging is required.

Image quality & dosimetric property of an investigational Imaging Beam Line MV-CBCT

To measure and compare the contrast to noise ratio (CNR) as a function of dose for the CBCTs produced by the mega‐voltage (MV) imaging beam line (IBL) and the treatment beam line (TBL), and to compare the dose to target and various critical structures of pediatric patients for the IBL CBCT versus standard TBL orthogonal port films. Two Siemens Oncor linear accelerators were modified at our institution such that the MV‐CBCT would operate under an investigational IBL rather than the standard 6MV TBL. Prior to the modification, several CBCTs of an electron density phantom were acquired with the TBL at various dose values. After the modification, another set of CBCTs of the electron density phantom were acquired for various doses using the IBL. The contrast to noise ratio (CNR) for each tissue equivalent insert was calculated. In addition, a dosimetric study of pediatric patients was conducted comparing the 1 cGy IBL CBCT and conventional TBL orthogonal pair port films. The CNR for eight tissue equivalent inserts at five different dose settings for each type of CBCT was measured. The CNR of the muscle insert was 0.8 for a 5 cGy TBL CBCT, 1.1 for a 1.5 cGy IBL CBCT, and 2.8 for a conventional CT. The CNR of the trabecular bone insert was 2.9 for a 5 cGy TBL CBCT, 5.5 for a 1.5 cGy IBL CBCT, and 14.8 for a conventional CT. The IBL CBCT delivered approximately one‐fourth the dose to the target and critical structures of the patients as compared to the TBL orthogonal pair port films. The IBL CBCT improves image quality while simultaneously reducing the dose to the patient as compared to the TBL CBCT. A 1 cGy IBL CBCT, which is used for bony anatomy localization, delivers one‐fourth the dose as compared to conventional ortho‐pair films. PACS number: 87.57.Q, 87.57.cj, 87.53.Jw

INTER- AND INTRAFRACTIONAL POSITIONAL UNCERTAINTIES IN PEDIATRIC RADIOTHERAPY PATIENTS WITH BRAIN AND HEAD AND NECK TUMORS

PURPOSE To estimate radiation therapy planning margins based on inter- and intrafractional uncertainty for pediatric brain and head and neck tumor patients at different imaging frequencies. METHODS Pediatric patients with brain (n = 83) and head and neck (n = 17) tumors (median age = 7.2 years) were enrolled on an internal review board-approved localization protocol and stratified according to treatment position and use of anesthesia. Megavoltage cone-beam CT (CBCT) was performed before each treatment and after every other treatment. The pretreatment offsets were used to calculate the interfractional setup uncertainty (SU), and posttreatment offsets were used to calculate the intrafractional residual uncertainty (RU). The SU and RU are the patient-related components of the setup margin (SM), which is part of the planning target volume (PTV). SU data was used to simulate four intervention strategies using different imaging frequencies and thresholds. RESULTS The SM based on all patients treated on this study was 2.1 mm (SU = 0.9 mm, RU = 1.9 mm) and varied according to treatment position (supine = 1.8 mm, prone = 2.6 mm) and use of anesthesia (with = 1.7 mm, without = 2.5 mm) because of differences in the RU. The average SU for a 2-mm threshold based on no imaging, once per week imaging, initial five images, and daily imaging was 3.6, 2.1, 2.2, and 0.9 mm, respectively. CONCLUSION On the basis of this study, the SM component of the PTV may be reduced to 2 mm for daily CBCT compared with 3.5 mm for weekly CBCT. Considering patients who undergo daily pretreatment CBCT, the SM is larger for those treated in the prone position or smaller for those treated under anesthesia because of differences in the RU.

Intensity modulated radiation therapy provides excellent local control in high‐risk abdominal neuroblastoma

Locoregional failure is a significant concern in patients with high‐risk abdominal neuroblastoma (NB) receiving radiotherapy. Locoregional control outcomes were studied in children with NB receiving intensity modulated radiotherapy (IMRT).

Dosimetric effect of setup motion and target volume margin reduction in pediatric ependymoma

PURPOSE Quantify the dosimetric effect of inter- and intrafractional motion on intensity-modulated radiation therapy (IMRT) and three-dimensional (3D) planning via changes in the generalized equivalent uniform dose (gEUD), predicted tumor control probability (TCP) and normal tissue complication probability (NTCP) for pediatric ependymoma. METHODS AND MATERIALS Twenty patients treated between 1998 and 2002 with a 3D plan (CTV = 1 cm, PTV = 5 mm) were selected. Two IMRT plans were created for the 1 cm CTV (PTV = 5 mm and PTV = 0 mm), and a third IMRT plan for a 5 mm CTV (PTV = 0 mm). Direct simulation with inter- and intrafractional motion was performed for 3D and IMRT plans based on daily pre and post-treatment cone beam CT information obtained from 20 well-matched patients (age, supine/prone, use of GA) on a localization protocol. Calculated TCP, NTCP, Conformity Index (CI), and predictive IQ were compared. RESULTS IMRT improved the calculated TCP by 2.8+/-2.8 vs. 3D (p<0.001). Inter- and intrafractional motion results in a TCP loss of 0.4+/-0.7 (p=0.02) and 0.0+/-0.1 (p=0.14) for the IMRT plan with PTV = 0 mm. Mean NTCP for 3D and IMRT with PTV = 5 mm, PTV = 0 mm, and CTV = 5 mm for the cochlea was: 66.6, 29.4, 8.7. Mean NTCP change due to motion was <5%. CI was 0.70+/-0.06 for IMRT and 0.5+/-0.10 for 3D. Predictive IQ was 10.0+/-10.3 points higher for IMRT vs. 3D. CONCLUSIONS IMRT improves calculated TCP vs. 3D. Daily localization can allow for a safe reduction in the PTV margin, while maintaining target coverage; reducing the CTV margin can further reduce NTCP and may reduce future side-effects.

Dosimetric consequences of rotational errors in radiation therapy of pediatric brain tumor patients.

PURPOSE To quantify the rotational offsets and estimate the dose effect of rotation on the target volume and normal tissues in children with brain tumor. METHODS Twenty-one pediatric patients with brain tumors were included in this study. Cone-beam CT was performed before each treatment and at the end of every other treatment. Translational offsets were corrected before the treatment. An offline analysis was performed to quantify rotational errors. The treatment plans were altered and recalculated to simulate a rotation of 2° and 4°, and the dose changes were quantified. RESULTS 1016 CBCT datasets were analyzed for this report. The mean of the rotations were not meaningfully different from zero. 18.1% of the fractions had rotations with a magnitude ≥2°, 5.0% had rotations ≥3° and 0.9% had rotations ≥4°. For the 2° rotational simulation, the gEUD values of the PTV and critical structures changed by less than 2%. For the 4° simulation, parallel type normal structures had minor changes (<2%), but serial type normal structures and the PTV had changes of 10% and 5%, respectively. CONCLUSIONS The majority of rotational errors observed were less than 1°. A rotational error of 2° produced negligible changes in the gEUD to critical structures or target volumes. Rotational errors ≥4° produced undesirable results, therefore, at a minimum, errors >2° should be corrected.

Daily image-guided localization for neuroblastoma

The purpose was to quantify the setup margin for pediatric patients with neuroblastoma using cone beam CT imaging (CBCT) and ultrasound localization. Ten patients, with a median age of 4.3 years (1.8 to 7.9) underwent daily pretreatment localization CBCT and every other day post‐treatment CBCT to calculate interfractional and intrafraction movement. Localization was based on CBCT to treatment planning CT registration in the lumbar spine region. Each subject was treated in the supine position under IV general anesthesia using intensity‐modulated radiation therapy. Patients were repositioned based on the daily pretreatment CBCT. Required setup margins based on inter‐ and intrafraction positioning errors were calculated based on weekly and daily imaging scenarios. Four patients had ultrasound localization of the kidneys performed before the CBCT. Correlation between daily CBCT and ultrasound was investigated. A lateral, longitudinal and vertical setup margin of 5.4, 5.6, and 5.9 mm is required without daily CBCT. When daily CBCT was incorporated, the setup margin was reduced to 1.5, 2.1, and 1.7 mm. There was no correlation between the suggested ultrasound shifts and the shifts based on the CBCT. Daily localization based on CBCT of the lumbar spine can reduce the required setup margin for neuroblastoma patients, thereby reducing normal tissue exposure for this young patient population. The internal margin needs further investigation before PTV reduction can be made. Ultrasound localization was highly variable and not correlated to CBCT shifts. PACS number: 87.53.Jw

Radiation therapy for children: evolving technologies in the era of ALARA

The evolution of ever more sophisticated oncologic imaging and technologies providing far more precise radiation therapy have combined to increase the utilization of sophisticated radiation therapy in childhood cancer. For a majority of children with common central nervous system, soft tissue, bone, and dysontogenic neoplasms, local irradiation is fundamental to successful multi-disciplinary management. Along with more precise target volume definition and radiation delivery, new technologies provide added certainty of patient positioning (electronic portal imaging, cone beam CT) and conformality of dose delivery (3-D conformal irradiation, intensity modulated radiation therapy, proton beam therapy). Each of the major areas of technology development are able to better confine the high-dose region to the intended target, but they are also associated with the potential for larger volumes of uninvolved tissues being exposed to low radiation doses. The latter issue plays a role in documented levels of secondary carcinogenesis, sometimes with greater anticipated incidence than that seen in conventional radiation therapy. Parameters related to carcinogenesis, such as dose–volume relationships and neutron contamination that accompanies high-energy photon irradiation and proton therapy, can be identified, sometimes modulated, and accepted as part of the clinical decision process in fine tuning radiation therapy in this more vulnerable age group.