David R. Grosshans

Neurocognitive function in patients with small cell lung cancer: Effect of prophylactic cranial irradiation

The use of prophylactic cranial irradiation (PCI) in patients with small cell lung cancer (SCLC) has been tempered by fears of detrimental effects on cognitive function. Neuropsychologic testing was prospectively conducted before and after PCI to evaluate its effects on cognitive function in patients with SCLC.

Dosimetric comparison of three-dimensional conformal proton radiotherapy, intensity-modulated proton therapy, and intensity-modulated radiotherapy for treatment of pediatric craniopharyngiomas

PURPOSE Cranial irradiation in pediatric patients is associated with serious long-term adverse effects. We sought to determine whether both three-dimensional conformal proton radiotherapy (3D-PRT) and intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) decrease integral dose to brain areas known to harbor neuronal stem cells, major blood vessels, and other normal brain structures for pediatric patients with craniopharyngiomas. METHODS AND MATERIALS IMRT, forward planned, passive scattering proton, and IMPT plans were generated and optimized for 10 pediatric patients. The dose was 50.4 Gy (or cobalt Gy equivalent) delivered in 28 fractions with the requirement for planning target volume (PTV) coverage of 95% or better. Integral dose data were calculated from differential dose-volume histograms. RESULTS The PTV target coverage was adequate for all modalities. IMRT and IMPT yielded the most conformal plans in comparison to 3D-PRT. Compared with IMRT, 3D-PRT and IMPT plans had a relative reduction of integral dose to the hippocampus (3D-PRT, 20.4; IMPT, 51.3%*), dentate gyrus (27.3, 75.0%*), and subventricular zone (4.5, 57.8%*). Vascular organs at risk also had reduced integral dose with the use of proton therapy (anterior cerebral arteries, 33.3*, 100.0%*; middle cerebral arteries, 25.9%*, 100%*; anterior communicating arteries, 30.8*, 41.7%*; and carotid arteries, 51.5*, 77.6*). Relative reduction of integral dose to the infratentorial brain (190.7*, 109.7%*), supratentorial brain without PTV (9.6, 26.8%*), brainstem (45.6, 22.4%*), and whole brain without PTV (19.4*, 34.4%*) were recorded with the use of proton therapy. (*Differences were significant based on Friedmans test with Bonferroni-Dunn correction, α = 0.05) CONCLUSIONS The current study found that proton therapy was able to avoid excess integral radiation dose to a variety of normal structures at all dose levels while maintaining equal target coverage. Future studies will examine the clinical benefits of these dosimetric advantages.

Low early ototoxicity rates for pediatric medulloblastoma patients treated with proton radiotherapy.

BackgroundHearing loss is common following chemoradiotherapy for children with medulloblastoma. Compared to photons, proton radiotherapy reduces radiation dose to the cochlea for these patients. Here we examine whether this dosimetric advantage leads to a clinical benefit in audiometric outcomes.MethodsFrom 2006-2009, 23 children treated with proton radiotherapy for medulloblastoma were enrolled on a prospective observational study, through which they underwent pre- and 1 year post-radiotherapy pure-tone audiometric testing. Ears with moderate to severe hearing loss prior to therapy were censored, leaving 35 ears in 19 patients available for analysis.ResultsThe predicted mean cochlear radiation dose was 30 60Co-Gy Equivalents (range 19-43), and the mean cumulative cisplatin dose was 303 mg/m2 (range 298-330). Hearing sensitivity significantly declined following radiotherapy across all frequencies analyzed (P < 0.05). There was partial sparing of mean post-radiation hearing thresholds at low-to-midrange frequencies and, consequently, the rate of high-grade (grade 3 or 4) ototoxicity at 1 year was favorable (5%). Ototoxicity did not correlate with predicted dose to the auditory apparatus for proton-treated patients, potentially reflecting a lower-limit threshold for radiation effect on the cochlea.ConclusionsRates of high-grade early post-radiation ototoxicity following proton radiotherapy for pediatric medulloblastoma are low. Preservation of hearing in the audible speech range, as observed here, may improve both quality of life and cognitive functioning for these patients.

Proton beam craniospinal irradiation reduces acute toxicity for adults with medulloblastoma.

PURPOSE Efficacy and acute toxicity of proton craniospinal irradiation (p-CSI) were compared with conventional photon CSI (x-CSI) for adults with medulloblastoma. METHODS AND MATERIALS Forty adult medulloblastoma patients treated with x-CSI (n=21) or p-CSI (n=19) at the University of Texas MD Anderson Cancer Center from 2003 to 2011 were retrospectively reviewed. Median CSI and total doses were 30.6 and 54 Gy, respectively. The median follow-up was 57 months (range 4-103) for x-CSI patients and 26 months (range 11-63) for p-CSI. RESULTS p-CSI patients lost less weight than x-CSI patients (1.2% vs 5.8%; P=.004), and less p-CSI patients had >5% weight loss compared with x-CSI (16% vs 64%; P=.004). p-CSI patients experienced less grade 2 nausea and vomiting compared with x-CSI (26% vs 71%; P=.004). Patients treated with x-CSI were more likely to have medical management of esophagitis than p-CSI patients (57% vs 5%, P<.001). p-CSI patients had a smaller reduction in peripheral white blood cells, hemoglobin, and platelets compared with x-CSI (white blood cells 46% vs 55%, P=.04; hemoglobin 88% vs 97%, P=.009; platelets 48% vs 65%, P=.05). Mean vertebral doses were significantly associated with reductions in blood counts. CONCLUSIONS This report is the first analysis of clinical outcomes for adult medulloblastoma patients treated with p-CSI. Patients treated with p-CSI experienced less treatment-related morbidity including fewer acute gastrointestinal and hematologic toxicities.

Spatial mapping of the biologic effectiveness of scanned particle beams: towards biologically optimized particle therapy

The physical properties of particles used in radiation therapy, such as protons, have been well characterized, and their dose distributions are superior to photon-based treatments. However, proton therapy may also have inherent biologic advantages that have not been capitalized on. Unlike photon beams, the linear energy transfer (LET) and hence biologic effectiveness of particle beams varies along the beam path. Selective placement of areas of high effectiveness could enhance tumor cell kill and simultaneously spare normal tissues. However, previous methods for mapping spatial variations in biologic effectiveness are time-consuming and often yield inconsistent results with large uncertainties. Thus the data needed to accurately model relative biological effectiveness to guide novel treatment planning approaches are limited. We used Monte Carlo modeling and high-content automated clonogenic survival assays to spatially map the biologic effectiveness of scanned proton beams with high accuracy and throughput while minimizing biological uncertainties. We found that the relationship between cell kill, dose, and LET, is complex and non-unique. Measured biologic effects were substantially greater than in most previous reports, and non-linear surviving fraction response was observed even for the highest LET values. Extension of this approach could generate data needed to optimize proton therapy plans incorporating variable RBE.

Preliminary Results of a Phase II Trial of Proton Radiotherapy for Pediatric Rhabdomyosarcoma

PURPOSE This prospective phase II study was designed to assess disease control and to describe acute and late adverse effects of treatment with proton radiotherapy in children with rhabdomyosarcoma (RMS). PATIENTS AND METHODS Fifty-seven patients with localized RMS (age 21 years or younger) or metastatic embryonal RMS (age 2 to 10 years) were enrolled between February 2005 and August 2012. All patients were treated with chemotherapy based on either vincristine, actinomycin, and cyclophosphamide or vincristine, actinomycin, and ifosfamide-based chemotherapy and proton radiation. Surgical resection was based on tumor site and accessibility. Common Terminology Criteria for Adverse Events, Version 3.0, was used to assess and grade adverse effects of treatment. Concurrent enrollment onto Childrens Oncology Group or European Pediatric Sarcoma Study Group protocols was allowed. All pathology and imaging were reviewed at the treating institution. RESULTS Median follow-up was 47 months (range, 14 to 102 months) for survivors. Five-year event-free survival (EFS), overall survival (OS), and local control (LC) were 69%, 78%, and 81%, respectively, for the entire cohort. The 5-year LC by risk group was 93% for low-risk and 77% for intermediate-risk disease. There were 13 patients with grade 3 acute toxicity and three patients with grade 3 late toxicity. There were no acute or late toxicities higher than grade 3. CONCLUSION Five-year LC, EFS, and OS rates were similar to those observed in comparable trials that used photon radiation. Acute and late toxicity rates were favorable. Proton radiation appears to represent a safe and effective radiation modality for pediatric RMS.

Comparing Intelligence Quotient Change After Treatment With Proton Versus Photon Radiation Therapy for Pediatric Brain Tumors

PURPOSE Compared with photon radiation (XRT), proton beam radiation therapy (PBRT) reduces dose to normal tissues, which may lead to better neurocognitive outcomes. We compared change in intelligence quotient (IQ) over time in pediatric patients with brain tumors treated with PBRT versus XRT. PATIENTS AND METHODS IQ scores were available for 150 patients (60 had received XRT, 90 had received PBRT). Linear mixed models examined change in IQ over time since radiation therapy (RT) by RT group, controlling for demographic/clinical characteristics. Craniospinal and focal RT subgroups were also examined. RESULTS In the PBRT group, no change in IQ over time was identified (P = .130), whereas in the XRT group, IQ declined by 1.1 points per year (P = .004). IQ slopes did not differ between groups (P = .509). IQ was lower in the XRT group (by 8.7 points) versus the PBRT group (P = .011). In the craniospinal subgroup, IQ remained stable in both the PBRT (P = .203) and XRT groups (P = .060), and IQ slopes did not differ (P = .890). IQ was lower in the XRT group (by 12.5 points) versus the PBRT group (P = .004). In the focal subgroup, IQ scores remained stable in the PBRT group (P = .401) but declined significantly in the XRT group by 1.57 points per year (P = .026). IQ slopes did not differ between groups (P = .342). CONCLUSION PBRT was not associated with IQ decline or impairment, yet IQ slopes did not differ between the PBRT and XRT groups. It remains unclear if PBRT results in clinically meaningful cognitive sparing that significantly exceeds that of modern XRT protocols. Additional long-term data are needed to fully understand the neurocognitive impact of PBRT in survivors of pediatric brain tumors.

Clinical evidence of variable proton biological effectiveness in pediatric patients treated for ependymoma

BACKGROUND AND PURPOSE A constant relative biological effectiveness (RBE) is used for clinical proton therapy; however, experimental evidence indicates that RBE can vary. We analyzed pediatric ependymoma patients who received proton therapy to determine if areas of normal tissue damage indicated by post-treatment image changes were associated with increased biological dose effectiveness. MATERIAL AND METHODS Fourteen of 34 children showed T2-FLAIR hyperintensity on post-treatment magnetic resonance (MR) images. We delineated regions of treatment-related change and calculated dose and linear energy transfer (LET) distributions with Monte Carlo. Voxel-level image change data were fit to a generalized linear model incorporating dose and LET. Cross-validation was used to determine model parameters and for receiver operating characteristic curve analysis. Tolerance dose (TD50; dose at which 50% of patients would experience toxicity) was interpolated from the model. RESULTS Image changes showed dependence on increasing LET and dose. TD50 decreased with increasing LET, indicating an increase in biological dose effectiveness. The cross-validated area under the curve for the model was 0.91 (95% confidence interval 0.88-0.94). CONCLUSIONS Our correlation of changes on MR images after proton therapy with increased LET constitutes the first clinical evidence of variable proton biological effectiveness.

A dosimetric comparison of proton and intensity modulated radiation therapy in pediatric rhabdomyosarcoma patients enrolled on a prospective phase II proton study

BACKGROUND Pediatric rhabdomyosarcoma (RMS) is highly curable, however, cure may come with significant radiation related toxicity in developing tissues. Proton therapy (PT) can spare excess dose to normal structures, potentially reducing the incidence of adverse effects. METHODS Between 2005 and 2012, 54 patients were enrolled on a prospective multi-institutional phase II trial using PT in pediatric RMS. As part of the protocol, intensity modulated radiation therapy (IMRT) plans were generated for comparison with clinical PT plans. RESULTS Target coverage was comparable between PT and IMRT plans with a mean CTV V95 of 100% for both modalities (p=0.82). However, mean integral dose was 1.8 times higher for IMRT (range 1.0-4.9). By site, mean integral dose for IMRT was 1.8 times higher for H&N (p<0.01) and GU (p=0.02), 2.0 times higher for trunk/extremity (p<0.01), and 3.5 times higher for orbit (p<0.01) compared to PT. Significant sparing was seen with PT in 26 of 30 critical structures assessed for orbital, head and neck, pelvic, and trunk/extremity patients. CONCLUSIONS Proton radiation lowers integral dose and improves normal tissue sparing when compared to IMRT for pediatric RMS. Correlation with clinical outcomes is necessary once mature long-term toxicity data are available.

Postoperative proton therapy for chordomas and chondrosarcomas of the spine: adjuvant versus salvage radiation therapy.

Study Design. Retrospective comparative cohort series. Objective. The aim of this study was to evaluate patients treated with proton therapy for chordoma and chondrosarcoma of the spine in the postoperative setting and to report local control, relapse-free, and overall survival outcomes. Summary of Background Data. Margin-negative resection of spinal chordomas and chondrosarcomas can be challenging, so adjuvant radiotherapy is often recommended. However, delivery of adequate radiotherapy is complicated by the relative radioresistance of these tumors, necessitating high doses, as well as the proximity of the spinal cord and exiting nerve roots increasing the risk for toxicity. Proton radiotherapy has favorable physical properties for avoiding nearby nontarget structures and is increasingly used for such lesions. Methods. Nineteen patients who underwent postoperative proton therapy at a single institution from 2006 to 2012 were identified including 13 with chordoma and 6 with chondrosarcoma. Surgical approach varied by tumor location in the cervical (n = 3), thoracic (n = 1), lumbar (n = 2), or sacral (n = 13) spine. Eight patients were categorized as receiving “early adjuvant” and 11 patients as receiving “salvage” treatment, as determined by initiation of radiation therapy after primary surgery or local recurrence, respectively. The median radiation dose delivered was 70 Gy relative biologic effectiveness (range: 56–78 Gy relative biologic effectiveness). Results. For the entire cohort, 2-year local control, relapse-free survival, and overall survival were 58%, 51.9%, and 93.3%, respectively. The early adjuvant group had significantly higher 2-year local control (80% vs. 45.5%; P = 0.024). Conclusion. Patients referred early for primary adjuvant radiation therapy after surgery had higher rates of disease control than those referred for salvage treatment of recurrent disease. Recurrence rates in our cohort were higher overall than other published series, indicating that even higher radiation doses may be helpful for further improving local control in the presence of gross or recurrent disease. Level of Evidence: 3