Search

Purpose Our previous work demonstrated that 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (18F-DOPA) positron emission tomography (PET) is sensitive and specific for identifying regions of high density and biologically aggressive glioblastoma. The purpose of this prospective phase 2 study was to determine the safety and efficacy of biologic-guided, dose-escalated radiation therapy (DERT) using 18F-DOPA PET in patients with glioblastoma. Methods and Materials Patients with newly diagnosed, histologically confirmed glioblastoma aged ≥18 years without contraindications to 18F-DOPA were eligible. Target volumes included 51, 60, and 76 Gy in 30 fractions with a simultaneous integrated boost, and concurrent and adjuvant temozolomide for 6 months. 18F-DOPA PET imaging was used to guide DERT. The study was designed to detect a true progression-free survival (PFS) at 6 months (PFS6) rate ≥72.5% in O6‐methylguanine methyltransferase (MGMT) unmethylated patients (DE-Un), with an overall significance level (alpha) of 0.20 and a power of 80%. Kaplan-Meier analysis was performed for PFS and overall survival (OS). Historical controls (HCs) included 139 patients (82 unmethylated) treated on prospective clinical trials or with standard RT at our institution. Toxicities were evaluated with Common Terminology Criteria for Adverse Events v4.0. Results Between January 2014 and December 2018, 75 evaluable patients were enrolled (39 DE-Un, 24 methylated [DE-Mth], and 12 indeterminate). PFS6 for DE-Un was 79.5% (95% confidence interval, 63.1%-90.1%). Median PFS was longer for DE-Un patients compared with historical controls (8.7 months vs 6.6 months; P = .017). OS was similarly longer, but the difference was not significant (16.0 vs 13.5 months; P = .13). OS was significantly improved for DE-Mth patients compared with HC-Mth (35.5 vs 23.3 months; P = .049) despite nonsignificant improvement in PFS (10.7 vs 9.0 months; P = .26). Grade 3 central nervous system necrosis occurred in 13% of patients, but treatment with bevacizumab improved symptoms in all cases. Conclusions 18F-DOPA PET–guided DERT appears to be safe, and it significantly improves PFS in MGMT unmethylated glioblastoma. OS is significantly improved in MGMT methylated patients. Further investigation of 18F-DOPA PET biologic guided DERT for glioblastoma is warranted.

Purpose The relative biologic effectiveness (RBE) rises with increasing linear energy transfer toward the end of proton tracks. Presently, there is no consensus on how RBE heterogeneity should be accounted for in breast cancer proton therapy treatment planning. Our purpose was to determine the dosimetric consequences of incorporating a brachial plexus (BP) biologic dose constraint and to describe other clinical implications of biologic planning. Methods and Materials We instituted a biologic dose constraint for the BP in the context of MC1631, a randomized trial of conventional versus hypofractionated postmastectomy intensity modulated proton therapy (IMPT). IMPT plans of 13 patients treated before the implementation of the biologic dose constraint (cohort A) were compared with IMPT plans of 38 patients treated on MC1631 after its implementation (cohort B) using (1) a commercially available Eclipse treatment planning system (RBE = 1.1); (2) an in-house graphic processor unit-based Monte Carlo physical dose simulation (RBE = 1.1); and (3) an in-house Monte Carlo biologic dose (MCBD) simulation that assumes a linear relationship between RBE and dose-averaged linear energy transfer (product of RBE and physical dose = biologic dose). Results Before implementation of a BP biologic dose constraint, the Eclipse mean BP D0.01 cm3 was 107%, and the MCBD estimate was 128% (ie, 64 Gy [RBE = biologic dose] in 25 fractions for a 50-Gy [RBE = 1.1] prescription), compared with 100.0% and 116.0%, respectively, after the implementation of the constraint. Implementation of the BP biologic dose constraint did not significantly affect clinical target volume coverage. MCBD plans predicted greater internal mammary node coverage and higher heart dose than Eclipse plans. Conclusions Institution of a BP biologic dose constraint may reduce brachial plexopathy risk without compromising target coverage. MCBD plan evaluation provides valuable information to physicians that may assist in making clinical judgments regarding relative priority of target coverage versus normal tissue sparing.

While dose escalation of radiotherapy (DERT) has failed to improve overall survival (OS) or progression-free survival (PFS) for glioblastoma in previous studies, a recent phase II clinical trial utilizing 18F-DOPA-PET-directed DERT demonstrated improved PFS in MGMT-unmethylated patients and OS in MGMT-methylated patients compared to historical controls. This planned secondary analysis sought to determine 1) how 18F-DOPA-PET changes RT volumes beyond standard MRI-planning, 2) which patients benefit most and least from this protocol, 3) which are mostly likely to experience clinically significant radionecrosis after DERT, and 4) patterns of failure after DERT. For 69 evaluable patients, median MRI-defined, PET-defined, and combined low-dose gross tumor volumes (GTV51) were 54 cc (range 9-248), 23 cc (0.4-179), and 62 cc (10-260), respectively. Median MRI-defined, PET-defined, and combined high-dose GTVs (GTV76) were 32 cc (range 4-136), 6 cc (0.1-138), and 34 cc (4-162), respectively. 18F-DOPA-PET resulted in a median volumetric expansion of 13% (0-243%) and 5% (0-217%) from MRI-defined low-dose and high-dose GTV’s, respectively. Central failures ( >95% of recurrence tumor volume) occurred within the 76 Gy, 60 Gy, and 51 Gy isodose lines in 32 (46%), 60 (87%), and 64 (93%) patients, respectively. Recursive partitioning analysis stratified patients by OS and PFS. Patients with 18F-DOPA-PET-defined GTV76 > 7.8cc, MRI-defined GTV76 > 42.7cc, and MGMT promotor-unmethylated tumors had the shortest OS, while patients with smaller PET and MRI-defined tumors had the longest OS (median 10.4 vs. 64.6 months, p< 0.001). Similarly, PFS was worst in patients with 18F-DOPA-PET-defined GTV76 > 2.17 cc who had biopsy only (median PFS 3.2 months, p< 0.001). Patients with 18F-DOPA-PET-defined GTV51 > 50 cc had the highest risk of grade 3+ radionecrosis (p< 0.001). In conclusion, larger 18F-DOPA-PET and MRI-defined tumor volumes were associated with worse outcomes, and 18F-DOPA-PET-directed DERT appears to reduce risk of central recurrence in high-dose volumes.

Purpose To evaluate the incidence of imaging changes in our pediatric brain tumor population treated with spot-scanning proton therapy and analyze the spatial correlation of imaging changes with a novel biologic dose model. Methods and Materials All pediatric patients treated during the first year of our institution's experience who received a minimum treatment planning dose (TPD) of 5040 cGyE with available follow-up magnetic resonance imaging scans were selected for analysis. Posttreatment magnetic resonance imaging scans were fused with the treatment planning computed tomography. All T1 post–gadolinium enhancement, T2 fluid attenuated inversion recovery changes, TPD, and biologic dose (BD) volumes outside of the original gross tumor volume were contoured for analysis. Results Thirty patients were included in the analysis, 7 of whom developed posttreatment radiologic changes. The volumetric overlap of the T2 fluid attenuated inversion recovery changes and BD volumes was significantly greater than the overlap with the TPD volumes. Median volumetric overlaps of 85%, 18%, and 0% were observed with the BD105%, BD110%, and TPD105%, respectively. A nonsignificant increase in the volumetric overlap of the T1C+ changes and BD volumes was also observed. No correlation was observed between the total volume of BD110%, BD105%, or physical dose 105% and the development of imaging changes. Conclusions Within our pediatric brain tumor population treated with spot-scanning proton therapy, our BD model demonstrated superior volumetric overlap with posttreatment T2 changes compared with the TPD model. Using a BD model in treatment planning for spot-scanning proton therapy may help avoid delivery of excessive BD to critical structures and may help minimize the risk of radiation-related late effects.

BACKGROUND: 18F-DOPA-PET thresholds reliably delineate areas of high-grade astrocytoma not otherwise recognized with standard MRI and may more accurately identify regions of aggressive, high-density disease. Herein we report the preliminary safety and feasibility data from an ongoing phase II study (MC1374; R01CA178200) evaluating 18F-DOPA-PET guided-dose-escalated radiotherapy for glioblastoma. METHODS: Newly diagnosed glioblastoma patients without contra-indications to 18F-DOPA-PET are eligible for study enrollment. Target volumes include: CTV51Gy=T1-gadolinium contrast-enhancing (T1-CE) disease, T2 FLAIR signal abnormality, and low-grade 18F-DOPA-PET uptake, +1cm; CTV60Gy=T1-CE and high-grade 18F-DOPA-PET uptake, +1cm; and CTV76Gy=T1-CE and high-grade 18F-DOPA-PET disease without expansion all given in 30 fractions simultaneously. Patients are followed with 18F-DOPA-PET in addition to standard clinical follow-up. Safety stopping rule specifies that after 10 or more patients have been enrolled, if more than 10% experience any of the following adverse events considered to be at least possibly related to treatment, enrollment will be suspended: Grade 3 or 4 irreversible CNS toxicity, Grade 4 non-hematologic, non-CNS toxicity, any Grade 5 toxicity. Futility analysis (and primary study aim) is powered to consider a success to be an MGMT-unmethylated patient who is without progression within 6 months from the time of craniotomy. If 16 or more successes are observed in the first 25 evaluable patients study will continue. RESULTS: 77 patients have been accrued since December 2013 with 68 evaluable for toxicity. Grade 3 CNS necrosis was noted in 3 (4.4%) patients; 2 additional patients developed symptoms that resolved in the subsequent cycle so did not count towards stopping rule. Other grade 3+ toxicities include: 1 patient with pre-existing vision dysfunction had Grade 4 optic nerve dysfunction; 2 Grade 4 hematologic events and 1 Grade 5 event(sepsis) due to temozolamide-induced cytopenias. CONCLUSION: 18F-DOPA-PET -guided dose escalation appears reasonably safe and tolerable in patients with high-grade glioma.

Purpose Our aim is to demonstrate the feasibility of fast Monte Carlo (MC)–based inverse biological planning for the treatment of head and neck tumors in spot-scanning proton therapy. Methods and Materials Recently, a fast and accurate graphics processor unit (GPU)–based MC simulation of proton transport was developed and used as the dose-calculation engine in a GPU-accelerated intensity modulated proton therapy (IMPT) optimizer. Besides dose, the MC can simultaneously score the dose-averaged linear energy transfer (LET d ), which makes biological dose (BD) optimization possible. To convert from LET d to BD, a simple linear relation was assumed. By use of this novel optimizer, inverse biological planning was applied to 4 patients, including 2 small and 1 large thyroid tumor targets, as well as 1 glioma case. To create these plans, constraints were placed to maintain the physical dose (PD) within 1.25 times the prescription while maximizing target BD. For comparison, conventional intensity modulated radiation therapy (IMRT) and IMPT plans were also created using Eclipse (Varian Medical Systems) in each case. The same critical-structure PD constraints were used for the IMRT, IMPT, and biologically optimized plans. The BD distributions for the IMPT plans were obtained through MC recalculations. Results Compared with standard IMPT, the biologically optimal plans for patients with small tumor targets displayed a BD escalation that was around twice the PD increase. Dose sparing to critical structures was improved compared with both IMRT and IMPT. No significant BD increase could be achieved for the large thyroid tumor case and when the presence of critical structures mitigated the contribution of additional fields. The calculation of the biologically optimized plans can be completed in a clinically viable time ( Conclusions By exploiting GPU acceleration, MC-based, biologically optimized plans were created for small–tumor target patients. This optimizer will be used in an upcoming feasibility trial on LET d painting for radioresistant tumors.

BACKGROUND: Multiple studies have demonstrated that amino acid PET tracers identify aggressive disease beyond what is contrast enhancing on T1-weighted conventional MR (T1CE). In this study, we explored discrepancies between 18F-DOPA PET and conventional MR for defining target volumes in newly diagnosed glioblastoma (GBM) radiotherapy patients. METHODS: In an ongoing NCI-funded trial (NCT:R01CA178200), 18F-DOPA PET was acquired prior to chemoradiation for newly diagnosed GBM patients and incorporated prospectively into the target volumes, modifying low and high dose target volumes, and guiding dose escalation to the most aggressive disease. Based on the results of our pilot biopsy-validation study, two 18F-DOPA PET volumes were defined, one with a T/N threshold >2.0 (PET_high) depicting the most aggressive disease and another with a T/N threshold default of ≥1.5 (PET_low) with modifications if needed by a Nuclear Medicine physician. Both PET volumes were compared with the T1CE+cavity MR volumes for 30 MGMT unmethylated newly diagnosed GBM patients. RESULTS: The PET_low volume extended beyond T2-FLAIR signal abnormality for all patients, and extended beyond standard CTV expansion in 60% of patients. Sixty-seven per cent of patients had at least 20% of the PET_high uptake outside the T1CE volume, and would not have been covered by standard CTV expansion in 8% of patients. The average (range) Dice Similarity Coefficient comparing T1CE with PET_high was 0.3(0.0–0.7). The average (range) Haursdorff maximum distance (cm) between PET uptake and T1CE was found to be 2.4(0.9–7.1). CONCLUSIONS: 18F-DOPA-PET identified regions of biologically active disease outside the T1CE in 67% of patients with significant discordance in volumes. Evaluation of the impact prospective 18F-DOPA PET guidance for dose escalated radiation therapy is under investigation in the ongoing trial.

Purpose: Conventional spot scanning intensity modulated proton therapy (IMPT) treatment planning systems (TPSs) optimize proton spot weights based on analytical dose calculations. These analytical dose calculations have been shown to have severe limitations in heterogeneous materials. Monte Carlo (MC) methods do not have these limitations; however, MC-based systems have been of limited clinical use due to the large number of beam spots in IMPT and the extremely long calculation time of traditional MC techniques. In this work, the authors present a clinically applicable IMPT TPS that utilizes a very fast MC calculation. Methods: An in-house graphics processing unit (GPU)-based MC dose calculation engine was employed to generate the dose influence map for each proton spot. With the MC generated influence map, a modified least-squares optimization method was used to achieve the desired dose volume histograms (DVHs). The intrinsic CT image resolution was adopted for voxelization in simulation and optimization to preserve spatial resolution. The optimizations were computed on a multi-GPU framework to mitigate the memory limitation issues for the large dose influence maps that resulted from maintaining the intrinsic CT resolution. The effects of tail cutoff and starting condition were studied and minimized in this work. Results: For relatively large and complex three-field head and neck cases, i.e., >100 000 spots with a target volume of ∼1000 cm3 and multiple surrounding critical structures, the optimization together with the initial MC dose influence map calculation was done in a clinically viable time frame (less than 30 min) on a GPU cluster consisting of 24 Nvidia GeForce GTX Titan cards. The in-house MC TPS plans were comparable to a commercial TPS plans based on DVH comparisons. Conclusions: A MC-based treatment planning system was developed. The treatment planning can be performed in a clinically viable time frame on a hardware system costing around 45 000 dollars. The fast calculation and optimization make the system easily expandable to robust and multicriteria optimization.