A case-control study of linear energy transfer and relative biological effectiveness related to symptomatic brainstem toxicity following pediatric proton therapy

Background and purpose A fixed relative biological effectiveness (RBE) of 1.1 (RBE1.1) is used clinically in proton therapy even though the RBE varies with properties such as dose level and linear energy transfer (LET). We therefore investigated if symptomatic brainstem toxicity in pediatric brain tumor patients treated with proton therapy could be associated with a variable LET and RBE. Materials and methods 36 patients treated with passive scattering proton therapy were selected for a case-control study from a cohort of 954 pediatric brain tumor patients. Nine children with symptomatic brainstem toxicity were each matched to three controls based on age, diagnosis, adjuvant therapy, and brainstem RBE1.1 dose characteristics. Differences across cases and controls related to the dose-averaged LET (LETd) and variable RBE-weighted dose from two RBE models were analyzed in the high-dose region. Results LETd metrics were marginally higher for cases vs. controls for the majority of dose levels and brainstem substructures. Considering areas with doses above 54 Gy(RBE1.1), we found a moderate trend of 13% higher median LETd in the brainstem for cases compared to controls (P =.08), while the difference in the median variable RBE-weighted dose for the same structure was only 2% (P =.6). Conclusion Trends towards higher LETd for cases compared to controls were noticeable across structures and LETd metrics for this patient cohort. While case-control differences were minor, an association with the observed symptomatic brainstem toxicity cannot be ruled out.publishedVersio

Radiotherapy for marginally resected, unresectable or recurrent giant cell tumor of the bone: a rare cancer network study

The role of radiotherapy for local control of marginally resected, unresectable, and recurrent giant cell tumors of bone (GCToB) has not been well defined. The number of patients affected by this rare disease is low. We present a series of 58 patients with biopsy proven GCToB who were treated with radiation therapy. A retrospective review of the role of radiotherapy in the treatment of GCToB was conducted in participating institutions of the Rare Cancer Network. Eligibility criteria consisted of the use of radiotherapy for marginally resected, unresectable, and recurrent GCToB. Fifty-eight patients with biopsy proven GCToB were analyzed from 9 participating North American and European institutions. Forty-five patients had a primary tumor and 13 patients had a recurrent tumor. Median radiation dose was 50 Gy in a median of 25 fractions. Indication for radiation therapy was marginal resection in 33 patients, unresectable tumor in 13 patients, recurrence in 9 patients and palliation in 2 patients. Median tumor size was 7.0 cm. A significant proportion of the tumors involved critical structures. Median follow-up was 8.0 years. Five year local control was 85% . Of the 7 local failures, 3 were treated successfully with salvage surgery. All patients who received palliation achieved symptom relief. Five year overall survival was 94%. None of the patients experienced grade 3 or higher acute toxicity. This study reports a large published experience in the treatment of GCToB with radiotherapy. Radiotherapy can provide excellent local control for incompletely resected, unresectable or recurrent GCToB with acceptable morbidity

Perfusion MRI derived indices of microvascular shunting and flow control correlate with tumor grade and outcome in patients with cerebral glioma.

Deficient microvascular blood flow control is thought to cause tumor hypoxia and increase resistance to therapy. In glioma patients, we tested whether perfusion-weighted MRI (PWI) based indices of microvascular flow control provide more information on tumor grade and patient outcome than does the established PWI angiogenesis marker, cerebral blood volume (CBV).Seventy-two glioma patients (sixty high-grade, twelve low-grade gliomas) were included. Capillary transit time heterogeneity (CTH) and the coefficient of variation (COV), its ratio to blood mean transit time, provide indices of microvascular flow control and the extent to which oxygen can be extracted by tumor tissue. The ability of these parameters and CBV to differentiate tumor grade were assessed by receiver operating characteristic curves and logistic regression. Their ability to predict time to progression and overall survival was examined by the Cox proportional-hazards regression model, and by survival curves using log-rank tests.The best prediction of grade (AUC = 0.876; p < 0.05) was achieved by combining knowledge of CBV and CTH in the enhancing tumor and peri-focal edema, and patients with glioblastoma multiforme were identified best by CTH (AUC = 0.763; p<0.001). CTH outperformed CBV and COV in predicting time to progression and survival in all gliomas and in a subgroup consisting of only high-grade gliomas.Our study confirms the importance of microvascular flow control in tumor growth by demonstrating that determining CTH improves tumor grading and outcome prediction in glioma patients compared to CBV alone

Average values for different glioma types and grades.

<p>Average (± standard deviation; SD) values for different tumor types and grades (GBM: glioblastoma; AC3: astrocytoma grade 3; AC2+AC1: astrocytoma grade 2 and 1, respectively; ODG3: oligodendroglioma grade 3; ODG2: oligodendroglioma grade 2; HGG: high grade glioma; LGG: low grade glioma).</p><p>Average values for different glioma types and grades.</p

Image examples of a high-grade and a low-grade glioma.

<p>Contrast-enhanced T1, T2FLAIR, cerebral blood volume (CBV), capillary transit time heterogeneity (CTH), and coefficient of variance (COV) maps in a patient with (A) a glioblastoma and (B) an astrocytoma grade 2. The enhancing tumor and the peri-focal edema are outlined with black lines on the parameter maps. (A) The glioblastoma shows increased COV in the enhancing part and high CTH in the peri-tumoral edema, whereas (B) the astrocytoma grade 2 is characterized by low CBV, CTH, and COV.</p

Survival curves for high-grade glioma patients.

<p>Time to progression and overall survival for all glioma and for high-grade glioma (HGG) cases are shown. Curves for patients with high mean rCBV, rCTH, and COV values in the enhancing tumor or in a combined region consisting of the enhancing part and the peri-tumoral edema are blue; curves for patients with low mean values are red. A p-value < 0.05 denotes significant difference between the two curves.</p

Correlation of rCBV and rCTH.

<p>Scatterplots showing the very weak correlation of rCBV and rCTH in (A) the enhancing tumor (R² = 0.01; p = 0.41) and (B) the peri-focal edema (R² = 0.06; p = 0.05), suggesting that they provide different information. Mean values for each patient are plotted. High-grade gliomas are marked with blue, low-grade gliomas with red.</p

Differentiation of high-grade from low-grade gliomas.

<p>Receiver Operating Characteristic curves illustrating the diagnostic performance of rCBV (blue), rCTH (green), and combined rCBV / rCTH (red) mean values within the enhancing tumor and the peri-focal edema to discriminate high-grade from low-grade gliomas.</p