James C. Marsh

Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: Safety profile for RTOG 0933

BACKGROUND AND PURPOSE RTOG 0933 is a phase II clinical trial of hippocampal avoidance during whole-brain radiotherapy (HA-WBRT) to prevent radiation-induced neurocognitive decline. By quantifying baseline incidence of perihippocampal or hippocampal metastasis, we sought to estimate the risk of developing metastases in the hippocampal avoidance region (the hippocampus plus 5mm margin). MATERIALS/METHODS Patients with < or = 10 brain metastases treated at two separate institutions were reviewed. Axial images from pre-treatment, post-contrast MRIs were used to contour each metastasis and hippocampus according to a published protocol. Clinical and radiographic variables were correlated with perihippocampal metastasis using a binary logistical regression analysis, with two-sided p<0.05 for statistical significance. RESULTS 1133 metastases were identified in 371 patients. Metastases within 5mm of the hippocampus were observed in 8.6% of patients (95% CI 5.7-11.5%) and 3.0% of brain metastases. None of the metastases lay within the hippocampus. A 1-cm(3) increase in the aggregate volume of intra-cranial metastatic disease was associated with an odds ratio of 1.02 (95% CI 1.006-1.034, p=0.003) for the presence of perihippocampal metastasis. CONCLUSION With an estimated perihippocampal metastasis risk of 8.6%, we deem HA-WBRT safe for clinical testing in patients with brain metastases as part of RTOG 0933.

Cognitive Sparing during the Administration of Whole Brain Radiotherapy and Prophylactic Cranial Irradiation: Current Concepts and Approaches

Whole brain radiotherapy (WBRT) for the palliation of metastases, or as prophylaxis to prevent intracranial metastases, can be associated with subacute and late decline in memory and other cognitive functions. Moreover, these changes are often increased in both frequency and severity when cranial irradiation is combined with the use of systemic or intrathecal chemotherapy. Approaches to preventing or reducing this toxicity include the use of stereotactic radiosurgery (SRS) instead of WBRT; dose reduction for PCI; exclusion of the limbic circuit, hippocampal formation, and/or neural stem cell regions of the brain during radiotherapy; avoidance of intrathecal and/or systemic chemotherapy during radiotherapy; the use of high-dose, systemic chemotherapy in lieu of WBRT. This review discusses these concepts in detail as well as providing both neuroanatomic and radiobiologic background relevant to these issues.

Intracranial Metastatic Disease Spares the Limbic Circuit: A Review of 697 Metastatic Lesions in 107 Patients

PURPOSE We report the incidence of metastatic involvement of the limbic circuit in a retrospective review of patients treated at our institution. This review was performed to assess the feasibility of selectively sparing the limbic system during whole-brain radiotherapy and prophylactic cranial irradiation. METHODS AND MATERIALS We identified 697 intracranial metastases in 107 patients after reviewing contrast-enhanced CT and/or MR image sets for each patient. Lesions were localized to the limbic circuit or to the rest of the brain/brain stem. Patients were categorized by tumor histology (e.g., non-small-cell lung cancer, small-cell lung cancer, breast cancer, and other) and by total number of intracranial metastases (1-3, oligometastatic; 4 or more, nonoligometastatic). RESULTS Thirty-six limbic metastases (5.2% of all metastases) were identified in 22 patients who had a median of 16.5 metastases/patient (limbic metastases accounted for 9.9% of their lesions). Sixteen metastases (2.29%) involved the hippocampus, and 20 (2.86%) involved the rest of the limbic circuit; 86.2% of limbic metastases occurred in nonoligometastatic patients, and 13.8% occurred in oligometastatic patients. The incidence of limbic metastases by histologic subtype was similar. The incidence of limbic metastases in oligometastatic patients was 4.9% (5/103): 0.97%, hippocampus; 3.9%, remainder of the limbic circuit. One of 53 oligometastatic patients (1.9%) had hippocampal metastases, while 4/53 (7.5%) had other limbic metastases. CONCLUSIONS Metastatic involvement of the limbic circuit is uncommon and limited primarily to patients with nonoligometastatic disease, supporting our hypothesis that it is reasonable to selectively exclude or reduce the dose to the limbic circuit when treating patients with prophylactic cranial irradiation or whole-brain radiotherapy for oligometastatic disease not involving these structures.

Sparing of the Neural Stem Cell Compartment During Whole-Brain Radiation Therapy: A Dosimetric Study Using Helical Tomotherapy

PURPOSE To assess the feasibility of dosimetrically sparing the hippocampus and neural stem cell (NSC) compartment during whole-brain radiotherapy (WBRT) and prophylactic cranial irradiation (PCI). METHODS AND MATERIALS We contoured the brain/brainstem on fused magnetic resonance /computed tomography images as the planning target volume (PTV) in 10 patients, excluding the hippocampus and NSC compartment as organs at risk. PCI and WBRT helical tomotherapy plans were prepared for each patient, with 1.0-cm field width, a pitch of 0.285, and a modulation factor of 2.5. We attempted to maximally spare the hippocampus and NSC compartment while treating the rest of the brain to 30 Gy in 15 fractions (PCI) or 35 Gy in 14 fractions (WBRT) with a V(100) of ≥95%. Plan quality was assessed by calculating mean dose, equivalent uniform dose (EUD), and biologically equivalent dose (BED) for organs at risk and the percent volume of the PTV receiving the prescribed dose of V(100). RESULTS In the PCI plans, mean doses/EUD/BED for the hippocampus and NSC compartment were 11.5 Gy/13.1 Gy/15.7 Gy(2) (BED assuming alpha/beta ratio of 2Gy) and 11.5 Gy/13.1 Gy/12.3 Gy(10) (BED assuming alpha/beta ratio of 10Gy), respectively. In the WBRT plans, mean doses/EUD/BED for the hippocampus and NSC compartment were 11.8 Gy/14.8 Gy/16.8 Gy(2) and 11.8 Gy/14.8 Gy/12.8 Gy(10), respectively. The mean V(95) for the rest of the brain (PTV) was 96.9% for both the PCI and WBRT plans. Mean PCI and WBRT treatment times were 15.93 min (range, 14.28 min-17.50 min) and 20.18 min (range, 18.43 min-22.32 min), respectively. CONCLUSIONS It is dosimetrically feasible to spare the hippocampus and NSC compartment using helical tomotherapy during the administration of whole-brain irradiation.

Sparing of the hippocampus, limbic circuit and neural stem cell compartment during partial brain radiotherapy for glioma: A dosimetric feasibility study

Introduction: The aim of this study was to assess the feasibility of sparing contralateral or bilateral neural stem cell (NSC) compartment, hippocampus and limbic circuit during partial brain radiotherapy (PBRT).

Current Status of Immunotherapy and Gene Therapy for High-Grade Gliomas

BACKGROUND Despite improvements in surgical technique, radiation therapy delivery, and options for systemic cytotoxic therapy, the median survival for patients with newly diagnosed glioblastoma multiforme remains poor at 15 months with trimodality therapy. Multiple immunologic approaches are being tested to enhance the response of these tumors to existing therapy and/or to stimulate innate immune responses. METHODS We review the existing data that support the continued development of immunologic therapy in the treatment armamentarium against glioblastoma multiforme, with a focus on clinical data documenting outcomes. RESULTS In phase I and phase II trials, antitumor vaccines (dendritic and formalin-fixed) have demonstrated clinical efficacy with mild toxicity, suggesting that innate immune responses can be amplified and directed against these tumors. Suicide gene therapy (gene-mediated cytotoxic therapy) using a number of viral vectors and molecular pathways has also shown efficacy in completed phase I and ongoing phase II trials. In addition, neural stem cells are being investigated as vectors in this approach. CONCLUSIONS Although phase III data are needed before immunologic therapies can be widely implemented into clinical practice, the existing phase I and phase II data suggest that these therapies can produce meaningful and sometimes durable responses in patients with glioblastoma multiforme with mild toxicity compared with other existing therapies.

Sparing of the hippocampus and limbic circuit during whole brain radiation therapy: A dosimetric study using helical tomotherapy.

Introduction:  The study aims to assess the feasibility of dosimetrically sparing the limbic circuit during whole brain radiation therapy (WBRT) and prophylactic cranial irradiation (PCI).

Integral dose delivered to normal brain with conventional intensity-modulated radiotherapy (IMRT) and helical tomotherapy IMRT during partial brain radiotherapy for high-grade gliomas with and without selective sparing of the hippocampus, limbic circuit and neural stem cell compartment

We compared integral dose with uninvolved brain (IDbrain) during partial brain radiotherapy (PBRT) for high‐grade glioma patients using helical tomotherapy (HT) and seven field traditional inverse‐planned intensity‐modulated radiotherapy (IMRT) with and without selective sparing (SPA) of contralateral hippocampus, neural stem cell compartment (NSC) and limbic circuit.

ORIGINAL ARTICLE: Sparing of the hippocampus and limbic circuit during whole brain radiation therapy: A dosimetric study using helical tomotherapy

Introduction:  The study aims to assess the feasibility of dosimetrically sparing the limbic circuit during whole brain radiation therapy (WBRT) and prophylactic cranial irradiation (PCI).

Integral dose delivered to normal brain with conventional intensity‐modulated radiotherapy (IMRT) and helical tomotherapy IMRT during partial brain radiotherapy for high‐grade gliomas with and without selective sparing of the hippocampus, limbic circuit a

We compared integral dose with uninvolved brain (IDbrain) during partial brain radiotherapy (PBRT) for high‐grade glioma patients using helical tomotherapy (HT) and seven field traditional inverse‐planned intensity‐modulated radiotherapy (IMRT) with and without selective sparing (SPA) of contralateral hippocampus, neural stem cell compartment (NSC) and limbic circuit.