Involvement of the neural stem cell compartment by pediatric and adult gliomas: a retrospective review of 377 cases.

To assess frequency of neural stem cell compartment (NSC) involvement in adult and pediatric gliomas [World Health Organization (WHO) grades 1-4], and to assess whether NSC involvement at presentation impacts on survival, recurrence rates, and/or transformation from low grade (WHO grade 1-2) to high grade disease (WHO grades 3-4). Cranial MRIs for 154 pediatric and 223 adult glioma patients treated from 2000 to 2012 were reviewed. NSC involvement was documented. Tumors were stratified by age (adult vs. pediatric), histology, tumor grade, tumor location, and involvement of midline structures. Odds ratios (OR) for death were calculated based on NSC status at presentation. Rates of transformation and recurrence rates (ORR) were compared using Fisher's Exact Test. Time to recurrence (TTR) was calculated using student t test. Among recurrent and transformed tumors, we also assessed the rate of NSC involvement at time of recurrence or transformation. 74.8 % of tumors had NSC involvement. Higher rates of NSC involvement were seen among adult (p = .0001); high grade (p = .0001)); grade 2 versus grade 1 (p = .0001) and other grade 1 histologies (p = .0001) versus JPA (juvenile pilocytic astrocytoma) patients); grade 2-4 tumors (p = .0001); and supratentorial tumors (p < .0001). No transformation was noted among pediatric low grade tumors or adult grade 1 tumors. 22/119 (18.5 %) adult grade 2 tumors transformed. Rates of transformation were not impacted by NSC status (p = .47). ORR was 15.1 %, and was greater for NSC+ tumors at presentation (p = .05). 36/41 recurrences (87.8 %) involved NSC at time of recurrence. OR for death was 2.62 (1.16-5.9), p = .02 for NSC+ tumors at presentation. Adult and pediatric gliomas (all grades) frequently involve NSC at presentation, although rates are lower in pediatric JPA and all infratentorial tumors. NSC involvement at presentation increases OR death and reduces TTR for pediatric gliomas (all grades) and adult low grade gliomas, and shows a strong trend toward increased ORR.

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.

INTRODUCTION: 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. METHODS: We prepared four PBRT treatment plans for four patients with high-grade gliomas (60 Gy in 30 fractions delivered to planning treatment volume (PTV60Gy)). For all plans, a structure denoted 'uninvolved brain' was created, which included all brain tissue not part of PTV or standard (STD) organs at risk (OAR). No dosimetric constraints were included for uninvolved brain. Selective SPA plans were prepared with IMRT and HT; contralateral hippocampus, NSC and limbic circuit were contoured; and dosimetric constraints were entered for these structures without compromising dose to PTV or STD OAR. We compared V100 and D95 for PTV46Gy and PTV60Gy, and IDbrain for all plans. RESULTS: There were no significant differences in V100 and D95 for PTV46Gy and PTV60Gy. IDbrain was lower in traditional IMRT versus HT plans for STD and SPA plans (mean IDbrain 23.64 Gy vs. 28 Gy and 18.7 Gy vs. 24.5 Gy, respectively) and in SPA versus STD plans both with IMRT and HT (18.7 Gy vs. 23.64 Gy and 24.5 Gy vs. 28 Gy, respectively). CONCLUSIONS: In the setting of PBRT for high-grade gliomas, IMRT reduces IDbrain compared with HT with or without selective SPA of contralateral hippocampus, limbic circuit and NSC, and the use of selective SPA reduces IDbrain compared with STD PBRT delivered with either traditional IMRT or HT.

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.

High-grade glioma relationship to the neural stem cell compartment: a retrospective review of 104 cases.

PURPOSE: To assess the incidence of involvement of the neural stem cell (NSC) compartment by high-grade astrocytomas in a series of adult patients. METHODS AND MATERIALS: One hundred four initial diagnostic cranial magnetic resonance imaging series were reviewed. For each series, the gross tumor volume (GTV; enhancing tumor on T(1)), edema (hyperintensity on T(2) FLAIR), and the NSC compartment (hippocampal formation and lateral ventricle plus a 5-mm expansion) were identified. Involvement of NSC by GTV and edema was assessed. For tumors not involving NSC, we measured distances from NSC to GTV and edema. Maximum diameters of GTV were measured for each case. Subset analysis was performed for GTV of ≤ 2 cm and ≤ 3 cm in maximum diameter to assess the incidence of involvement of NSC by this group of smaller tumors. For 10 representative tumors, minimum distances from GTV center to NSC were calculated. RESULTS: A total of 103/104 (99.0%) tumors, regardless of GTV maximum diameter, demonstrated involvement of NSC. A total of 101/104 (97.1%) tumors had NSC involvement by GTV, and 2/104 (1.9%) patients showed edema only. For GTV not involving NSC, the mean distance from NSC to GTV was 0.8 cm (range, 0.5--1.4 cm). The mean shortest distance from the center of GTV to NSC was 1.5 cm (range, 0.9--2.6 cm). Involvement of NSC by GTV was 90.9% (10/11 tumors) for GTV of ≤ 2 cm and 95.7% (22/23 tumors) for GTV of ≤ 3 cm. CONCLUSIONS: Our results support the hypothesis that the NSC compartment represents the putative site of origin for these tumors. NSC involvement does not appear to represent a volumetric phenomenon.

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). METHODS AND MATERIALS: Treatment plans were generated for five hemispheric high-grade gliomas, five hemispheric low-grade gliomas and two brainstem gliomas (12 patients). For each, standard intensity-modulated radiotherapy (IMRT) plans were generated, as well as IMRT plans which spared contralateral (hemispheric cases) or bilateral (brainstem cases) limbic circuit, hippocampus, and NSC. Biologically equivalent dose for late effects (BED(late effects)) was generated for limbic circuit, hippocampus and NSC. Per cent relative reduction in mean physical dose and BED was calculated for each plan (standard vs. sparing). RESULTS: We were able to reduce physical dose and BED(late effects) to these critical structures by 23.5-56.8% and 23.6-66%, respectively. CONCLUSION: It is possible to spare contralateral limbic circuit, NSC and hippocampus during PBRT for both high- and low-grade gliomas using IMRT, and to spare the hippocampus bilaterally during PBRT for brainstem low-grade gliomas. This approach may reduce late cognitive sequelae of cranial radiotherapy.

Split-course chemoradiotherapy for locally advanced non-small cell lung cancer: a single-institution experience of 144 patients.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is a standard of care in the treatment of unresectable locally advanced non-small cell lung cancer (NSCLC). At Rush University Medical Center, patients with locally advanced NSCLC are treated with split-course CRT in an attempt to maximize efficacy and tolerability. We reviewed our experience in advanced NSCLC since 1999. Subset analysis was performed on poor-risk patients. METHODS: All patients with a diagnosis of stage IIIA/IIIB NSCLC and treated with definitive split-course CRT between January 1999 and December 2008 were included in this retrospective study. The primary end point was overall survival. Poor-risk patients were defined in accordance with ongoing cooperative group trials. RESULTS: One hundred forty-four patients were identified, 35% stage IIIA and 65% stage IIIB. There were 52 poor-risk patients and 92 average-risk patients. Median survival for all patients was 20.4 months with an actuarial 32.1% 3-year overall survival rate. Poor-risk patients demonstrated a median survival of 22.1 months, statistically indistinguishable from the remainder of the cohort (p = 0.21). Acute esophagitis was mild, with a 3% rate of grade 3 esophagitis and no cases of grade 4 or 5. CONCLUSIONS: Split-course CRT appeared effective and was delivered with a favorable toxicity profile. Poor-risk patients experienced better than expected survival. Prospective evaluation of split-course CRT must be completed before it can be considered a standard treatment option in locally advanced NSCLC.

Weight gain in advanced non-small-cell lung cancer patients during treatment with split-course concurrent chemoradiotherapy is associated with superior survival.

BACKGROUND: Preoperative concurrent chemoradiotherapy (CRT) is an accepted treatment for potentially resectable, locally advanced, non-small-cell lung cancer (NSCLC). We reviewed a decade of single institution experience with preoperative split-course CRT followed by surgical resection to evaluate survival and identify factors that may be helpful in predicting outcome. METHODS AND MATERIALS: All patients treated with preoperative split-course CRT and resection at Rush University Medical Center (RUMC) between January 1999 and December 2008 were retrospectively analyzed. Endpoints included overall survival (OS), progression-free survival (PFS), local-regional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS). Patient and treatment related variables were assessed for correlation with outcomes. RESULTS: A total of 54 patients were analyzed, 76% Stage IIIA, 18% Stage IIIB, and 6% oligometastatic. The pathologic complete response (pCR) rate was 31.5%, and the absence of nodal metastases (pN0) was 64.8%. Median OS and 3-year actuarial survival were 44.6 months and 50%, respectively. Univariate analysis revealed initial stage (p < 0.01) and percent weight change during CRT (p < 0.01) significantly correlated with PFS/OS. On multivariate analysis initial stage (HR, 2.4; 95% CI, 1.18-4.90; p = 0.02) and percent weight change (HR, 0.79; 95% CI, 0.67-0.93; p < 0.01) maintained significance with respect to OS. There were no cases of Grade 3+ esophagitis, and there was a single case of Grade 3 febrile neutropenia. CONCLUSIONS: The strong correlation between weight change during CRT and OS/PFS suggests that this clinical parameter may be useful as a complementary source of predictive information in addition to accepted factors such as pathological response.

Helical tomotherapy delivery of an IMRT boost in lieu of interstitial brachytherapy in the setting of gynecologic malignancy: feasibility and dosimetric comparison.

Interstitial brachytherapy is an important means by which to improve local control in gynecologic malignancy when intracavitary brachytherapy is untenable. Patients unable to receive brachytherapy have traditionally received conventional external beam radiation alone with modest results. We investigated the ability of Tomotherapy (Tomotherapy Inc., Madison, WI) to replace interstitial brachytherapy. Six patients were selected. The planning CT of each patient was contoured with the planning target volume (PTV), bladder, rectum, femoral heads, and bowel. Identical contour sets were exported to Tomotherapy and Nucletron PLATO (Nucletron B.V., Veenendaal, The Netherlands). With Tomotherapy, the PTV was prescribed 31 Gy in 5 fractions to 90% of the volume. With PLATO, 600 cGy × 5 fractions was prescribed to the surface of the PTV. Dose delivered was normalized to 2 Gy fractions (EQD2) and added to a hypothetical homogenous 45-Gy pelvic dose. Tomotherapy achieved a D90 of 87 Gy EQD2 versus 86 Gy with brachytherapy. PTV dose was more homogeneous with tomotherapy. The dose to the most at-risk 2 mL of bladder and rectum with Tomotherapy was of 78 and 71 Gy EQD2 versus 81 and 75 Gy with brachytherapy. Tomotherapy delivered more dose to the femoral heads (mean 1.23 Gy per fraction) and bowel. Tomotherapy was capable of replicating the peripheral dose achieved with brachytherapy, without the PTV hotspots inherent to interstitial brachytherapy. Similar maximum doses to bowel and bladder were achieved with both methods. Excessive small bowel and femoral head toxicity may result if previous pelvic irradiation is not planned accordingly. Significant challenges related to interfraction and intrafraction motion must be overcome if treatment of this nature is to be contemplated.

A dosimetric comparison between the supine and prone positions for three-field intact breast radiotherapy.

PURPOSE: Supine tangential radiotherapy for the intact breast is a standard component of breast conservation management; a supraclavicular (SCV) field can be added for patients at high risk for nodal failure. Treatment in the prone position has demonstrated improvements in lung sparing, but has been limited to early-stage patients in whom radiation to only the breast was indicated. We sought to investigate the dosimetric feasibility of treating women in the prone position, using a 3-field monoisocentric technique. METHODS: A total of 10 patients previously simulated supine and prone were selected for replanning. The heart, ipsilateral breast, contralateral breast, and axillary/SCV lymph node regions were contoured in accordance with Radiation Therapy Oncology Group guidelines. The 3-field monoisocentric plans were created for both the supine and prone scans. Target coverage, homogeneity, and organ at risk sparing were examined. RESULTS: Both plans achieved acceptable coverage of the breast. The mean percentage of the breast receiving at least 95% of the prescription dose (V95%) were similar in the prone and supine positions, 89.3% versus 90.7% (P = 0.29). Mean V95% of the level 3 axilla and SCV were 93.8% versus 97.0% prone versus supine (P = 0.16). The percentage of ipsilateral lung receiving >20 Gy was substantially reduced from 21.2% supine to 9.3% prone (P = 0.001). CONCLUSION: Three-field radiotherapy in the prone position appears to be dosimetrically equivalent to supine treatment with respect to target coverage, but the prone position decreases lung dose.

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.

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.

Intracranial metastatic disease rarely involves the pituitary: retrospective analysis of 935 metastases in 155 patients and review of the literature.

We present a case report of a patient recently treated at our institution for an isolated non-small cell lung cancer metastatic lesion to the sella, report the lack of involvement of the pituitary gland in a large single-institution series of treated intracranial parenchymal metastases, and review the pertinent literature. We reviewed cranial imaging studies (CT and MRI) for 935 metastases in 155 patients treated at our institution over the previous 3 years for intracranial metastatic disease. Special attention was paid to the skull base to document the presence of any metastatic disease involving the pituitary gland, infundibular stalk, sella turcica (including anterior and posterior clinoids), or diaphragm sellae. We found no other involvement of the pituitary gland or other sellar structures by metastatic disease in this series. Intracranial metastatic disease rarely involves the pituitary gland and infundibular stalk parenchyma, suggesting that this structure may be safely omitted from the treatment field during WBRT and prophylactic cranial irradiation (PCI). This treatment approach should reduce the late sequelae of treatment to this critical organ.

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.

Helical tomotherapy and larynx sparing in advanced oropharyngeal carcinoma: a dosimetric study.

Intensity-modulated radiation therapy (IMRT) is gaining acceptance as a standard treatment technique for advanced squamous cell carcinoma (SCC) of the oropharynx. Dose to the uninvolved larynx and surrounding structures can pose a problem in patients with significant neck disease, potentially compromising laryngeal function and quality of life. Tomotherapy may allow greater laryngeal sparing. Seven patients with stage IV SCC of the oropharynx were replanned using Tomotherapy version 3.1. All contours/planning target volumes (PTVs) from the original plans were preserved, with the exception of the larynx, which was drawn to include all soft tissue encompassed by the thyroid/cricoid cartilage. A simultaneous integrated boost technique was used with PTV 1, 2, and 3 receiving 69.96, 59.40, and 54.00 Gy, respectively in 33 fractions. Dosimetry was evaluated via the Pinnacle treatment planning system (TPS). Equivalent uniform dose (EUD) was calculated from the dose volume histogram (DVH) using the general method with "a" = 5.0. Mean larynx dose for all patients was 24.4 Gy. Mean EUD to the larynx was 34.2 Gy. Homogeneity was adequate; average maximum dose was 109.7% of the highest prescription. All other organs at risk (OAR) were adequately spared. Tomotherapy can spare the uninvolved larynx in the setting of advanced SCC of the oropharynx to levels that are similar to or better than those reported with other techniques. Sparing is achieved without compromising target coverage or other OAR sparing. The clinical benefit of this sparing remains to be determined in a prospective study.