Faculty Bibliography

High-grade gliomas (HGGs) represent a heterogenous group of tumors and account for most primary brain tumors. Despite aggressive therapies, they are invariably associated with poor patient outcome. These tumors include the anaplastic (World Health Organization [WHO] grade III) histologies of astrocytomas, oligodendrogliomas, and ependymomas and the WHO grade IV glioblastoma multiforme (GBM). The recent elucidation of the fundamental molecular alterations associated with these tumors has begun to unravel the critical events in their tumorigenesis but for the most part has done little to alter patient survival. Prognostication for patients with these tumors has relied principally on tumor grade and clinical factors (age, performance status, and so on) and has been inexact at best in identifying those with long-term survival potential. An even greater challenge has been to identify predictive biomarkers of therapy in the hope of tailoring a patient's therapy based on their tumor's molecular characteristics. This review discusses the molecular pathology of high-grade gliomas, with particular emphasis on anaplastic astrocytomas and GBMs because these represent the most common forms of malignant gliomas. It also focuses on the molecular signatures defined by large-scale gene expression profiling experiments because these studies are at the forefront in developing new biomarkers and identifying new therapeutic targets.

PURPOSE/OBJECTIVE:Institutional and cooperative group experience has demonstrated the feasibility of reirradiation for head and neck cancer. Limited data are available regarding the use of intensity-modulated radiotherapy (IMRT) for this indication. We reviewed our initial experience using IMRT for previously irradiated head and neck cancer patients. METHODS AND MATERIALS/METHODS:Records of 78 consecutive patients reirradiated with IMRT for head and neck cancer between 1999 and 2004 were reviewed; 74 cases were analyzed. Reirradiation was defined as any overlap between original and new radiation treatment volumes regardless of the time interval between initial and subsequent treatment. Severe reirradiation-related toxicity was defined as toxic events resulting in hospitalization, corrective surgery, or patient death. Longitudinal estimates of survival were calculated by Kaplan-Meier technique. RESULTS:Twenty (27%) patients underwent salvage surgical resection and 36 (49%) patients received chemotherapy. Median follow-up from reirradiation was 25 months. Median time interval between initial radiation and reirradiation was 46 months. Median reirradiation dose was 60 Gy. Median lifetime radiation dose was 116.1 Gy. The 2-year overall survival and locoregional control rates were 58% and 64%, respectively. Severe reirradiation related toxicity occurred in 15 patients (20%); one treatment-related death was observed. CONCLUSIONS:The use of IMRT for reirradiation of recurrent or second primary head and neck cancers resulted in encouraging local control and survival. Reirradiation-related morbidity was significant, but may be less severe than previously published reports using conventional techniques.

BACKGROUND:Controversy still exists regarding the long-term outcome of patients whose uninvolved lymph node stations are not prophylactically irradiated for non-small cell lung cancer (NSCLC) treated with definitive radiotherapy. To determine the frequency of elective nodal failure (ENF) and in-field failure (IFF), we examined a large cohort of patients with NSCLC staged with positron emission tomography (PET)/computed tomography (CT) and treated with 3-dimensional conformal radiotherapy (3D-CRT) that excluded uninvolved lymph node stations. METHODS:We retrospectively reviewed the records of 115 patients with non-small cell lung cancer treated at our institution with definitive radiation therapy with or without concurrent chemotherapy (CHT). All patients were treated with 3D-CRT, including nodal regions determined by CT or PET to be disease involved. Concurrent platinum-based CHT was administered for locally advanced disease. Patients were analyzed in follow-up for survival, local regional recurrence, and distant metastases (DM). RESULTS:The median follow-up time was 18 months (3 to 44 months) among all patients and 27 months (6 to 44 months) among survivors. The median overall survival, 2-year actuarial overall survival and disease-free survival were 19 months, 38%, and 28%, respectively. The majority of patients died from DM, the overall rate of which was 36%. Of the 31 patients with local regional failure, 26 (22.6%) had IFF, 5 (4.3%) had ENF and 2 (1.7%) had isolated ENF. For 88 patients with stage IIIA/B, the frequencies of IFF, any ENF, isolated ENF, and DM were 23 (26%), 3 (9%), 1 (1.1%) and 36 (40.9%), respectively. The comparable rates for the 22 patients with early stage node-negative disease (stage IA/IB) were 3 (13.6%), 1(4.5%), 0 (0%), and 5 (22.7%), respectively. CONCLUSION/CONCLUSIONS:We observed only a 4.3% recurrence of any ENF and a 1.7% recurrence of isolated ENF in patients with NSCLC treated with definitive 3D-CRT without prophylactic irradiation of uninvolved lymph node stations. Thus, distant metastasis and IFF remain the primary causes of treatment failure and cancer death in such patients, suggesting little value of ENI in this cohort.

INTRODUCTION/BACKGROUND:The lineages assumed by stem cells during hematopoiesis can be identified by the pattern of protein markers present on the surface of cells at different stages of differentiation. Specific antibodies directed at these markers have facilitated the isolation of hematopoietic stem cells by flow cytometry. DISCUSSION/CONCLUSIONS:Similarly, stem cells in solid organs also can be identified using cell surface markers. In addition, solid tumors have recently been found to contain small proportions of cells that are capable of proliferation, self-renewal, and differentiation into the various cell types seen in the bulk tumor. Of particular concern, these tumor-initiating cells (termed cancer stem cells when multipotency and self-renewal have been demonstrated) often display characteristics of treatment resistance, particularly to ionizing radiation. Thus, it is important to be able to identify these cells in order to better understand the mechanisms of resistance, and to be able to predict outcome and response to treatment. This depends, of course, on identifying markers that can be used to identify the cells, and for some solid tumors, a specific pattern of cell surface markers is emerging. In breast cancer, for example, the tumor-initiating cells have a characteristic Lin(-)CD44(+)CD24(-/lo) ESA(+) antigenic pattern. In cells derived from some high-grade gliomas, expression of CD133 on the cell surface appears to select for a population of tumor-initiating, treatment resistant cells. CONCLUSION/CONCLUSIONS:Because multiple markers, typically examined on single cells using flow cytometry, are used routinely to identify the subpopulation of tumor-initiating cells, and because the number of these cells is small, the challenge remains to detect them in clinical samples and to determine their ability to predict outcome and/or response to treatment, the hallmarks of established biomarkers.

PURPOSE/OBJECTIVE:Dosimetric studies suggested several advantages to defining the radiotherapy target by using positron-emission tomography (PET)/computed tomography (CT) compared with CT alone. We investigated patterns of treatment failure in patients treated to a PET-defined radiotherapy target and evaluated the effect of standardized uptake value (SUV) on recurrence after radiotherapy. METHODS AND MATERIALS/METHODS:Thirty-five patients with non-small-cell lung cancer who underwent PET/CT simulation for definitive radiotherapy were included. The PET/CT scans were obtained with patients in the treatment position with custom immobilization for use in radiation treatment planning. Nine to 11 regions of interest (ROIs) were identified for each patient, including the primary tumor and regional nodes. Maximum SUV, volume, and mean dose received were recorded for each ROI, and follow-up scans were used to evaluate for recurrence in each ROI. RESULTS:We identified 353 ROIs from 35 patients; 5.7% of patients developed isolated out-of-field recurrences. Recursive partitioning analysis was used to divide ROIs into low, intermediate, and high risk by using volume and SUV. All low-risk ROIs with volumes less than 1.2 cm3 were recurrence free compared with 73% of intermediate-risk ROIs (volume >or=1.2 cm3; SUV <or=13.8) and 29% of high-risk ROIs (SUV > 13.8). CONCLUSION/CONCLUSIONS:Limiting the target volume to predominantly PET-positive disease resulted in a low rate of isolated out-of-field recurrences. The SUV and volume were predictors of recurrence. Recursive partitioning analysis identified SUVs greater than 13.8 as the best identifier of ROIs at the greatest risk of recurrence; control rates for this subgroup did not show a dose-response relationship within the range of doses administered.

PURPOSE/OBJECTIVE:The clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression in glioblastoma multiforme (GBM) and its relationship with other key molecular markers are not clear. We sought to evaluate the clinical significance of GBM subtypes as defined by EGFRvIII status. PATIENTS AND METHODS/METHODS:The expression of EGFRvIII was assessed by immunohistochemistry in 649 patients with newly diagnosed GBM. These data were then examined in conjunction with the expression of phospho-intermediates (in a subset of these patients) of downstream AKT and Ras pathways and YKL-40 as well as with known clinical risk factors, including the Radiation Therapy Oncology Group's recursive partitioning analysis (RTOG-RPA) class. RESULTS:The RTOG-RPA class was highly predictive of survival in EGFRvIII-negative patients but much less predictive in EGFRvIII-positive patients. These findings were seen in both an initial test set (n = 268) and a larger validation set (n = 381). Similarly, activation of the AKT/MAPK pathways and YKL-40 positivity were predictive of poor outcome in EGFRvIII-negative patients but not in EGFRvIII-positive patients. Pair-wise combinations of markers identified EGFRvIII and YKL-40 as prognostically important. In particular, outcome in patients with EGFRvIII-negative/YKL-40-negative tumors was significantly better than the outcome in patients with the other three combinations of these two markers. CONCLUSION/CONCLUSIONS:Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.