Allen Waziri

Phase II Trial of Hypofractionated IMRT With Temozolomide for Patients With Newly Diagnosed Glioblastoma Multiforme

PURPOSEnTo report toxicity and overall survival (OS) in patients with newly diagnosed glioblastoma multiforme (GBM) treated with hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concurrent and adjuvant temozolomide (TMZ).nnnMETHODS AND MATERIALSnPatients with newly diagnosed GBM after biopsy or resection and with adequate performance status and organ or bone marrow function were eligible for this study. Patients received postoperative hypo-IMRT to the surgical cavity and residual tumor seen on T1-weighted brain MRI with a 5-mm margin to a total dose of 60 Gy in 10 fractions (6 Gy/fraction) and to the T2 abnormality on T2-weighted MRI with 5-mm margin to 30 Gy in 10 fractions (3 Gy/fraction). Concurrent TMZ was given at 75 mg/m(2)/day for 28 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m(2)/day for 5 days every 28 days. Toxicities were defined using Common Terminology Criteria for Adverse Events version 3.0.nnnRESULTSnTwenty-four patients were treated, consisting of 14 men, 10 women; a median age of 60.5 years old (range, 27-77 years); and a median Karnofsky performance score of 80 (range, 60-90). All patients received hypo-IMRT and concurrent TMZ according to protocol, except for 2 patients who received only 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles wasxa06.5 (range, 0-14).With a median follow-up of 14.8 months (range, 2.7-34.2 months) for all patients and a minimum follow-up of 20.6 months for living patients, no instances of grade 3xa0or higher nonhematologic toxicity were observed. The median OS was 16.6 months (range, 4.1-35.9 months). Six patients underwent repeated surgery for suspected tumor recurrence; necrosis was found in 50% to 100% of the resected specimens.nnnCONCLUSIONnIn selected GBM patients, 60 Gy hypo-IMRT delivered in 6-Gy fractions over 2xa0weeks with concurrent and adjuvant TMZ is safe. OS in this small cohort of patients was comparable to that treated with current standard of care therapy.

Phase I Trial of Hypofractionated Intensity-Modulated Radiotherapy With Temozolomide Chemotherapy for Patients With Newly Diagnosed Glioblastoma Multiforme

PURPOSEnTo determine the maximal tolerated biologic dose intensification of radiotherapy using fractional dose escalation with temozolomide (TMZ) chemotherapy in patients with newly diagnosed glioblastoma multiforme.nnnMETHODS AND MATERIALSnPatients with newly diagnosed glioblastoma multiforme after biopsy or resection and with adequate performance status, bone marrow, and organ function were eligible. The patients underwent postoperative intensity-modulated radiotherapy (IMRT) with concurrent and adjuvant TMZ. All patients received a total dose of 60 Gy to the surgical cavity and residual tumor, with a 5-mm margin. IMRT biologic dose intensification was achieved by escalating from 3 Gy/fraction (Level 1) to 6 Gy/fraction (Level 4) in 1-Gy increments. Concurrent TMZ was given at 75 mg/m(2)/d for 28 consecutive days. Adjuvant TMZ was given at 150-200 mg/m(2)/d for 5 days every 28 days. Dose-limiting toxicity was defined as any Common Terminology Criteria for Adverse Events, version 3, Grade 3-4 nonhematologic toxicity, excluding Grade 3 fatigue, nausea, and vomiting. A standard 3+3 Phase I design was used.nnnRESULTSnA total of 16 patients were accrued (12 men and 4 women, median age, 69 years; range, 34-84. The median Karnofsky performance status was 80 (range, 60-90). Of the 16 patients, 3 each were treated at Levels 1 and 2, 4 at Level 3, and 6 at Level 4. All patients received IMRT and concurrent TMZ according to the protocol, except for 1 patient, who received 14 days of concurrent TMZ. The median number of adjuvant TMZ cycles was 7.5 (range, 0-12). The median survival was 16.2 months (range, 3-33). One patient experienced vision loss in the left eye 7 months after IMRT. Four patients underwent repeat surgery for suspected tumor recurrence 6-12 months after IMRT; 3 had radionecrosis.nnnCONCLUSIONSnThe maximal tolerated IMRT fraction size was not reached in our study. Our results have shown that 60 Gy IMRT delivered in 6-Gy fractions within 2 weeks with concurrent and adjuvant TMZ is tolerable in selected patients with a T(1)-weighted enhancing tumor <6 cm.

Prospective evaluation of health-related quality of life in patients with glioblastoma multiforme treated on a phase II trial of hypofractionated IMRT with temozolomide

To report health-related quality of life (HRQOL) in glioblastoma (GBM) patients treated on a phase II trial of hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with temozolomide (TMZ). GBM patients received postoperative hypo-IMRT to 60xa0Gy in 10 fractions with TMZ. HRQOL was assessed using the EORTC quality of life questionnaire core-30 and the EORTC brain cancer module, performed at baseline, RT completion, 1 mo post-RT, and every 3 mos thereafter. Changes from baseline were calculated for each specific HRQOL scale. Axa0≥xa010 point change in any HRQOL scale from the mean baseline score was significant. 24 patients were treated. Compliance with HRQOL assessments at baseline, RT completion, and 1, 3, 6, 9, and 12 mos post-RT was 100, 96, 92, 79, 70, 68 and 53xa0%, respectively. Up to 12xa0mos post-RT, no significant changes were seen in global health status, physical functioning, role functioning, emotional functioning, fatigue, nausea, vision, headache or seizure. Significant improvement was seen in insomnia, future uncertainty, motor dysfunction and drowsiness. Significant worsening was observed in cognitive functioning, social functioning, appetite loss and communication deficit. 60xa0Gy hypo-IMRT in 6-Gy fractions with TMZ does not appear to negatively impact overall HRQOL.

Phase I Dose Escalation Trial of Vandetanib With Fractionated Radiosurgery in Patients With Recurrent Malignant Gliomas

PURPOSEnTo determine the maximum tolerated dose (MTD) of vandetanib with fractionated stereotactic radiosurgery (SRS) in patients with recurrent malignant gliomas.nnnMETHODS AND MATERIALSnPatients with a recurrent malignant glioma and T1-enhancing recurrent tumor ≤ 6 cm were eligible. Vandetanib was given orally, once per day, 7 days a week, starting at least 7 days before SRS and continued until a dose-limiting toxicity (DLT) or disease progression. The planned vandetanib daily dose was 100 mg, 200 mg, and 300 mg for the cohorts 1, 2, and 3, respectively, and was escalated using a standard 3+3 design. A total SRS dose of 36 Gy, 12 Gy per fraction, was delivered over 3 consecutive days. The MTD was defined as the dose of vandetanib at which less than 33% of patients developed DLTs, defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 3 as any Grade 3 or greater nonhematologic toxicity and Grade 4 or greater hematologic toxicity.nnnRESULTSnTen patients were treated, 6 on cohort 1 and 4 on cohort 2. Treatment characteristics were: 7 men, 3 women; median age, 40 years (range, 22-72); 7 GBM, 3 anaplastic astrocytoma (AA); median initial radiation (RT) dose, 60 Gy (range, 59.4-70); median interval since initial RT, 14.5 months (range, 7-123); All patients received SRS per protocol. The median follow-up time was 4 months (range, 1-10 months). Median time on vandetanib was 3 months (range 1-11). One of 6 patients in the first cohort developed a DLT of Grade 3 hemothorax while on anticoagulation. The MTD was reached when 2 of the 4 patients enrolled in the second cohort developed DLTs. Six patients had radiographic response, 2 with stable disease.nnnCONCLUSIONnThe MTD of vandetanib, with SRS in recurrent malignant glioma, is 100 mg daily. Further evaluation of safety and efficacy is warranted.

Favorable prognosis in patients with high-grade glioma with radiation necrosis: the University of Colorado reoperation series.

PURPOSEnTo analyze the pathology, outcomes, and prognostic factors in patients with high-grade glioma undergoing reoperation after radiotherapy (RT).nnnMETHODS AND MATERIALSnFifty-one patients with World Health Organization Grade 3-4 glioma underwent reoperation after prior RT. The median dose of prior RT was 60 Gy, and 84% received chemotherapy as part of their initial treatment. Estimation of the percentage of necrosis and recurrent tumor in each reoperation specimen was performed. Pathology was classified as RT necrosis if ≥80% of the specimen was necrotic and as tumor recurrence if ≥20% was tumor. Predictors of survival were analyzed using log-rank comparisons and Cox proportional hazards regression.nnnRESULTSnThe median interval between the completion of RT and reoperation was 6.7 months (range, 1-59 months). Pathologic analysis showed RT necrosis in 27% and recurrence in 73% of cases. Thirteen patients required a reoperation for uncontrolled symptoms. Among them, 1 patient (8%) had pathology showing RT necrosis, and 12 (92%) had tumor recurrence. Median survival after reoperation was longer for patients with RT necrosis (21.8 months vs. 7.0 months, p=0.047). In 7 patients with Grade 4 tumors treated with temozolomide-based chemoradiation with RT necrosis, median survival from diagnosis and reoperation were 30.2 months and 21.8 months, respectively.nnnCONCLUSIONSnPatients with RT necrosis at reoperation have improved survival compared with patients with tumor recurrence. Future efforts to intensify local therapy and increase local tumor control in patients with high-grade glioma seem warranted.

Phase II trial of hypofractionated intensity-modulated radiation therapy combined with temozolomide and bevacizumab for patients with newly diagnosed glioblastoma

Bevacizumab blocks the effects of VEGF and may allow for more aggressive radiotherapy schedules. We evaluated the efficacy and toxicity of hypofractionated intensity-modulated radiation therapy with concurrent and adjuvant temozolomide and bevacizumab in patients with newly diagnosed glioblastoma. Patients with newly diagnosed glioblastoma were treated with hypofractionated intensity modulated radiation therapy to the surgical cavity and residual tumor with a 1xa0cm margin (PTV1) to 60xa0Gy and to the T2 abnormality with a 1xa0cm margin (PTV2) to 30xa0Gy in 10 daily fractions over 2xa0weeks. Concurrent temozolomide (75xa0mg/m2 daily) and bevacizumab (10xa0mg/kg) was administered followed by adjuvant temozolomide (200xa0mg/m2) on a standard 5/28xa0day cycle and bevacizumab (10xa0mg/kg) every 2xa0weeks for 6xa0months. Thirty newly diagnosed patients were treated on study. Median PTV1 volume was 131.1xa0cm3 and the median PTV2 volume was 342.6xa0cm3. Six-month progression-free survival (PFS) was 90xa0%, with median follow-up of 15.9xa0months. The median PFS was 14.3xa0months, with axa0median overall survival (OS) of 16.3xa0months. Grade 4 hematologic toxicity included neutropenia (10xa0%) and thrombocytopenia (17xa0%). Grades 3/4 non-hematologic toxicity included fatigue (13xa0%), wound dehiscence (7xa0%) and stroke, pulmonary embolism and nausea each in 1 patient. Presumed radiation necrosis with clinical decline was seen in 50xa0% of patients, two with autopsy documentation. The study was closed early to accrual due to this finding. This study demonstrated 90xa0% 6-month PFS and OS comparable to historic data in patients receiving standard treatment. Bevacizumab did not prevent radiation necrosis associated with this hypofractionated radiation regimen and large PTV volumes may have contributed to high rates of presumed radiation necrosis.

Arginase I release from activated neutrophils induces peripheral immunosuppression in a murine model of stroke.

Transient suppression of peripheral immunity is a major source of complication for patients suffering from ischemic stroke. The release of Arginase I (ArgI) from activated neutrophils has recently been associated with T-cell dysfunction in a number of pathologies. However, this pathway has not been previously explored in ischemic stroke. Using the murine model of transient middle cerebral artery occlusion, we explored effects of stroke on peripheral T-cell function and evaluated the role of neutrophils and ArgI. Stimulation of splenic T cells from post-stroke animals with anti-CD3/CD28 resulted in decreased proliferation and interferon-γ production when compared with sham-surgery controls. Flow cytometric analysis of intrasplenic leukocytes exposed the presence of a transient population of activated neutrophils that correlated quantitatively with elevated ArgI levels in culture media. In vitro activation of purified resting neutrophils from unmanipulated controls confirmed the capacity for murine neutrophils to release ArgI from preformed granules. We observed decreased expression of the L-arg-sensitive CD3ζ on T cells, consistent with decreased functional activity. Critically, L-arg supplementation restored the functional response of post-stroke T cells to mitogenic stimulation. Together, these data outline a novel mechanism of reversible, neutrophil-mediated peripheral immunosuppression related to ArgI release following ischemic stroke.

Influence of human immune cells on cancer: studies at the University of Colorado

There will be over half a million cancer-related deaths in the United States in 2012, with lung cancer being the leader followed by prostate in men and breast in women. There is estimated to be more than one and a half million new cases of cancer in 2012, making the development of effective therapies a high priority. As tumor immunologists, we are interested in the development of immunotherapies because the immune response offers exquisite specificity and the potential to target tumor cells without harming normal cells. In this review, we highlight the current advances in the field of immunotherapy and the current work being completed by laboratories at University of Colorado School of Medicine in multiple malignancies, including breast cancer, lung cancer, melanoma, thyroid cancer, and glioblastoma. This work focuses on augmenting the anti-tumor response of CD8 T cells in the blood, lymph nodes, and tumors of patients, determining biomarkers for patients who are more likely to respond to immunotherapy, and identifying additional anti-tumor and immunosuppressive cells that influence the overall response to tumors. These collaborative efforts will identify mechanisms to improve immune function, which may elucidate therapeutic targets for clinical trials to improve patient health and survival.

Preoperative Evaluation of Pineal Tumors

The role of the neurosurgeon is critical for initiating preoperative evaluation and care for pineal region tumors. Preoperative evaluation of pineal region tumor can be simplified into a checklist: (1) evaluation for emergent surgical intervention due to symptomatic obstructive hydrocephalus or mass effect; (2) development of a focused differential after acquisition of craniospinal MRI, serum and cerebrospinal fluid oncoprotein levels, and cerebrospinal fluid cytology; and (3) decision on whether a biopsy, surgical resection, or both are necessary. Subsequent biopsy or surgical resection is the first step of tumor management and leads to coordination of consultation with medical and radiation oncology.

Potential Usefulness of Radiosensitizers in Glioblastoma

High-grade glioma continues to impart poor prognosis in spite of maximal treatment. Attempted gross total surgical resection followed by concurrent temozolomide and radiation therapy has become standard of care for glioblastoma. Ongoing clinical efforts have been directed at the further development of radiosensitizing agents that exploit tumor biology to maximize effects of concurrently administered radiation. The current article outlines the scientific rationale for the use of radiosensitizing agents and preliminary results from clinical trials using a variety of these approaches.