Andrew B. Lassman

Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

PATTERNS OF RELAPSE AND PROGNOSIS AFTER BEVACIZUMAB FAILURE IN RECURRENT GLIOBLASTOMA

Background: Bevacizumab has recently been approved by the US Food and Drug Administration for recurrent glioblastoma (GBM). However, patterns of relapse, prognosis, and outcome of further therapy after bevacizumab failure have not been studied systematically. Methods: We identified patients at Memorial Sloan-Kettering Cancer Center with recurrent GBM who discontinued bevacizumab because of progressive disease. Results: There were 37 patients (26 men with a median age of 54 years). The most common therapies administered concurrently with bevacizumab were irinotecan (43%) and hypofractionated reirradiation (38%). The median overall survival (OS) after progressive disease on bevacizumab was 4.5 months; 34 patients died. At the time bevacizumab was discontinued for tumor progression, 17 patients (46%) had an increase in the size of enhancement at the initial site of disease (local recurrence), 6 (16%) had a new enhancing lesion outside of the initial site of disease (multifocal), and 13 (35%) had progression of predominantly nonenhancing tumor. Factors associated with shorter OS after discontinuing bevacizumab were lower performance status and nonenhancing pattern of recurrence. Additional salvage chemotherapy after bevacizumab failure was given to 19 patients. The median progression-free survival (PFS) among these 19 patients was 2 months, the median OS was 5.2 months, and the 6-month PFS rate was 0%. Conclusions: Contrast enhanced MRI does not adequately assess disease status during bevacizumab therapy for recurrent glioblastoma (GBM). A nonenhancing tumor pattern of progression is common after treatment with bevacizumab for GBM and is correlated with worse survival. Treatments after bevacizumab failure provide only transient tumor control.

Molecular study of malignant gliomas treated with epidermal growth factor receptor inhibitors : Tissue analysis from north american brain tumor consortium trials 01-03 and 00-01

Purpose: We investigated the molecular effect of the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib in vivo on all available tumors from patients treated on North American Brain Tumor Consortium trials 01-03 and 00-01 for recurrent or progressive malignant glioma. Experimental Design: EGFR expression and signaling during treatment with erlotinib or gefitinib were analyzed by Western blot and compared with pre–erlotinib/gefitinib–exposed tissue or unexposed controls. Tumors were also analyzed for EGFR mutations and for other genomic abnormalities by array-based comparative genomic hybridization. Clinical data were used to associate molecular features with tumor sensitivity to erlotinib or gefitinib. Results: Erlotinib and gefitinib did not markedly affect EGFR activity in vivo. No lung signature mutations of EGFR exons 18 to 21 were observed. There was no clear association between erlotinib/gefitinib sensitivity and deletion or amplification events on array-based comparative genomic hybridization analysis, although novel genomic changes were identified. Conclusions: As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects. Additionally, the mechanism of erlotinib/gefitinib sensitivity likely differs between brain and lung tumors. Finally, novel genomic changes, including deletions of chromosomes 6, 21, and 22, represent new targets for further research.

A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy

Patients with (a) recurrent malignant glioma (MG): glioblastoma (GBM) or recurrent anaplastic glioma (AG), and (b) nonprogressive (NP) GBM following radiation therapy (RT) were eligible. Primary objective for recurrent MG was progression-free survival at 6 months (PFS-6) and overall survival at 12 months for NP GBM post-RT. Secondary objectives for recurrent MGs were response, survival, assessment of toxicity, and pharmacokinetics (PKs). Treatment with enzyme-inducing antiepileptic drugs was not allowed. Patients received 150 mg/day erlotinib. Patients requiring surgery were treated 7 days prior to tumor removal for PK analysis and effects of erlotinib on epidermal growth factor receptor (EGFR) and intracellular signaling pathways. Ninety-six patients were evaluable (53 recurrent MG and 43 NP GBM); 5 patients were not evaluable for response. PFS-6 in recurrent GBM was 3% with a median PFS of 2 months; PFS-6 in recurrent AG was 27% with a median PFS of 2 months. Twelve-month survival was 57% in NP GBMs post-RT. Primary toxicity was dermatologic. The tissue-to-plasma ratio normalized to nanograms per gram dry weight for erlotinib and OSI-420 ranged from 25% to 44% and 30% to 59%, respectively, for pretreated surgical patients. No effect on EGFR or intratumoral signaling was seen. Patients with NP GBM post-RT who developed rash in cycle 1 had improved survival (P < .001). Single-agent activity of erlotinib is minimal for recurrent MGs and marginally beneficial following RT for NP GBM patients. Development of rash in cycle 1 correlates with survival in patients with NP GBM after RT.

Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors.

UNLABELLED Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types. SIGNIFICANCE Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.

Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study

PURPOSE Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma. PATIENTS AND METHODS Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse. Aflibercept 4 mg/kg was administered intravenously on day 1 of every 2-week cycle. RESULTS The 6-month progression-free survival rate was 7.7% for the glioblastoma cohort and 25% for patients with anaplastic glioma. Overall radiographic response rate was 24% (18% for glioblastoma and 44% for anaplastic glioma). The median progression-free survival was 24 weeks for patients with anaplastic glioma (95% CI, 5 to 31 weeks) and 12 weeks for patients with glioblastoma (95% CI, 8 to 16 weeks). A total of 14 patients (25%) were removed from the study for toxicity, on average less than 2 months from treatment initiation. The main treatment-related National Cancer Institute Common Terminology Criteria grades 3 and 4 adverse events (38 total) included fatigue, hypertension, and lymphopenia. Two grade 4 CNS ischemias and one grade 4 systemic hemorrhage were reported. Aflibercept rapidly decreases permeability on dynamic contrast enhanced magnetic resonance imaging, and molecular analysis of baseline tumor tissue identified tumor-associated markers of response and resistance. CONCLUSION Aflibercept monotherapy has moderate toxicity and minimal evidence of single-agent activity in unselected patients with recurrent malignant glioma.

A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM)

Twenty-two patients with recurrent glioblastoma (GBM) were prospectively treated with everolimus and gefitinib, designed to test the combined inhibition of mammalian target of rapamycin (mTOR) and epidermal growth factor receptor (EGFR) as part of a larger clinical trial. The primary endpoint was radiographic response rate. Secondary endpoints included progression-free survival and correlation of molecular profiles with treatment response. 36% of patients had stable disease and 14% a partial response; however, responses were not durable and only one patient was progression-free at six months. Radiographic changes were not well characterized by conventional response criteria, and implied differential effects of therapy within the tumor and/or antiangiogenic effects. EGFR and PTEN status did not clearly predict response to treatment.

Randomized Phase II Trial of Chemoradiotherapy Followed by Either Dose-Dense or Metronomic Temozolomide for Newly Diagnosed Glioblastoma

PURPOSE Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM. PATIENTS AND METHODS Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m(2) days 1 to 7 and 15 to 21) or metronomic (50 mg/m(2) continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. RESULTS Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm). CONCLUSION Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.

Survey of treatment recommendations for anaplastic oligodendroglioma

Anaplastic oligodendroglioma is a malignant brain tumor uniquely sensitive to treatment with both chemotherapy and radiotherapy. There are few prospective clinical trials for newly diagnosed patients and multiple approaches to the treatment of these patients. This study explored the recommended treatment offered by experts in neuro-oncology. A Web-based survey was developed and distributed to 800 members of the Society of Neuro-Oncology (SNO) who had an e-mail address listed with SNO. Questions addressed use of molecular genetic information and treatment recommendations. A total of 99 clinical SNO members (20%) responded. The majority reported practicing at an academic center in the United States. Two-thirds of respondents see more than five patients with newly diagnosed anaplastic oligodendroglioma annually. Molecular genetic testing was requested for more than 75% of patients, and the results significantly influenced treatment recommendations (p = 0.000003). Regardless of molecular genetic status, the most commonly recommended treatment was the use of concurrent temozolomide and radiotherapy followed by adjuvant temozolomide (18%-34%). The current survey demonstrates that although neuro-oncologists have embraced the use of molecular genetic studies in newly diagnosed anaplastic oligodendroglioma, treatment recommendations vary widely and are often independent of the molecular data.

International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors

Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion. We retrospectively identified 1013 adults diagnosed from 1981-2007 treated initially with RT alone (n = 200), CT + RT (n = 528), CT alone (n = 201), or other strategies (n = 84). Median overall survival (OS) was 6.3 years and time to progression (TTP) was 3.1 years. 1p19q codeletion correlated with longer OS and TTP than no 1p or 19q deletion. In codeleted cases, median TTP was longer following CT + RT (7.2 y) than following CT (3.9 y, P = .003) or RT (2.5 y, P < .001) alone but without improved OS; median TTP was longer following treatment with PCV alone than temozolomide alone (7.6 vs. 3.3 y, P = .019). In cases with no deletion, median TTP was longer following CT + RT (3.1 y) than CT (0.9 y, P = .0124) or RT (1.1 y, P < .0001) alone; OS also favored CT + RT (median 5.0 y) over CT (2.2 y, P = .02) or RT (1.9 y, P < .0001) alone. In codeleted cases, CT alone did not appear to shorten OS in comparison with CT + RT, and PCV appeared to offer longer disease control than temozolomide but without a clear survival advantage. Combined CT + RT led to longer disease control and survival than did CT or RT alone in cases with no 1p19q deletion. Ongoing trials will address these issues prospectively.