Macdonald Criteria Research Articles

Pseudoprogression and Pseudoresponse: Imaging Challenges in the Assessment of Posttreatment Glioma

The current standard of care for newly diagnosed cases of high-grade glioma is surgical resection followed by RT with concurrent chemotherapy. The most widely used criteria for assessing treatment response are based on a 2D measurement of the enhancing area on MR imaging known as the Macdonald Criteria. Recently, nontumoral increases (pseudoprogression) and decreases (pseudoresponse) in enhancement have been found, and these can confuse outcome evaluation. Here we review pseudoprogression and pseudoresponse and describe how better understanding of these phenomena can aid interpretation.

Irinotecan and bevacizumab in recurrent glioblastoma multiforme

Introduction: Glioblastoma multiforme (GBM) is the most common high grade primary brain tumor in adults. Despite significant advances in treatment, the prognosis remains poor. Bevacizumab (BVZ) and irinotecan (CPT-11) are currently being investigated in the treatment of GBM patients. Although treatment with BVZ and irinotecan provides impressive response rates (RR), it is still uncertain if this treatment translates into improved clinical benefit in GBM patients.Areas covered: This review discusses the clinical efficacy, safety and difficulties regarding response evaluation when treating with BVZ and CPT-11 in recurrent GBM. Particular attention is placed on the literature and a discussion on whether treatment with BVZ and CPT-11 improves clinical outcome. Antiangiogenic treatment has led to difficulties when evaluating objective response by the conventional MacDonald criteria. In the present paper the authors discuss selected key aspects of this treatment modality. A literature search was performed using PubMed in February 2011.Expert opinion: BVZ + irinotecan leads to high RR and to an increased 6-month progression-free survival. However, no improvement in median overall survival has been observed compared with conventional chemotherapy. Nevertheless, the GBM patients who respond to treatment with BVZ and irinotecan have survived significantly longer than non-responders, indicating that it could be beneficial for a selection of patients to receive this treatment.

A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma

This phase II study evaluated the efficacy and safety of AMG 102 (rilotumumab), a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in patients with recurrent glioblastoma (GBM). Patients with histologically confirmed, measurable recurrent GBM or gliosarcoma (World Health Organization grade 4) and ≤3 relapses or prior systemic therapies received AMG 102 (10 or 20 mg/kg) by infusion every 2 weeks. The primary endpoint was best confirmed objective response rate (central assessment) per Macdonald criteria. Of the 61 patients who enrolled, 60 received AMG 102. Twenty-nine patients (48%) had previously received bevacizumab. There were no objective responses per central assessment, but 1 patient had an objective response per investigator assessment. Median overall survival (95% CI) in the 10- and 20-mg/kg cohorts was 6.5 months (4.1-9.8) and 5.4 months (3.4-11.4), respectively, and progression-free survival (PFS) per central assessment was 4.1 weeks (4.0-4.1) and 4.3 weeks (4.1-8.1), respectively. PFS was similar among patients who had previously received bevacizumab compared with bevacizumab-naive patients. The most common adverse events were fatigue (38%), headache (33%), and peripheral edema (23%). AMG 102 serum concentrations increased approximately dose-proportionally with 2-fold accumulation at steady state. Plasma total HGF/SF and soluble c-Met concentrations increased 12.05- and 1.12-fold, respectively, from baseline during AMG 102 treatment. AMG 102 monotherapy at doses up to 20 mg/kg was not associated with significant antitumor activity in heavily pretreated patients with recurrent GBM.

Response Assessment in Neuro-Oncology

Accuracy and reproducibility in determining response to therapy and tumor progression can be difficult to achieve for nervous system tumors. Current response criteria vary depending on the pathology and have several limitations. Until recently, the most widely used criteria for gliomas were "Macdonald criteria," based on two-dimensional tumor measurements on neuroimaging studies. However, the Response Assessment in Neuro-Oncology (RANO) Working Group has published new recommendations in high-grade gliomas and is working on recommendations for other nervous system tumors. This article reviews current response criteria for high-grade glioma, low-grade glioma, brain metastasis, meningioma, and schwannoma.

Glioblastoma multiforme of the elderly: the prognostic effect of resection on survival

According to recent developments the best treatment options for glioblastoma (GBM) consist in maximum safe resection and additional adjuvant treatment with radiotherapy (RT) and alkylating chemotherapy (CHX). These options have been evaluated for populations with a median age of approximately 58 years. We therefore addressed the issue of whether elderly patients (>65 years) could also benefit from cytoreductive surgery (CS) and adjuvant treatment using alkylating chemotherapy. One-hundred and three patients suffering from newly diagnosed, primary supratentorial glioblastoma multiforme >65 years (median 70.8 years) were identified in our single-center glioma database (2002-2007) and retrospectively divided into group A (n = 31) treated with surgery alone (biopsy, BY, n = 21, CS n = 10), group B (n = 37) surgery plus radiation (BY n = 18, CS n = 19), and group C (n = 35) surgery, RT and CHX (BY n = 4, CS n = 31). Progression-free survival (PFS) and overall survival (OAS) were determined in each group and correlated to age, Karnofsky performance score (KPS), and extent of resection (biopsy (BY), partial (PR), and complete resection (CR)). Progression was defined according the Macdonald criteria. For all patients PFS and OAS were 3.2 months and 5.1 months (m) respectively. PFS and OAS for groups A/B/C were 1.8/3.2/6.4 m (P = 0.000) and 2.2/4.4/15.0 m (P = 0.000), respectively. Median age for groups A/B/C was 74.4/70.6/68.5 years and median KPS was 60/70/80. Age (<75, ≥75) was inversely correlated with OAS (5.8/2.5 m, P = 0.01). KPS (<70, ≥70) was correlated with OAS 2.4/6.5 m (P = 0.000). Extent of resection (BY, PR, or CR) correlated with PFS (2.1/3.4/6.4 m, P = 0,000) and OS (2.2/7.0/13.9 m, P = 0,000), respectively. Our study shows that elderly GBM patients can benefit from maximum treatment procedures with cytoreductive microsurgery, radiation therapy, and chemotherapy. Treatment options are obviously affected by KPS and age. The most impressive outcome predictor in this population was the extent of microsurgical resection for patients treated with adjuvant radiotherapy and chemotherapy. To conclude, elderly GBM patients should not be per se excluded from intensive treatment procedures.

Chemotherapy for low-grade gliomas: When? How? How long?

Low-grade gliomas have remained among the most controversial brain tumors, in many ways, for decades. Their spontaneous behavior, as well as their response to therapy, is difficult to predict, and their outcome is highly variable. Standards of care are difficult to define for these tumors: subpopulations of patients certainly benefit from surgery, and radiotherapy prolongs progression-free survival, as may alkylating-agent chemotherapy. For all therapeutic interventions, timing is also a controversial issue. In this issue of Neuro-Oncology, Peyre and colleagues (1) report on the retrospectively determined time course of radiological responses to procarbazine + CCNU + vincristine (PCV) polychemotherapy in a series of 21 patients with low-grade gliomas, predominantly oligodendroglial, who had not previously been treated with radiotherapy or other chemotherapy. Six cycles of PCV were intended to be given. Unexpectedly, the median tumor diameters of all patients decreased during PCV therapy; more surprisingly, they continued to decrease in 20 of the 21 cases for a median duration of 2.7 years after cessation of PCV therapy (1). According to their modified Macdonald criteria (2), the rates of partial and minor responses were 5% and 38% at the end of PCV therapy but 38% and 42% at the time of maximal mean tumor diameter decrease, which occurred a median of 3.4 years after PCV therapy onset. While it is well recognized that response assessment in patients with low-grade gliomas is challenging (3), the authors are to be commended for carefully assessing imaging changes over a fairly long follow-up. Nevertheless, it is almost astonishing that all of their 21 patients showed a reduction of mean tumor diameter after PCV therapy. No data for a control group of patients treated with radiotherapy were presented. This would have helped to weigh these data against the suggested benefit from PCV therapy that may not correspond to everybody's clinical experience with this regimen. Admittedly, of 21 patients, 15 had oligodendrogliomas, and 4 had oligoastrocytomas. That tumor sizes in general may continue to shrink after the completion of a cytotoxic or more likely genotoxic stimulus is clinically recognized in irradiated tumors; it is often assumed that vasoocclusive, antiangiogenic effects are involved. Alternatively, Peyre et al. (1) propose that an altered balance between spontaneous cell death and proliferation might account for the delayed responses. If this occurs with radiotherapy, why should it not occur after delivery of a genotoxic signal via chemotherapy? Maybe this has just never been evaluated. Yet a related group of authors from France previously analyzed a similar group of low-grade glioma patients who were treated with temozolomide (4). The dynamics of tumor growth were quite different: although 92% of tumors responded initially, responses were often short-lasting despite continued treatment, and many tumors resumed growth early after the cessation of temozolomide. Importantly, the authors acknowledge the differential safety and tolerability of temozolomide versus PCV and refrain from treatment recommendations in favor of PCV on the basis of this small but impressive set of data.

Evaluation des ADC-Mappings als Prädiktor für ein Ansprechen von Glioblastomrezidiven auf eine Therapie mit Avastin

The assessment of the radiological response of recurrent glioma is based on the Macdonald or RECIST criteria 8 to 10 weeks from the start of treatment. Magnetic resonance imaging using an apparent diffusion coefficient map may provide an earlier measure for predicting the response to therapy of recurrent glioma. Twelve patients with recurrent high-grade glioma were enrolled in a feasibility study of pretreatment MRI on day 1, intra-treatment MRI in week 3, and post-treatment MRI in week 12. Prognostically relevant ADC values (ADCprog) of each recurrent glioma at 3 weeks were calculated as a function of their pre- and intra-therapy ADC values (ADCpre - ADCintra = ADCprog). Because we hypothesized that smaller ADC values correlate with less Brownian motion of water molecules in the extracellular space and that a higher cell density may restrain this water diffusion, we set smaller ADC values at a second time point as "progressive disease" (PD) and higher ADC values as "partial response" (PR). A change in ADCprog of less than 10 × 10⁻⁶mm² /sec was set as "stable disease" (SD). The ADCprog values were always calculated before the final scan after 3 months was performed. The readers were blinded to the future development of the tumor. In 10 of the 12 patients we could correctly predict the tumor response to chemotherapy. One patient died before the three-month control, and one recurrent glioma did not develop as predicted. ADC mapping is found to predict patient response at 3 weeks from the start of treatment, revealing that early changes in tumor diffusion values could be used as a prognostic indicator also for chemotherapeutically treated recurrences of high-grade glioma.

A new schedule of fotemustine in temozolomide-pretreated patients with relapsing glioblastoma

In the present study we investigated the feasibility and effectiveness of a new biweekly schedule of fotemustine (FTM) in patients with recurrent glioblastoma, after at least one previous treatment. The primary endpoint was progression-free survival at 6 months; secondary objectives were clinical response, overall survival, disease-free survival, and toxicity. Forty patients (median age 52.8 years; median Karnofsky Performance Status at progression 90) underwent second-line chemotherapy with FTM. Selected patients were previously treated with a standard radiotherapy course with concomitant temozolomide (TMZ). After tumor relapse or progression proven by magnetic resonance imaging (MRI), all patients underwent chemotherapy with FTM, given intravenously at dose of 80 mg/m2 every 2 weeks for five consecutive administrations (induction phase), and then every 3 weeks at 100 mg/m2 as maintenance. A total of 329 infusions were administered; the median number of cycles administered was 8. All patients completed the induction phase, and 29 patients received at least one maintenance infusion. Response to treatment was assessed using MacDonald criteria. One complete response [2.5%, 95% confidence interval (CI): 0–10%], 9 partial responses (22.5%, 95% CI: 15–37%), and 16 stable diseases (40%, 95% CI: 32–51%) were observed. Median time to progression was 6.7 months (95% CI: 3.9–9.1 months). Progression-free survival at 6 months was 61%. Median survival from beginning of FTM chemotherapy was 11.1 months. The schedule was generally well tolerated; the main toxicities were hematologic (grade 3 thrombocytopenia in two cases). To the best of our knowledge, this is the first report specifically dealing with the use of a biweekly induction schedule of FTM. The study demonstrates that FTM has therapeutic efficacy as single-drug second-line chemotherapy with a favorable safety profile.

Changes in Relative Cerebral Blood Volume 1 Month after Radiation-Temozolomide Therapy Can Help Predict Overall Survival in Patients with Glioblastoma

To evaluate perfusion parameter changes in patients with glioblastoma multiforme by comparing the perfusion magnetic resonance (MR) imaging measurements obtained before combined radiation and temozolomide therapy (RT-TMZ) with the follow-up MR imaging measurements obtained 1 month after completion of this treatment. Institutional review board approval was obtained, and HIPAA guidelines were followed. The data of 36 patients (24 male [median age, 63 years]; 12 female [median age, 59 years]) with glioblastoma multiforme who were treated with RT-TMZ were retrospectively reviewed. The hypothesis was that a change in relative cerebral blood volume (rCBV) 1 month after RT-TMZ is predictive of overall survival. Linear regression analysis was performed to correlate changes in tumor size and perfusion parameters with overall survival. Receiver operating characteristic (ROC) curves were evaluated for 1-year survival. Overall survival was assessed with Kaplan-Meir survival curves and log-rank testing. Percentage change in rCBV at 1 month after RT-TMZ correlated with overall survival. Increased rCBV after treatment was a strong predictor of poor survival (median survival, 235 days versus 529 days with decreased rCBV) (P < .008, log-rank test). The ROC curves for 1-year survival showed a greater area under the curve (0.806; 95% confidence interval [CI]: 0.698, 0.970) (P = .005) with rCBV than with tumor size (0.556; 95% CI: 0.342, 0.729) (P = .382). The overall survival for patients with increased tumor size, based on Macdonald criteria, was shorter than that for patients who showed no progression (stable or partial response), but the difference was not significant (median survival, 442 days versus 598 days) (P = .761, log-rank test). Change in rCBV after RT-TMZ appears to correlate with overall survival.

Efficacy and safety of bevacizumab plus irinotecan in patients with recurrent malignant poor-prognosis glioma.

e12555 Background: There is currently no standard of care for recurrent glioblastoma multiforme (GBM), although the anti-VEGF monoclonal antibody bevacizumab (Bev) has shown efficacy in conjunction with irinotecan (Iri). We present a retrospective analysis of patients with recurrent malignant brain tumors treated with Bev-Iri at our clinic. Methods: 37 adult patients with recurrent malignant brain tumors were included. Patient characteristics: median age 46 years, GBM diagnosis n = 26, other brain tumor histology n = 11. Prior surgery n = 34, prior chemotherapy n = 37, prior radiotherapy n = 32. Patients received Bev 10 mg/kg i.v. and Iri 125 mg/m2 i.v. (340 mg/m2 in one patient receiving enzyme-inducing antiepileptic drugs) every 14 days. Treatment was stopped on progression, patient's wish or physician's decision. Response was assessed using MacDonald's criteria on post-contrast MRI with inclusion of FLAIR, T2 and perfusion-weighted MRI. Adverse events (AEs) were monitored throughout therapy. Results: Patients received a median of 7 cycles of Bev-Iri (range 3–15) and 8 patients received maintenance Bev until progression. 26 patients (70%) achieved a complete or partial response with Bev-Iri, and 4 (11%) had stable disease. Median time to progression was 5.8 months (range 1.4–not reached) and median overall survival was 11.1 months (range 2.7–not reached) without difference between GBM patients and the group with other types of malignant brain tumors. The bevacizumab/irinotecan combination was well tolerated, with few grade 3 AEs (8 lymphocytopenia, 2 leucocytopenia, 1 diarrhea); there were no AEs of grade > 3. The most common grade 1–2 AEs were leucocytopenia (n = 7), hypertension (n = 5) and lymphocytopenia (n = 4). Conclusions: Our data show that bevacizumab plus irinotecan is an effective combination for recurrent malignant brain tumors and correspond with Phase II data for this strategy. The median overall survival of over 11 months in our study represents a considerable improvement in prognosis for these patients and warrants a larger, more thorough prospective exploration of this combination. The potential for bevacizumab-containing maintenance regimens also exists. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche

Use of FLAIR MRI in determining glioblastoma response to cediranib.

2063 Background: Due to an ability to reverse blood-brain barrier permeability, antiangiogenic agents lead to a decrease in contrast enhancement (CE). In a subset of patients, tumors may grow by co-opting blood vessels with an intact BBB and appear as an increase in FLAIR signal without corresponding increase in CE. The neuro-oncology community has proposed new radiographic response criteria (RANO criteria) that incorporate change in FLAIR signal into the older, CE-based Macdonald criteria. Methods: We evaluated MRI scans from 30 patients who participated in a trial of cediranib for recurrent glioblastoma and compared responses based on RANO and Macdonald criteria. Patients underwent MRI scans at day -5, -1, 1, 28, 56, 112, and 168 of treatment. Both volumetric and area measurements of abnormal FLAIR hyperintensity and CE were recorded for each MRI and response was determined as PD ≥ 25% increase, MR 25%-50% shrinkage, PR ≥ 50% shrinkage, SD all else. Results: Using volumetric analysis, 11 patients would have been taken off study based on increase in FLAIR prior to PD on CET1. Three of these patients showed a decrease in FLAIR on the next scan that no longer met PD criteria. In 13 patients, changes in FLAIR and CET1 paralleled each other (both PR/MR/SD or both PD). Six patients had PD on CET1 with stable or decreasing FLAIR. For area measurements, 8 patients would have been taken off study based on an increase in FLAIR prior to PD on CET1 (3 with subsequent decrease that no longer met criteria for PD). In 16 patients changes in FLAIR and CET1 paralleled each other and 6 patients had an increase in CE that preceded any increase in FLAIR. Determination of progression was influenced by whether or not the pretreatment or the nadir scan was used for comparison with PD occurring earlier if the nadir scan was used. Conclusions: RANO criteria incorporate a significant change in FLAIR but do not define significant. Based on cut-offs used for CE changes, we found that using FLAIR would change response rate in our study and lead to termination of study drug in several patients. The variability in measuring FLAIR volume presents a challenge to using FLAIR to assess response. It is also critical to clearly state if the baseline scan or the nadir scan should be used to determine radiographic response. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Genentech, Novartis, Regeneron AstraZeneca, Genentech, Novartis, Takeda

Dose-intensified rechallenge with temozolomide: One week on/one week off versus 3 weeks on/one week off in patients with progressive or recurrent glioblastoma.

TPS154 Background: No standard of care has been defined for patients with glioblastoma who relapse or progress on or after standard temozolomide (TMZ)-based radiochemotherapy. Rechallenge with TMZ using various dose-intensified regimens is a common approach for recurrent glioblastoma. O6-methylguanylmethyltransferase (MGMT) promoter methylation is a strong prognostic marker in newly diagnosed glioblastoma. However, in recurrent glioblastoma, the prognostic value of the MGMT status has remained unclear. Methods: The DIRECTOR trial will investigate whether dose-intensified regimens of TMZ can overcome MGMT-mediated chemoresistance and which TMZ rechallenge regimen is most effective and tolerable in recurrent glioblastoma. Results: DIRECTOR is a prospective, randomized, open-label phase II trial which assesses the efficacy of 2 regimens of dose-intensified TMZ, 1 week on/1 week off (120 mg/m2) versus 3 weeks on/1 week off (80 mg/m2), in patients with glioblastoma who progress or relapse after standard first-line TMZ radiochemotherapy and at least 2 cycles of TMZ maintenance. To assess the MGMT promoter methylation status at recurrence, patients will have to undergo resection or biopsy at relapse. The primary endpoint is time-to-treatment failure (TTF) defined as progression, intolerability of study treatment, or death from any cause. Secondary endpoints are progression-free survival (PFS), overall survival (OS), response and MGMT correlations. 166 patients are needed to show a statistically significant difference in median TTF between arm A and B (HR 0.63) with 80% power. Efficacy is assessed every 2 months by MRI using MacDonald criteria. Quality-of-life will be evaluated utilizing QLQ-C30 and QLQ-BN20 EORTC scores. Dose adjustments for TMZ will be implemented according to protocol. Patients will be followed up until treatment failure (last study visit) and the centers are encouraged to further document the course of disease in 3-monthly intervals. Conclusions: The trial is performed in 13 sites in Austria, Germany, and Switzerland. Six of 166 patients have been enrolled. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, Merck Serono, Roche, Schering-Plough Merck, Merck Serono, Roche, Schering-Plough, Wyeth Lilly, Merck Serono, Schering-Plough

An academic prospective single-arm phase II clinical trial for evaluation of advanced functional neuroimaging and molecular markers during bevacizumab/irinotecan therapy for recurrent malignant glioma.

TPS153 Background: Bevacizumab has been approved by the FDA for treatment of recurrent GBM. Standard MRI using Macdonald criteria is insufficient to adequately predict response to antiangiogenic tr...

A clinical study investigating MPC-6827 with carboplatin in the treatment of patients with relapsed glioblastoma multiforme.

2095 Background: MPC-6827 (Azixa; 4-arylaminoquinazoline) is a microtubule destabilizing agent that achieves high brain concentrations. MPC-6827 disrupts newly formed blood vessels in xenografts. We determined the safety and tolerability of MPC-6827 administered in combination with carboplatin. Methods: Three preselected doses of MPC-6827 were tested: 2.1, 2.7, and 3.3 mg/m2 in a standard “3 + 3” design. MPC-6827 was given as a 2-hr IV infusion every 2 of a 6 wk cycle in the 2.1 mg/m2 cohort or 3 wks of 4 in subsequent cohorts. Carboplatin was administered IV at AUC 4 every 2 wks for the cohort receiving 2.1 mg/m2 of MPC-6827 (n = 8) or on Day 1 of each 4 wk cycle for the 2.7 mg/m2 (n = 3) and 3.3 mg/m2 dose levels (n = 8). Patients were observed for acute DLTs during the first cycle. PK evaluations were performed. Results: As of December 7, 2009, 19 patients (median age, 51, range, 21-75; median number of prior therapies, 2, range 1-4) in first or second relapse were enrolled in the study. Fourteen patients (74%) had one lesion. Sixteen patients (95%) had a Karnofsky performance score greater than 70. All patients had previously received the Stupp regimen. Three patients (15.7%) experienced a grade 3 or greater MPC-6827 or carboplatin-related adverse event, including pyrexia (5.3%), transient ischemic attack (TIA) (5.3%), and thrombocytopenia (5.3%). The TIA occurred at the 3.3 mg/m2 dose level and was the only MPC-6827-related SAE and DLT at this dose level. The grade 4 thrombocytopenia occurred in a patient receiving carboplatin on the every 2 wk schedule. The median plasma half life of MPC-6827 was 3.22 hrs (range 2.04-9.03). Two subjects achieved a partial response in this study (duration 7.5 mos and at least 4.3 mos) by Macdonald criteria. Another 6 patients achieved stable disease (duration range 1–7 mos). The median progression-free survival time was 1.8 mos (95% CI: [1.3, 7.1]). Data collection is ongoing. Conclusions: The combination of MPC-6827 at 3.3 mg/m2 with carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized tumor, no incidence of cerebral hemorrhage has been reported. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Myriad Pharmaceuticals Myriad Pharmaceuticals Myriad Pharmaceuticals

Prolonged response without prolonged chemotherapy: A lesson from PCV chemotherapy in low-grade gliomas.

e12519 Background: Previous studies with temozolomide suggest that a prolonged duration of chemotherapy is important for treating low-grade gliomas (LGGs). The objective of this retrospective study was to evaluate the impact of first-line PCV chemotherapy on LGGs growth. Methods: For this purpose, the mean tumor diameter (MTD) of 21 LGGs was evaluated on serial magnetic resonance images before (n = 13), during and after PCV onset (= 21). Results: During PCV, a decrease of the MTD was observed in all patients. After the end of PCV, though at a slower rate, a continuing decrease of the MTD was observed in 20 out of 21 patients. Median duration of this persistent decrease was 2.7 years (0-7 years). According to MacDonald's criteria, the rates of partial and minor responses were 44% at the end of PCV (6% partial and 38% minor responses) but 75 % at the time of maximal tumor response, after a median of 3.4 years following PCV onset (43% partial and 32% minor responses). A persistent and prolonged decrease of L...

Long-term survival from the initial trial of bevacizumab and irinotecan.

2045 Background: The prognosis for recurrent glioblastoma multiforme (GBM) is poor, with median overall survivals of 5- 7 months, and < 10% survival at two years. GBMs are highly vascular tumors, with the highest concentration of vascular endothelial growth factor (VEGF) of any tumor. Bevacizumab is a humanized monoclonal antibody to VEGF. We performed a phase II trial of bevacizumab and irinotecan for patients with recurrent GBM from April, 2005 to November 2005. Methods: 35 patients with recurrent GBM were enrolled. All of the patients had received standard radiation therapy and temozolomide. Patients were treated with bevacizumab at 10 mg/kg every 14 days (N = 23) in cohort 1 or 15 mg/kg every 21 days (n = 12) in cohort 2. The irinotecan was dosed at 125 mg/m2 for patients not on enzyme-inducing anti- epileptic drugs (EIAED) and 340 mg/m2 for patients on EIAEDs given every 14 days for the first cohort. For cohort 2, the irinotecan was given on day 1, 8, 22 and 29. Each cycle was 6 weeks, with an MRI after each cycle. Patients were treated for up to 9 cycles. Two investigators independently reviewed each MRI, and used the modified MacDonald criteria using T1 + C and FLAIR sequences. Results: The regimen was the first to produce a response rate > 20%, 20/35 (57%) had a partial response. The clinical benefit was durable with a 6 month PFS of 46% compared to historical controls of < 20%. The median overall survival was 9.7 months. In this small phase II study, the 4-year overall survival was 11%. One patient remains progression-free. Of the other three patients alive at 4 years, all three responded to a bevacizumab containing regimen at the time of progression. Conclusions: Bevacizumab and irinotecan is an active regimen for recurrent GBM, with durable improvements in overall survival for a subset of patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Roche Genentech Genentech

A phase II study to assess the efficacy and impact of BIBW 2992 on QTc interval in patients with solid tumors, including brain metastases and recurrent glioblastoma multiforme (GBM).

TPS187 Background: BIBW 2992 is an oral, irreversible inhibitor of EGFR/HER1 and HER2. EGFR and HER2 are amplified and overexpressed in most epithelial cancers as well as 50%–60% of GBMs. In a phase I study, one patient with NSCLC and brain metastases showed a response in both systemic and CNS disease. Preclinical and retrospective ECG analyses did not suggest an effect of BIBW 2992 on QTc, although this has not been prospectively assessed according to ICH E14 Cardiac Assessment of New Drugs Guidelines. The primary objectives of this study are to evaluate the effect of BIBW 2992 on QTc interval and the efficacy in patients with GBM, and patients with eligible tumors with and without brain metastases. Methods: In this phase II open label study, patients ≥18 years, with tumors known to historically overexpress EGFR or HER2, including those with brain metastases, and GBM at 1st recurrence, adequate organ function and ECOG PS 0–2, are eligible for treatment with BIBW 2992 50 mg PO OD q28. Patients with a QTcF-interval >470 ms, a PR-interval >230 ms, a QRS-interval >120 ms and ST-segment and T/U-wave abnormalities at screening, as assessed by central cardiology review, are excluded. All concomitant medications and dose changes within the initial 14 days on BIBW 2992 treatment are recorded. Up to 60 patients are to be recruited and treated until disease progression. Time-matched 24-h electrocardiograms are being performed at baseline, prior to drug exposure, after single dose and at steady state, i.e. Days -1, +1 and +14. PK samples are to be drawn at single dose and at steady state coincident with ECGs The primary endpoints are QTcF interval and objective tumor response according to the Macdonald criteria for GBM patients and for patients with brain metastases, and the RECIST 1.0 for other patients. Secondary endpoints include prolongation of QTcF, PR and QRS interval of ECG, heart rate, T wave and U wave morphology, disease control rate, PFS, molecular determinants of response, adverse events and PK characteristics of BIBW 2992 after single dose and at steady state. To date, 40 patients have been treated and 33 patients have completed ECG assessments on Days -1, +1 and +14. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Boehringer Ingelheim Boehringer Ingelheim Boehringer Ingelheim Boehringer Ingelheim

Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma

Even after gross tumor resection and combined radiochemotherapy, glioblastomas recur within a few months. Salvage therapy often consists of rechallenging with temozolomide in a dose-intensified schedule. Previously, low-dose metronomic temozolomide in combination with cyclo-oxigenase 2 inhibitors has had a beneficial effect as first-line treatment for glioblastoma. We report our experience with this procedure in recurrent glioblastomas after standard treatment. From June 2007 to April 2009, 28 patients with recurrent glioblastoma received continuous low-dose temozolomide of 10 mg/m(2) twice daily and 200 mg celecoxib. Before therapy the recurrent tumor was resected in 19 of 28 patients. Microvessel density (MVD) was determined by immunohistochemistry in 19 patients, and MGMT promoter methylation status, using the pyrosequencing method, was determined in 17 patients. In 14/28 patients, positron emission tomography with [F-18]-fluoroethyl)-L-tyrosine (FET-PET) was performed. Tumor progression was defined by the Macdonald criteria on MRI every 8-12 weeks or by clinical deterioration. The median time to progression was 4.2 months. Progression-free survival (PFS) after 6 months was 43%. Except for a lymphopenia in one patient, there was no grade 3 or 4 toxicity. PFS did not correlate with MVD or MGMT status. A high FET uptake correlated with tumor control after 6 months under therapy (P = 0.041, t-test). Low-dose continuous temozolomide in combination with celecoxib seems to have activity in recurrent glioblastoma without relevant toxicity. High FET uptake correlated with a better outcome under metronomic therapy.

High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

High-grade malignant glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up R. Stupp, J.-C. Tonn, M. Brada & G. Pentheroudakis On behalf of the ESMO Guidelines Working Group* Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, and Department of Oncology-Hematology Riveria-Chablais, Vevey, Switzerland; Department of Neurosurgery, Universitatsklinikum Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany; Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, Sutton, UK; Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

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.