[Show abstract][Hide abstract] ABSTRACT: Background
Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients.Methods
We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients.ResultsTwenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho-)S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months.Conclusion
Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The treatment of patients with primary CNS lymphomas (PCNSL) has dramatically changed since the 1970's when whole
brain radiation generated median survivals of about 12 months, significant neurotoxcity, and few long term survivors. High
dose methotrexate (HD-MTX) monotherapy without radiation provides excellent response rates and 30% long term survivors without
neurotoxicity. In general, relapses occur in the first two to four years after diagnosis and reports of very late relapses
are rare. METHODS: Charts of all patients treated with HD-MTX monotherapy for newly diagnosed PCNSL between 1995 and 2012
at The Johns Hopkins Hospital were reviewed retrospectively. Patients with less than 5 years of follow-up data were excluded.
First relapses over 10 years from diagnosis were identified and reviewed. RESULTS: Long-term follow-up data was available
for 37 patients treated with HD-MTX monotherapy during this period. Four of 37 (11%) survived disease free for >10 years from
initial diagnosis and maintain their excellent clinical status. All received methotrexate (8 gm/m2) every two weeks until complete response and then monthly to complete one year of therapy. Two of these long survivors (50%)
presented with new seizures 10.8 and 11.2 years after initial diagnosis. Imaging revealed recurrent intraparenchymal disease,
re-biopsy confirmed PCNSL in one, and both responded very well to retreatment with high dose methotrexate and Rituximab. The
other two patients remain relapse free 12 and 13.7 years after initial diagnosis. CONCLUSION: Very late relapses have occurred
in 2 of 4 long term survivors. These observations suggest that PCNSL patients treated with HD-MTX who were considered "cured"
may be at substantial risk for late recurrences. A concerted effort to follow patients with this rare disease is needed to
determine the frequency of late recurrences. More information is needed to determine if the addition of rituximab or other
therapies reduce late recurrence rates.
[Show abstract][Hide abstract] ABSTRACT: Therapeutic outcomes for patients with brain metastases need to improve. A critical review of trials specifically addressing brain metastases shows key issues that could prevent acceptance of results by regulatory agencies, including enrolment of heterogeneous groups of patients and varying definitions of clinical endpoints. Considerations specific to disease, modality, and treatment are not consistently addressed. Additionally, the schedule of CNS imaging and consequences of detection of new or progressive brain metastases in trials mainly exploring the extra-CNS activity of systemic drugs are highly variable. The Response Assessment in Neuro-Oncology (RANO) working group is an independent, international, collaborative effort to improve the design of trials in patients with brain tumours. In this two-part series, we review the state of clinical trials of brain metastases and suggest a consensus recommendation for the development of criteria for future clinical trials.
No preview · Article · Sep 2013 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE.
This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission.
No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations.
VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation.
[Show abstract][Hide abstract] ABSTRACT: Background
The objective of this study was to examine the predictive value of parameters of 3D (1)H magnetic resonance spectroscopic imaging (MRSI) prior to treatment with radiation/chemotherapy (baseline) and at a postradiation 2-month follow-up (F2mo) in relationship to 6-month progression-free survival (PFS6) and overall survival (OS).Methods
Sixty-four patients with newly diagnosed glioblastoma multiforme (GBM) being treated with radiation and concurrent chemotherapy were involved in this study. Evaluated were metabolite indices and metabolite ratios. Logistic linear regression and Cox proportional hazards models were utilized to evaluate PFS6 and OS, respectively. These analyses were adjusted by age and MR scanner field strength (1.5 T or 3 T). Stepwise regression was performed to determine a subset of the most relevant variables.ResultsAssociated with shorter PFS6 were a decrease in the ratio of N-acetyl aspartate to choline-containing compounds (NAA/Cho) in the region with a Cho-to-NAA index (CNI) >3 at baseline and an increase of the CNI within elevated CNI regions (>2) at F2mo. Patients with higher normalized lipid and lactate at either time point had significantly worse OS. Patients who had larger volumes with abnormal CNI at F2mo had worse PFS6 and OS.Conclusions
Our study found more 3D MRSI parameters that predicted PFS6 and OS for patients with GBM than did anatomic, diffusion, or perfusion imaging, which were previously evaluated in the same population of patients.
[Show abstract][Hide abstract] ABSTRACT: The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-β, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 × 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose-limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To report octreotide scan and magnetic resonance spectroscopy (MRS) characteristics in a patient with brain metastases
from transitional cell carcinoma of the bladder. BACKGROUND: Metastatic brain tumors are the most common tumors of the central
nervous system (CNS). The differential diagnosis of a single or a few brain lesions in cancer patients remains broad. Transitional
cell carcinoma metastasis to the CNS is uncommon, but an increasing incidence has been suggested as systemic treatment improves.
Functional and metabolic imaging modalities may increase diagnostic yield and aid treatment planning in a noninvasive way.
DESIGN/METHOD: A 52-year-old man with known metastatic high-grade transitional cell carcinoma of the bladder presented with
subacute cognitive dysfunction and episodic presyncope. Magnetic resonance imaging (MRI) revealed left temporal and left cerebellar
mass lesions. While the cerebellar mass was an intra-axial tumor that suggested metastatic disease, the left temporal lesion
was suspicious for a meningioma. Octreotide scanning and MRS were performed for further evaluation. RESULTS: Octreotide scanning
showed both lesions were octreotide avid. Long-TE MRS of the left temporal lesion revealed a single large lipid peak at 1.3
ppm, small N-acetyl aspartate peak, and markedly increased choline:creatine ratio. Resection of both lesions revealed metastatic,
poorly differentiated carcinoma that was morphologically similar to the patient's previous cystoprostatectomy specimen. CONCLUSIONS:
This is the first report of octreotide scan characteristics in a patient with transitional cell carcinoma with CNS metastases.
The constellation of the MRS findings is relatively characteristic of metastases. Furthermore, octreotide avidity in our case
suggests the presence of somatostatin receptor in a transitional cell carcinoma, which might be considered a potential therapeutic
target in octreotide-positive CNS metastases.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG).
This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m(2)/day for 5 days of the first cycle and 200 mg/m(2)/day for 5 days of the subsequent 28-day cycles.
In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells.
Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway.
Preview · Article · Aug 2012 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Advances in the management of gliomas, including the approval of agents such as temozolomide and bevacizumab, have created an evolving therapeutic landscape in glioma treatment, thus affecting our ability to reliably use historical controls to comparatively assess the activity of new therapies. Furthermore, the increasing availability of novel, targeted agents--which are competing for a small patient population, in view of the low incidence of primary brain tumours--draws attention to the need to improve the efficiency of phase 2 clinical testing in neuro-oncology to expeditiously transition the most promising of these drugs or combinations to potentially practice-changing phase 3 trials. In this report from the Response Assessment in Neurooncology (RANO) group, we review phase 2 trial designs that can address these challenges and capitalise on scientific and clinical advances in brain tumour treatment in neuro-oncology to accelerate and optimise the selection of drugs deserving further testing in phase 3 trials. Although there is still a small role for single-arm and non-comparative phase 2 designs, emphasis is placed on the potential role that comparative randomised phase 2 designs--such as screening designs, selection designs, discontinuation designs, and adaptive designs, including seamless phase 2/3 designs--can have. The rational incorporation of these designs, as determined by the specific clinical setting and the trial's endpoints or goals, has the potential to substantially advance new drug development in neuro-oncology.
Full-text · Article · May 2012 · The Lancet Oncology
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to evaluate the roles of resection extent and adjuvant radiation in the treatment of craniopharyngiomas. We reviewed the records of 122 patients ages 11-52 years who received primary treatment for craniopharyngioma between 1980 and 2009 at the University of California, San Francisco (UCSF). Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were development of panhypopituitarism, diabetes insipidus (DI), and visual field defects. Of 122 patients, 30 (24%) were treated with gross total resection (GTR) without radiation therapy (RT), 3 (3%) with GTR + RT, 41 (33.6%) with subtotal resection (STR) without RT, and 48 (39.3%) with STR + RT. Median age at diagnosis was 30 years, with 46 patients 18 years or younger. Median follow-up for all patients was 56.4 months (interquartile range 18.9-144.2 months) and 47 months (interquartile range 12.3-121.8 months) for the 60 patients without progression. Fifty six patients progressed, 10 have died, 6 without progression. Median PFS was 61.1 months for all patients. PFS rate at 2 years was 61.5% (95% CI: 52.1-70.9). OS rate at 10 years was 91.1% (95% CI 84.3-97.9). There was no significant difference in PFS and OS between patients treated with GTR vs. STR + XRT (PFS; p = 0.544, OS; p = 0.735), but STR alone resulted in significantly shortened PFS compared to STR + RT or GTR (p < 0.001 for both). STR was associated with significantly shortened OS compared to STR + RT (p = 0.050) and trended to shorter OS compared to GTR (p = 0.066). GTR was associated with significantly greater risk of developing DI (56.3 vs. 13.3% with STR + XRT, p < 0.001) and panhypopituitarism (54.8 vs. 26.7% with STR + XRT, p = 0.014). In conclusion, for patients with craniopharyngioma, STR + RT may provide superior clinical outcome, achieving better disease control than STR and limiting side effects associated with aggressive surgical resection.
No preview · Article · Feb 2012 · Journal of Neuro-Oncology
[Show abstract][Hide abstract] ABSTRACT: The spatial heterogeneity in magnetic resonance (MR) metabolic and diffusion parameters and their relationship were studied for patients with treatment-naive grade 3 gliomas. MR data were evaluated from 51 patients with newly diagnosed grade 3 gliomas. Anatomic, diffusion, and metabolic imaging data were considered. Variations in metabolite levels, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were evaluated in regions of gadolinium enhancement and T2 hyperintensity as well as regions with abnormal metabolic signatures. Contrast enhancement was present in only 21 of the 51 patients. When present, the enhancing component of the lesion had higher choline-to-N-acetylaspartate index (CNI), higher choline, lower N-acetylaspartate, similar creatine, similar ADC and FA, and higher lactate/lipid than the nonenhancing lesion. Regions with CNI ≥ 4 had higher choline, lower N-acetylaspartate, higher lactate/lipid, higher ADC, and lower FA than normal-appearing white matter and regions with intermediate CNI values. For lesions that exhibited gadolinium enhancement, the metabolite levels and diffusion parameters in the region of enhancement were consistent with it corresponding to the most abnormal portion of the tumor. For nonenhancing lesions, areas with CNI ≥ 4 were the most abnormal in metabolic and diffusion parameters. This suggests that the region with the highest CNI might provide a good target for biopsies for nonenhancing lesions to obtain a representative histologic diagnosis of its degree of malignancy. Metabolic and diffusion parameter levels may be of interest not only for directing tissue sampling but also for defining the targets for focal therapy and assessing response to therapy.
Full-text · Article · Feb 2012 · Translational oncology
[Show abstract][Hide abstract] ABSTRACT: To evaluate prognostic factors for survival after stereotactic radiosurgery (SRS) for new, progressive, or recurrent brain metastases (BM) after prior whole brain radiotherapy (WBRT).
Patients treated between 1991 and 2007 with Gamma Knife SRS for BM after prior WBRT were retrospectively reviewed. Potential prognostic factors were analyzed overall and by primary site using univariate and stepwise multivariate analyses and recursive partitioning analysis, including age, Karnofsky performance status (KPS), primary tumor control, extracranial metastases, number of BM treated, total SRS target volume, and interval from WBRT to SRS.
A total of 310 patients were analyzed, including 90 breast, 113 non-small-cell lung, 31 small-cell lung, 42 melanoma, and 34 miscellaneous patients. The median age was 56, KPS 80, number of BM treated 3, and interval from WBRT to SRS 8.1 months; 76% had controlled primary tumor and 60% had extracranial metastases. The median survival was 8.4 months overall and 12.0 vs. 7.9 months for single vs. multiple BM treated (p = 0.001). There was no relationship between number of BM and survival after excluding single-BM patients. On multivariate analysis, favorable prognostic factors included age <50, smaller total target volume, and longer interval from WBRT to SRS in breast cancer patients; smaller number of BM, KPS >60, and controlled primary in non-small-cell lung cancer patients; and smaller total target volume in melanoma patients.
Among patients treated with salvage SRS for BM after prior WBRT, prognostic factors appeared to vary by primary site. Although survival time was significantly longer for patients with a single BM, the median survival time of 7.9 months for patients with multiple BM seems sufficiently long for salvage SRS to appear to be worthwhile, and no evidence was found to support the use of a cutoff for number of BM appropriate for salvage SRS.
No preview · Article · Nov 2011 · International journal of radiation oncology, biology, physics
[Show abstract][Hide abstract] ABSTRACT: The disease outcome for patients with cancer is typically described in terms of estimated survival from diagnosis. Conditional probability offers more relevant information regarding survival for patients once they have survived for some time. We report conditional survival probabilities on the basis of 498 patients with glioblastoma multiforme receiving radiation and chemotherapy. For 1-year survivors, we evaluated variables that may inform subsequent survival. Motivated by the trend in data, we also evaluated the assumption of constant hazard.
Patients enrolled onto seven phase II protocols between 1975 and 2007 were included. Conditional survival probabilities and 95% CIs were calculated. The Cox proportional hazards model was used to evaluate prognostic values of age, Karnofsky performance score (KPS), and prior progression 1-year post diagnosis. To assess the constant hazard assumption, we used a likelihood-ratio test to compare the Weibull and exponential distributions.
The probabilities of surviving an additional year given survival to 1, 2, 3, and 4 years were 35%, 49%, 69%, and 93%, respectively. For patients who survived for 1 year, lower KPS and progression were significantly predictive of shorter survival (both P < .001), but age was not (hazard ratio, 1.22 for a 10-year increase; P = .25). The Weibull distribution fits the data significantly better than exponential (P = .02), suggesting nonconstant hazard.
Conditional probabilities provide encouraging information regarding life expectancy to survivors of glioblastoma multiforme. Our data also showed that the constant hazard assumption may be violated in modern brain tumor trials. For single-arm trials, we advise using individual patient data from historical data sets for efficacy comparisons.
Full-text · Article · Nov 2011 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: INTRODUCTION: Greater extent of resection for low-grade glioma patients corresponds with improved clinical outcome, yet remains
a central challenge to the neurosurgical oncologist. Although 5-aminolevulinic acid (5-ALA)-induced tumor fluorescence is
a strategy that can improve glioma extent of resection, only glioblastomas routinely fluoresce following 5-ALA administration.
Intraoperative confocal microscopy adapts conventional confocal technology to a hand-held probe that provides real-time fluorescent
imaging at up to 1000-fold magnification. We report a combined approach using intraoperative confocal microscopy to visualize
5-ALA tumor fluorescence in low-grade gliomas during the course of microsurgical resection. METHODS: Following 5-ALA administration,
newly diagnosed low-grade glioma patients underwent microsurgical resection. Intraoperative confocal microscopy was conducted
at (1) the initial encounter with the tumor, (2) the midpoint of tumor resection, and (3) the presumed brain-tumor interface.
Histopathological analysis of these sites correlated tumor infiltration with intraoperative cellular tumor fluorescence. RESULTS:
Ten consecutive patients with World Health Organization (WHO) grades I and II gliomas underwent microsurgical resection with
5-ALA and intraoperative confocal microscopy. Macroscopic tumor fluorescence was not evident in any patient. However, in each
case, intraoperative confocal microscopy identified tumor fluorescence at a cellular level, a finding that corresponded to
tumor infiltration on matched histological analyses. CONCLUSIONS: Intraoperative confocal microscopy can visualize cellular
5-ALA-induced tumor fluorescence within WHO grades I and II low-grade gliomas and at the brain-tumor interface. To assess
the clinical value of 5-ALA for high-grade gliomas in conjunction with neuronavigation and for low-grade gliomas in combination
with intraoperative confocal microscopy and neuronavigation, a phase IIIa randomized, placebo-controlled trial (BALANCE) is
underway at our institution.
[Show abstract][Hide abstract] ABSTRACT: This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.
[Show abstract][Hide abstract] ABSTRACT: The management and prognosis of glioblastoma patients after Stupp protocol treatment and progression during bevacizumab (BV) treatment remain undefined.
We compared the morbidity and survival of patients whose glioblastomas progressed during BV treatment requiring craniotomy with those of patients not treated with BV.
We retrospectively reviewed patients who underwent craniotomy for recurrent glioblastoma from 2005 to 2009. Patients operated on for progression during BV (preoperative BV) were compared with patients receiving no BV or receiving BV after surgery (postoperative BV). Patients receiving BV preoperatively were compared with those patients whose gliobastoma progressed on BV treatment but were not operated on (no surgery).
There were 23 preoperative BV patients, 135 no BV patients, 16 postoperative BV patients, and 25 no surgery patients. Patients receiving BV preoperatively had a worse postoperative overall survival rate (hazard ratio, 3.1; P < .001) and worse postoperative progression-free survival rate (hazard ratio, 3.4, P < .001) than patients not receiving BV. Patients receiving BV preoperatively had a higher perioperative morbidity rate (44%) than patients not receiving preoperative BV (21%) (P = 0.02). Survival after diagnosis was comparable between groups (86-93 weeks, P = .9), consistent with glioblastomas developing BV evasion being not intrinsically more aggressive, but possibly BV evasion conferring a uniquely poor prognosis. No surgery patients had a shorter overall survival after progression during BV treatment compared with preoperative BV patients (hazard ratio, 3.6, P < .001).
Patients whose glioblastomas progress while receiving BV leading to craniotomy exhibit shorter postoperative survival and more perioperative morbidity than patients not treated with BV. Although there may be benefits to surgical debulking, the decision to pursue repeat surgery in patients in whom BV treatment failed must be balanced against the increased risk of perioperative complications.
[Show abstract][Hide abstract] ABSTRACT: Historically, the North American Brain Tumor Consortium used 6-month progression-free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes. Two data sets were analyzed. The first included 511 patients enrolled during the period 1998-2005, 105 of whom had surgery (excluding biopsies) during the study or ≤ 30 days prior to registration. Analysis was stratified on the basis of whether temozolomide was part of the protocol treatment regimen. The second data set included 247 patients enrolled during 2005-2008, 103 of whom underwent surgery during the clinical trial or immediately prior to study registration. A combined data set consisting of all patients who did not receive temozolomide was also compiled. No statistically significant difference in PFS6 or OS was found between the surgery and nonsurgery groups in either data set alone or in the combined data set (P > .45). We conclude that PFS6 and OS results for patients with and without surgical intervention at the time of progression are similar, allowing data from these patients to be combined in assessing the benefit of new treatments without the need for stratification or other statistical adjustment.