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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4714-4721 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.5825 Predicting Treatment Response of Malignant Gliomas to Bevacizumab and Irinotecan by Imaging Proliferation With [18F] Fluorothymidine Positron Emission Tomography: A Pilot Study
From the Ahmanson Biological Imaging Division and the Departments of Molecular and Medical Pharmacology, Biostatistics, Radiology, and Neurology, University of California, Los Angeles, Los Angeles, CA Address reprint requests to Wei Chen, MD, PhD, Department of Molecular and Medical Pharmacology, CHS AR-127, University of California, Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90005-6942; e-mail: weichen{at}mednet.ucla.edu
Purpose: Evaluation of treatment effects in malignant brain tumors is challenging because of the lack of reliable response predictors of tumor response. This study examines the predictive value of positron emission tomography (PET) using [18F] fluorothymidine (FLT), an imaging biomarker of cell proliferation, in patients with recurrent malignant gliomas treated with bevacizumab in combination with irinotecan. Patients and Methods: Patients with recurrent malignant gliomas treated with biweekly cycles of bevacizumab and irinotecan were prospectively studied with FLT-PET at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. A more than 25% reduction in tumor FLT uptake as measured by standardized uptake value was defined as a metabolic response. FLT responses were compared with response as shown by magnetic resonance imaging (MRI) and patient survival. Results: Twenty-one patients were included, and 19 were assessable for metabolic response evaluation with FLT-PET. There were nine responders (47%) and 10 nonresponders (53%). Metabolic responders survived three times as long as nonresponders (10.8 v 3.4 months; P = .003), and tended to have a prolonged progression-free survival (P = .061). Both early and later FLT-PET responses were more significant predictors of overall survival (1 to 2 weeks, P = .006; 6 weeks, P = .002), compared with the MRI responses (P = .060 for both 6-week and best responses). Conclusion: FLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.
Bevacizumab, a recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), disrupts a critical process in the regulation of angiogenesis.1,2 When administered as single agents, antiangiogenic drugs produce modest clinical or radiographic responses, but have not yielded survival benefits.3 In contrast, when administered with chemotherapy, bevacizumab increased survival in previously treated or untreated colorectal and untreated lung cancer patients.4,5 Improvement in progression-free survival but not overall survival was observed in previously untreated breast cancer patients.6 It has been hypothesized that antiangiogenic agents may normalize the abnormal structure and function of blood vessels supplying the tumors to make them more efficient for oxygen and drug delivery.7 Despite several active investigations, no reliable biomarkers predictive of treatment responses have been established.3 Glioblastoma cell lines secrete VEGF. 8 In situ analysis of tumor specimens demonstrated that production of VEGF is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci and clustering of capillaries.9 Moreover, critical tumor subpopulations within gliomas shared characteristics with neural stem cells, and these stem cell–like glioma cells secreted elevated levels of VEGF, which were further induced by hypoxia.10 Further, bevacizumab displayed potent antiangiogenic efficacy and suppressed the growth in mice xenografts derived from stem cell–like glioma cells.10 Significant changes in magnetic resonance imaging (MRI) contrast enhancement in 14 patients with recurrent malignant gliomas treated with bevacizumab in combination with various chemotherapeutic agents have been observed.11 A response rate of 63% was seen in 32 patients with recurrent high-grade gliomas treated with bevacizumab and irinotecan.12 The extent of MRI contrast enhancement in malignant gliomas has been used as an indicator of therapeutic response.13 However, this approach is limited by the difficulty in distinguishing between tumor and treatment-induced necrosis,14 and reliable prognostic information can be obtained only many weeks after treatment starts. [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) has prognostic value in imaging brain tumors.15 However, the high physiological glucose metabolic rate of the brain reduces the sensitivity of FDG-PET for lesion characterization.16-18 [18F]fluorothymidine (FLT) was developed as a noninvasive PET biomarker for imaging cell proliferation.19 In a previously published study in 25 patients with gliomas,20 FLT tumor uptake was well correlated with the proliferation index Ki-67. Thus, FLT-PET has the potential to serve as an imaging marker for treatment monitoring. In this study, we sought to determine whether FLT-PET is predictive of the outcome of patients with recurrent malignant gliomas who were treated with bevacizumab and irinotecan; whether early and late PET studies provide similar information; and whether prognostic information obtained with MRI is comparable to that obtained from PET.
Patients Twenty-one patients with recurrent high-grade gliomas were prospectively studied (Table 1). Seventeen had WHO grade 4 and four had WHO grade 3 glioma. Every patient had undergone surgical resection, radiation, and chemotherapy. All had tumor recurrence determined by MRI and/or neurological deterioration. The median number of recurrences and prior treatments was two (range, 1 to 5 and 1 to 6, respectively).
All patients gave written consent to participate in this study, which was approved by the University of California, Los Angeles (Los Angeles, CA), Office for Protection of Research Subjects. This was an imaging study. None of the patients were enrolled in treatment trials, and all were treated off-label with irinotecan and bevacizumab.
Treatment
PET Imaging For FLT-PET imaging, a dynamic emission acquisition sequence in three-dimensional mode over 60 minutes was started with the intravenous injection of 2.0 MBq/kg FLT, followed by a 5-minute transmission scan for attenuation correction. PET emission data were reconstructed using iterative reconstruction ordered-subsets expectation maximization (eight iterations with six subsets) and a Gaussian filter with 5 mm full width at half maximum, using measured attenuation correction. The final reconstructed volume-set had a matrix size of 128 x 128 mm with a voxel size of 2.4 x 2.4 x 2.4 mm. For region of interest (ROI) analysis, FLT data were summed between 30 and 60 minutes to obtain static images. The PET slice with the maximum tumor uptake was chosen for ROI analysis, and the two adjacent axial slices one plane above and one plane below the chosen slice were included to improve count statistics. A circular ROI (diameter 1.0 cm, 16 pixels) was placed over the area of the tumor. The radiotracer concentration in the ROIs was normalized to the injected dose per patient's body weight to derive the standardized uptake values (SUVs; g/mL).
Response Evaluation and Follow-Up Survival time was the interval from the date of the start of the treatment to the date of death. Time to tumor progression was the time interval from the date of the start of treatment to the date of first documented evidence of disease progression, based on MRI and/or neurological deterioration. The median time from baseline FLT-PET to the start of the treatment was 2 days. Patients were followed for survival until death. No patient was lost to follow-up.
Statistical Analysis Differences between groups of patients were tested by the t test. Patients who were alive at the date of the last follow-up were excluded on that date. Patients who died without progressive disease (PD) documented were considered to have had PD at the time of death. Receiver operating characteristic (ROC) curves analysis was used to identify the optimum cutoff value of the tumor FLT uptake reduction for differentiation of responding and nonresponding patients. Survival estimates were calculated according to the Kaplan-Meier method.28 Statistical analyses of multiple variables were performed with the Cox proportional hazards model.29 Variables reaching a significance of P < .05 by univariate analysis were included in the multivariate analysis.
Changes of FLT-PET Uptake During Treatment Twenty-one patients were registered for the FLT-PET study between June 2005 and February 2006. All 21 patients underwent baseline FLT-PET scan. These data were used to determine whether baseline FLT-PET was predictive of patient outcome. Two patients did not complete the follow-up PET study (Table 2), and cannot be analyzed for the metabolic response. Thus, 19 patients were assessable for metabolic responses (Fig 1). The baseline FLT-PET was performed 2.0 ± 1.7 days before start of treatment, and follow-up scans were performed at 12 ± 6 days (1.7 ± 0.8 weeks) and 43 ± 12 days (6.1 ± 1.7 weeks) after start of treatment. Three patients (patients 2, 7, and 15) did not undergo the third FLT-PET because of clinical deterioration, with one death occurring before the third scan. Therefore, early PET after 1 to 2 weeks was available in 19 patients, and PET after 6 weeks was available in 16 patients.
SUVs from the tumor ROIs were obtained from each FLT-PET (Table 2). ROC curve analysis was performed using the clinical criteria of 6 months survival to separate responders from those with PD. The area under the ROC curve was 0.761 ± 0.11, with a sensitivity of 72.7% and a specificity of 87.5%. A 25% reduction in FLT-PET uptake at 6 weeks served as the optimal threshold for response. Using this threshold, nine (43%) of the 19 patients sustained a metabolic response at 6 weeks, whereas 10 patients (57%) did not. The metabolic responders demonstrated a 43% ± 9% decrease of FLT uptake from baseline to the first follow-up scan and a 40% ± 13% decrease of FLT uptake from baseline to the second follow-up study (Table 3). Among the 10 nonresponders, FLT uptake increased by 2% ± 20% at the time of the first follow-up scan and by 27% ± 61% at the second follow-up scan.
Response Evaluation and Patient Survival At the time of this writing, 16 patients had died. Overall 6-month survival was 62% and 65% for patients with grade 4 glioma. Patients with a metabolic response had a significantly longer survival compared with patients without metabolic response (median survival, 10.8 v 3.4 months; P = .003). Of note, five (56%) of the nine metabolic responders were still alive, whereas none of the 10 nonresponders (0%) were. FLT response at 6 weeks predicted patient survival, as demonstrated by Kaplan-Meier survival analysis (P = .002;  Fig 2). FLT-PET at 1 to 2 weeks was also significant for overall survival (P = .006). A trend for improved progression-free survival of metabolic responders was seen (P = .061).
We also examined whether single measurements of FLT SUVs at any time point were predictive of patient outcome. Using various cutoff values, the maximum FLT SUVs were at no time significant predictors of patients' survival (Kaplan-Meier log-rank P = .752, .412, and .231 for SUVs at baseline, 1 to 2 weeks, and 6 weeks, respectively). Likewise, neither baseline tumor to normal background FLT uptake ratios nor their temporal changes were predictive of survival (P = .446, .495, and .685, respectively). Response by MRI was evaluated at approximately 6 weeks (5.8 ± 1.0 weeks) after the start of the treatment and was available for 20 patients (except for patient 2, who died before 6 weeks). By MRI, four (19%) of 21 patients had partial response (PR), 10 (48%) of 21 had stable disease (SD), and 7 (33%) of 21 had PD. An MRI response at 6 weeks tended to predict prolonged survival (P = .060). Best response predictions assessed with MRI occurred at 7 weeks (range, 2.1 to 18.6 weeks). At this time point, twice as many patients (eight of 21, 38%) demonstrated PR, seven (33%) of 21 had PD, and six (29%) of 21 had SD. Best response by MRI also tended to predict prolonged survival (P = .060). Multiple clinical variables were tested in univariate and multivariate analyses (Table 4). In univariate analysis, survival was better if patients had fewer recurrences or fewer prior treatments. Other clinical variables such as age, tumor grade, dexamethasone treatments, and time from prior radiation therapy did not predict survival. In the multivariate analysis, the number of prior treatment was the only clinical variable to significantly predict survival.
In considering all variables (clinical and imaging based), a lack of reduction in FLT uptake at 6 weeks after start of treatment was the strongest predictor of death (hazard ratio [HR] = 5.0), whereas a higher number of prior treatments had an HR for death of 1.5.
This prospective study provides the first evidence that FLT-PET can serve as an imaging biomarker for predicting treatment responses in patients with recurrent malignant gliomas. Changes in FLT tumor uptake stratified the patient population into two subgroups; FLT responders (nine of 19, 43%) had a median survival of 10.8 months, whereas nonresponders (10 of 19, 57%) lived one third as long, with a median survival of only 3.4 months (P = .003). The majority (56%) of patients with metabolic response, but none (0%) of the nonresponders, were alive at the end of the study. Changes in FLT uptake were predictive as early as 1 to 2 weeks (average, 12 days) after starting treatment (P = .006). Conventional imaging criteria based on MRI changes that demonstrated a PR rate of 19% (four of 21) at 6 weeks after start of treatment and 38% (eight of 21) at time of best response relatively weakly predicted survival (P = .060 for both). To our knowledge, this is the first published study demonstrating the ability of a PET imaging biomarker for predicting survival benefit in response to anti-VEGF therapy. No noninvasive biomarkers have yet been identified as being predictive of the outcome of bevacizumab treatment despite significant advances in identifying such candidate markers.30 Biomarkers are needed to identify responsive patients, to optimize treatment doses, and to predict treatment efficacy.31 Previous studies have demonstrated that, in rectal cancers, bevacizumab caused reduction in tumor perfusion, vascular volume, microvascular density, and interstitial fluid pressure as measured by functional computed tomography.32-33 However, whether these changes during treatment correlate with clinical outcome is not yet known. Uptakes of FLT correlates with activity of thymidine kinase-1 (TK1), an enzyme expressed during the DNA synthesis phase of the cell cycle.34 Phosphorylation of FLT intracellularly by TK1 results in trapping of the negatively charged FLT monophosphate.35-36 FLT tumor uptake is correlated with Ki-67, a common proliferation index used ex vivo, as demonstrated in a number of extracranial cancers.37-42 FLT uptake has also been investigated in brain tumors,43-44 and similar correlations have been observed.20,45,46 The current study suggests that early changes in FLT uptake could serve as a biomarker for predicting treatment effects in brain tumors, as has been recently reported for patients with breast cancer.47 A 6-month survival of 65% for glioblastoma patients was seen in our study. For a disease that historically has been generally associated with a bleak outcome, the high percentage of patients who showed a favorable response to treatment was remarkable. This favorable response argues against the hypothesis that bevacizumab-based chemotherapy in brain tumors only changes the permeability of the blood-brain barrier without a significant true antitumor effect. Multivariate analysis demonstrated that FLT response was the most powerful independent predictor of survival among all variables tested, including age, number of recurrences, number of prior treatments, tumor grade, dexamethasone treatment, and time from radiation therapy. The number of prior treatments was the only significant clinical variable with a lower HR (5.0 v 1.5). Although all of our patients had recurrent disease and had been treated previously with various regimens, the median recurrence was two, with 67% having two or fewer recurrences; the median number of prior treatment was two with 62% having two of fewer prior treatments. All patients were naïve to irinotecan, consistent with the recent report that, for patients with advanced colorectal cancer, adding bevacizumab to previously failed regimens did not lead to significant response or survival.48 In contrast to our previous study,20 baseline FLT SUVs were not predictive of patient survival. Several explanations might account for this finding. First, our prior study included patients with low- and high-grade gliomas as well as stable patients in long-term remission, whereas our current population consisted of patients with recurrent high-grade gliomas only. Further, the prior study was a study of imaging characteristics and not a study of treatment response. Thus, this lack of baseline FLT SUV in predicting outcome in the current study might reflect the lack of potential interaction of baseline SUV and treatment response. Through ROC curve analysis, a metabolic response of greater than 25% reduction in tumor FLT uptake was found to be the threshold with best predictive power for overall survival. This finding is consistent with literatures on criteria of metabolic response.26 Although those previous studies were performed in patients withextracranial tumors and with FDG-PET, the present study demonstrates that a metabolic response with FLT according to this definition also correlates with survival in patients with brain tumors. This is a small exploratory study with limitations. For example, FLT-PET response at 6 weeks after starting treatment was a more significant predictor of survival than response at 1 to 2 weeks (P = .002 v .006), but this difference was attributable to a single patient (patient 18). A larger study is warranted to establish whether FLT-PET as early as 1 to 2 weeks after starting treatment is just as predictive of overall survival as the 6-week FLT-PET. In conclusion, this prospective study demonstrated that bevacizumab and irinotecan treatment in patients with recurrent high-grade gliomas resulted in a significant survival benefit. Secondly, metabolic response is much more powerful in predicting overall survival than is response by anatomic imaging. Further, metabolic response as early as 1 to 2 weeks after starting treatment can be predictive. Because of difficulties in assessing response by conventional imaging modalities, the use of FLT-PET for prediction of response and survival appears promising and warrants validation with larger prospective series.
The author(s) indicated no potential conflicts of interest.
Conception and design: Wei Chen, Cheri Geist, Johannes Czernin, Michael E. Phelps, Timothy Cloughesy Administrative support: Michael E. Phelps Provision of study materials or patients: Wei Chen, Cheri Geist, Johannes Czernin, Nagichettiar Satyamurthy, Whitney Pope, Albert Lai, Timothy Cloughesy Collection and assembly of data: Wei Chen, Sibylle Delaloye, Daniel H.S. Silverman, Whitney Pope, Timothy Cloughesy Data analysis and interpretation: Wei Chen, Sibylle Delaloye, Daniel H.S. Silverman, Cheri Geist, Johannes Czernin, James Sayre, Whitney Pope, Timothy Cloughesy Manuscript writing: Wei Chen, Cheri Geist, Johannes Czernin, Timothy Cloughesy Final approval of manuscript: Wei Chen, Sibylle Delaloye, Daniel H.S. Silverman, Cheri Geist, Johannes Czernin, James Sayre, Nagichettiar Satyamurthy, Whitney Pope, Albert Lai, Michael E. Phelps, Timothy Cloughesy
Supported by Grant No. P50 CA086306 from the National Institutes of Health and National Cancer Institute, and by US Department of Energy contract DE-FC03-87-ER60615. Presented in part at the 53rd Annual Conference of the Society of Nuclear Medicine, June 3-7, 2006, San Diego, CA. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
