- Email: [email protected]
Tumor Volume Changes During and After Temozolomide Treatment for Newly Diagnosed Higher-Grade Glioma (III and IV)
Accepted Manuscript Tumor volume changes during and after temozolomide treatment for newly diagnosed higher-grade glioma (III and IV) Hung-Chen Wang, MD, PhD, Yu-Tsai Lin, MD, Wei-Che Lin, MD, PhD, Ren-Wen Ho, MD, Yu-Jun Lin, MD, Nai-Wen Tsai, MD, PhD, Jih-Tsun Ho, MD, PhD, Cheng-Hsien Lu, MD PII:
S1878-8750(18)30556-4
DOI:
10.1016/j.wneu.2018.03.078
Reference:
WNEU 7690
To appear in:
World Neurosurgery
Received Date: 23 October 2017 Accepted Date: 9 March 2018
Please cite this article as: Wang H-C, Lin Y-T, Lin W-C, Ho R-W, Lin Y-J, Tsai N-W, Ho J-T, Lu C-H, Tumor volume changes during and after temozolomide treatment for newly diagnosed higher-grade glioma (III and IV), World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.03.078. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Tumor volume changes during and after temozolomide treatment for newly diagnosed
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higher-grade glioma (III and IV)
Hung-Chen Wang, MD, PhD1; Yu-Tsai Lin, MD2; Wei-Che Lin, MD, PhD3; Ren-Wen Ho, MD4; Yu-Jun Lin, MD1; Nai-Wen Tsai, MD, PhD5; Jih-Tsun Ho, MD, PhD1*;
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Cheng-Hsien Lu, MD5 *()
Department of Neurosurgery1, Otolaryngology2, Neuroradiology3, Ophthalmology4 and
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Neurology5, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan Corresponding author: Jih-Tsun Ho and Cheng-Hsien Lu () Department of Neurology Chang Gung Memorial Hospital
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123, Ta Pei Road, Niao Sung District Kaohsiung, Taiwan TEL: +886-7-7317123 ext. 8011 FAX: +886-7-7902684
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E-mail: [email protected]
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Short title: Tumor volume changes in temozolomide treatment Funding: None of the authors have any commercial association, such as consultancies, stock ownership, or other equity interests or patent-licensing arrangements that may influence this study. E-mail address Hung-Chen Wang: [email protected] Yu-Tsai Lin: [email protected]
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Wei-Che Lin: [email protected] Ren-Wen Ho: [email protected] Yu-Jun Lin: [email protected]
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Nai-Wen Tsai: [email protected] Jih-Tsun Ho: [email protected] Cheng-Hsien Lu: [email protected]
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Abstract
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Background: A standard post-concomitant radiochemotherapy involving adjuvant temozolomide (TMZ) was stopped after 6 cycles for high-grade gliomas (HGG). Several
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studies demonstrated that prolonged TMZ treatment increased survival for these patients.
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Methods: This retrospective study aimed to compare changes in tumor volume during and after adjuvant TMZ treatment and overall survival (OS).
Results: There were 90 patients were administered adjuvant TMZ treatment. Comparing average tumor volume changes during TMZ treatment and after TMZ
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was stopped, a significant decrease in tumor volume was observed during TMZ treatment in the total patient population, the AA group, and the GBM group (P
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≤ .001, P = .042, and P = .005, respectively). Median OS was 78.4 weeks and was
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significant regarding the surgical tumor resection rate (r = 0.241; P = .04) and total TMZ treatment cycles (r = 0.631, P ≤ .001). Conclusions: During adjuvant TMZ treatment, tumor volume significantly decreased in patients with GBM and AA. Prolonged TMZ administration improved
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OS, without increased toxicity.
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Keywords: glioblastoma multiforme; anaplastic astrocytoma; temozolomide; tumor
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volume; overall survival
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Introduction
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High-grade gliomas (HGG) are the most frequent malignant primary brain tumor in adults and account for 80% of all gliomas in the United States.[1] The role of
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concomitant radiochemotherapy (CCRT) followed by adjuvant temozolomide (TMZ) has
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become the current standard of care for both anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). However, in a trial by Stupp et al., adjuvant TMZ was stopped after 6 cycles, but its optimal duration remains unknown.[2] Several institutions have studied the prolonged administration of TMZ and shown increased survival for
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these patients.[3-8] Canadian recommendations for the treatment of GBM suggest a longer duration may be considered in patients who experienced continuous improvement
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at the end of the sixth cycle.[9] Nevertheless, many questions remain, such as the best
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treatment choice for HGG, and there is a rationale for longer TMZ treatment cycles for the management of HGG. In this study, we evaluated the efficacy of prolonged TMZ treatment in patients with
HGG treated at a single institution. We aimed to compare changes in tumor volume
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during and after adjuvant TMZ treatment and overall survival (OS) with additional TMZ
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cycles.
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Materials and Methods
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Patients who were ≥20 years of age with newly diagnosed, histologically confirmed, supratentorial HGG were eligible for participation in the study (WHO grade III and IV
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astrocytoma). Additional eligibility criteria included adequate hematologic, renal, and
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hepatic function. Patients with histologically confirmed malignant gliomas who were initially treated at hospitals other than ours but who were subsequently transferred to our hospital for additional treatment were eligible.
From January 2009 to December 2014, there were 106 patients with newly
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diagnosed and histologically confirmed malignant HGG treated in our hospital. Three patients with histology consistent with AA who were administered RT only were excluded.
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There were 103 patients included in this study. The study protocol was approved by
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Institutional Review Committees on Human Research at the Chang Gung Memorial Hospital (Institutional Review Board numbers: 104-3909B). The demographic characteristics of these patients were documented, including length
of hospital stay, neurosurgical interventions, and underlying systemic diseases. The
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Glasgow Coma Score (GCS) was determined by neurosurgeons or a neurologist when
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patients arrived at our hospital.
After undergoing a surgical tumor resection or biopsy, patients were administered
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concurrent radiotherapy and CCRT. Radiotherapy consisted of fractionated focal
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irradiation administered at a dose of 180 cGy per fraction given once daily for 5 days a week for a total dose of 6660 cGy. Conformal therapy was delivered at an initial volume consisting of the area of enhancement or the postoperative cavity plus surrounding edema (or other abnormality as seen on fluid-attenuated inversion recovery [FLAIR] MRI scans)
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with a 2- to 3-cm margin for the clinical target volume. Radiotherapy was planned with dedicated CT and 3-dimensional planning systems.
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Chemotherapy treatment with TMZ, at a dose of 75 mg per square meter of body
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surface area (mg/m2), was started at the initiation of radiotherapy and continued daily until the completion of radiotherapy; then, 150 to 200 mg/m2 postirradiation on a 5-day schedule every 28 days if unacceptable toxic effects did not develop. Survivors obtained follow-up in the outpatient department (OPD) after discharge. Adverse effects of the TMZ
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therapy were regularly recorded.
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Each patient underwent an initial brain MRI scan during his or her first hospitalization. A repeat tumor-imaging study was performed as the following time points:
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1) approximately 4 weeks after surgical tumor excision or before radiotherapy; 2)
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approximately 4 weeks after completion of CCRT; 3) every 3 months for the first year; and 4) every 6 months annually. Emergency follow-up CT or MRI scans were performed in the event of clinical deterioration, including acute onset of focal neurologic deficits, seizures, or status epilepticus; and a progressive disturbance of consciousness.
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We measured tumor volumes using gadolinium-enhanced MRI scans. Changes in tumor volume during TMZ treatment were defined as follows: (the
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tumor volume in MRI most closed adjuvant TMZ was stopped) – (the tumor
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volume in MRI most closed adjuvant TMZ was started). The tumor volume changed after the TMZ treatment was stopped and was defined as follows: (tumor volume in a final MRI) – (the tumor volume in an MRI most closed adjuvant TMZ was stopped). A radiologist (W.-C. L.) experienced in MRI interpretation who was
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blinded to the patients’ clinical and biochemical data analyzed the MRIs so
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volumetric measurements of the tumor volumes could be determined. All images
were processed with image processing software (Vitrea version 3.9.0.1, Vital
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images, Minnesota, U.S.A) running on an offline workstation. The tumor volumes
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were calculated using a semiautomated process. The examiner manually drew regions of interest (ROI) in each slice throughout the tumor. Contiguous voxels were automatically summed to yield a tumor volume. The observer (W.-C. L.) drew the tumor twice at an interval of 1 month apart. Maps of the ROI that were used for
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measurement were stored and then confirmed by a neurosurgeon (H.-C. W.). Intraobserver and interobserver reproducibility of these measurements was
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evaluated using intraclass correlation coefficients. For tumor volume measurements,
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the intraobserver agreement (W.-C. L.) was r = 0.99, and the interobserver agreement (between W.-C. L. and H.-C. W.) was r = 0.99. Adverse events that occurred during treatment or after completion of therapy
were recorded and graded using the National Cancer Institute Common Toxicity
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Criteria (version 3). The follow-up period was terminated by death or the end of the
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study itself (August 15, 2015). Most patients obtained follow-up at an outpatient
department after discharge, and others were interviewed by telephone to identify
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neurological outcomes.
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The primary endpoint was OS, which was defined as the time until death from any cause. OS was calculated from date of diagnosis until death according to the Kaplan–Meier method.
Several separate statistical analyses were performed. First, a comparison
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was performed of patients who were administered ≤6 cycles of TMZ and those who were administered >6 cycles of TMZ. Baseline clinical data including gender,
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clinical manifestations, histology, neurosurgical intervention, adverse events, and
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mortality between the 2 patient groups were analyzed using a χ2 or Fisher’s exact test. The mean ages and OS between the 2 patient groups were assessed using a Mann–Whitney test. Changes in tumor volume during and after TMZ treatment were analyzed using a paired t-test. Correlation among OS, the surgical tumor
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resection rate, and total TMZ treatment cycles was analyzed. All statistical analyses
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Statistical Institute, Cary, North Carolina).
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were conducted using the SAS software package, version 9.1 (2002, SAS
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Results
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Patient Characteristics
The 103 patients with HGGs included 60 men and 43 women (age range,
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21-87 years; median age, 60 years). Of these patients, 75.7% had clear
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consciousness upon admission, and the other 25 (24.3%) patients were unclear. Surgical intervention included 6 biopsies (5.8%), 60 partial resections (58.3%), and 37 complete resections (35.9%). Further, 73.8% had GBM, and the other 27 (26.2%) had AA. The median time between surgery and CCRT treatment was 29
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days, with a range of 17–66 days. The median follow-up was 56.7 weeks with a range of 8–339.7 weeks (Table 1).
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Drug Exposure
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Patients treated with adjuvant TMZ (n = 90) were administered a median of 10 cycles (range, 1-53 cycles) (Table 1). Thirty-two patients treated with standard TMZ (≤6 cycles) were administered a median of 3 cycles (range, 1-6 cycles), and 58 patients treated with prolonged TMZ treatment (>6 cycles) were administered a
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median of 13 cycles (range, 7-53 cycles) (Table 2).
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Safety
Toxicity data were derived from detailed chart reviews performed by the
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treating physicians. In patients in the standard TMZ treatment group (≤6 cycles),
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major adverse events included grade III or IV thrombocytopenia (n = 4, 12.5%), leukopenia (n = 3, 9.5%), gastrointestinal toxicity (n = 2, 6.3%), and infection (n = 4, 12.5%). In patients in the prolonged TMZ treatment group (>6 cycles), major adverse events included grade III or IV thrombocytopenia (n = 5, 8.6%),
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leukopenia (n = 4, 6.9%), gastrointestinal toxicity (n = 3, 5.2%), and infection (n =
2).
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4, 6.9%). There were no significant adverse events between these 2 groups (Table
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Mortality and Overall Survival
There were a total 62 patients who died during this period, including 13 who
died between surgery and CCRT (2, AA, and 11, GBM); 4 died during the adjuvant TMZ treatment (2, AA, and 2, GBM), and 45 died after the adjuvant TMZ
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treatment was stopped (11, AA, and 34, GBM). Forty-seven of these 62 patients
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had GBM, and the other 15 had AA based on pathology. Median OS was 78.4 weeks, with a range of 6-339.7 weeks (Table 1). Comparing AA and GBM, the
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median survival time was 170.4 weeks and 72.3 weeks, respectively (P = .039,
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Figure 1). Comparing the standard and prolonged TMZ treatment groups, median OS was 46.3 weeks (range, 6-170.4 weeks) and 156.9 weeks (range, 31-339.7 weeks), respectively (P ≤ .001, Table 2). For patients who had histology comprising GBM, median OS was 46.3 weeks (range, 6-155.1 weeks) and 105.9
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weeks (range, 31-339.7 weeks) in the standard TMZ and prolonged TMZ groups, respectively (P ≤ .001, Table 2). For patients who had histology comprising AA,
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median OS was 66.3 weeks (range, 15.6-170.4 weeks) and 156.9 weeks (range,
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48.1-322 weeks) in the standard and prolonged TMZ groups, respectively (P = .025, Table 2).
Changes in tumor volumes observed in the MRIs of these 103 patients are
listed in Table 3. The mean total tumor resection rate was 72.5%, including 60.8%
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in the subtotal tumor resection group and 95.2% in the total tumor resection group.
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The tumor resection rate was not significant between the AA and GBM groups. The mean total tumor volume changed during TMZ treatment and was -2198mm3,
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-126mm3 in the AA group and -2940mm3 in the GBM group (P = .595). The
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average total tumor volume change during TMZ treatment was -340mm3, -370mm3 in the AA group and -329 mm3 in the GBM group (P = .889). The mean total tumor volume change after TMZ treatment was 11889mm3, 13463mm3 in the AA group and 11270mm3 in the GBM group (P = .785). The average total tumor volume
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change after TMZ treatment was 1043mm3, 1234mm3 in the AA group and 970mm3 in the GBM group (P = .767).
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A comparison of average tumor volume change during and after TMZ
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treatment indicated a significant decrease in tumor volume during TMZ treatment in all patients, the AA group, and the GBM group (P ≤ .001, P = .042, and P = .005, respectively, Table 4).
OS was significantly correlated with the surgical tumor resection rate
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(Spearman’s r = 0.631, P ≤ .001, Figure 3).
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(Spearman’s r = 0.241, P = .04, Figure 2) and duration of all TMZ treatment cycles
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Discussion
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To our knowledge, this is the first study to evaluate changes in tumor volumes during and after adjuvant TMZ treatment based on enhanced MRI. We found that
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tumor volumes were significantly decreased during adjuvant TMZ treatment and
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then increased after the adjuvant TMZ treatment was stopped (P ≤ .001; Figure 4), and the difference was more significant in patients with GBM than in patients with AA (P = .005 and P = .042, respectively, Table 4). One recent case report by Liu et al. reported on a case of a 30-year-old man with GBM that affected his right
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thalamus, left lateral ventricle, and pineal region. The patient underwent treatment including an operation, concurrent radiochemotherapy, and 12-cycle adjuvant TMZ
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treatment. In their report, the masses in this patient nearly disappeared 15 months
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after the primary diagnosis, and no severe adverse events or neurological sequel occurred.[10] Temozolomide is an oral alkylating agent, and its main mechanism of action is methylation of O6-guanine, which causes breakage of DNA strands leading to apoptosis.[11] The enzyme O6-alkylguanine-DNA alkyltransferase removes the
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methyl group from O6-guanine, resulting in resistance of tumor cells to
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temozolomide. Prolonged use of temozolomide leads to a depletion of this enzyme, diminishing tumor resistance to the drug.[12] This might explain how the tumor
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volume decreased during adjuvant TMZ treatment; therefore, prolonged adjuvant
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TMZ treatment could extend OS.
In this study, OS was significantly and positively correlated with the surgical tumor resection rate and the duration of TMZ treatment (P = .04 and P ≤ .001, respectively). Prolonged TMZ use was associated with longer OS in our study and
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previous studies.[3-8] Median OS ranged from 24.6 months to 28 months and was reported if TMZ use was ≥6 cycles.[5-7] In our study, median OS was 78.4 weeks
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(19.6 months) in all patients: 46.3 weeks (11.8 months) in patients administered
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standard adjuvant TMZ (≤6 cycles) and 156.9 weeks (39.2 months) in patients administered prolonged adjuvant TMZ treatment (>6 cycles) (P ≤ .001, Table 2). The difference in OS between our results and previous studies might be because of histology; there were 27 (26.2%) patients with AA in our study, and previous studies
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included only patients who had GBM. For patients with GBM in our study, median
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OS was 46.3 weeks (11.8 months) in patients administered standard adjuvant TMZ (≤6 cycles) and 105.9 weeks (26.5 months) in patients administered prolonged
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adjuvant TMZ treatment (>6 cycles) (P ≤ .001, Table 2). Further, for patients with
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AA in our study, median OS was 66.3 weeks (16.6 months) in patients administered standard adjuvant TMZ (≤6 cycles) and 156.9 weeks (39.2 months) in patients administered prolonged adjuvant TMZ treatment (>6 cycles) (P = .025, Table 2). There have been several different adjuvant TMZ treatments investigated in
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previous studies. One similar study by Seiz et al. reported on 114 patients with GBM who were administered a median of 6 cycles of adjuvant temozolomide (range,
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1-57). Median OS for all patients was 15 months. OS directly correlated with the
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adjuvant TMZ cycles (each P < .0001).[3] In our study, OS was significantly correlated with the surgical tumor resection rate (r = 0.241, P = .04, Figure 2) and duration of all TMZ treatment cycles (r = 0.631, P ≤ .001, Figure 3). However, no significant influence from the extent of surgical treatment on OS (P = 0.4308) could
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be detected in Seiz et al. study.[3]
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In a study by Erpolat et al.,[4] the important prognostic factors were type of surgery and adjuvant temozolomide treatment for at least 4 cycles. However, they
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used adjuvant TMZ cycles of ≤3 and >3 to define patient groups and obtained
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differences (8.7 vs 20 months, respectively). A retrospective analysis was conducted of 37 patients with newly diagnosed GBM. Their results showed that patients treated with >6 TMZ cycles had an OS that was significantly longer than patients administered standard treatment (median OS, 28 months vs 8 months, respectively;
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P = .0001).[6] In a study by Darlix et al.,[7] 38 patients were administered 6 cycles, and 20 patients were administered ≥9 (median, 14) cycles. Prolonged treatment
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improved OS (P = .01).[7] Furthermore, the risk of recurrence was significantly
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higher in the group administered 6 cycles, as compared with the other group.[7] In a study by Urgoiti et al., adjuvant TMZ for >6 cycles was an independent prognostic factor for OS.[5]
Different TMZ treatment protocols have been investigated by several study
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groups. In a study by Mao et al.,[13] 52 patients were treated with a CCRT regimen
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plus early postsurgical TMZ (early TMZ group), and 47 patients were treated with a standard CCRT regimen (control group). In the early TMZ treatment group, 14 days
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after surgery, TMZ was administered orally at 75 mg/m2/d for 14 days. The median
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OS time in the early TMZ treatment group was 17.6 months, as compared with 13.2 months in the control group (P = .021). According to their results, the addition of TMZ during an early break from a standard CCRT regimen improved OS for patients with GBM, as compared with the standard CCRT regimen, but OS was
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shorter, as compared with other prolonged TMZ treatment studies. In a dose-dense TMZ study by Gilbert et al.,[14] patients were randomly assigned to standard TMZ
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(arm 1) or dose-dense (75-100 mg/m2 on days 1 to 21 every 28 days for a maximum
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of 12 cycles) TMZ (arm 2) for 6 to 12 cycles. A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1173 registered). No difference was observed between arms regarding median OS (16.6 vs 14.9 months, respectively). There was an increased incidence of grade ≥3 toxicities in arm 2 (34% vs 53%; P < .001). Their
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diagnosed GBM, regardless of methylation status.[14]
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study did not demonstrate improved efficacy for dose-dense TMZ in newly
In patients with recurrent or progressive HGGs, Galldiks et al. suggested that
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adjuvant TMZ at 150 mg/m²/day on days 1–7 and 15–21 of a 28-day cycle (1-week
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on/1-week off scheme; TMZ 7/14).[15] Fifty-four patients with recurrent or progressive HGGs were treated with a 1-week on/1-week off scheme (TMZ 7/14) with individual dose adjustments depending on toxicity. The median number of treatment weeks was 7 (range, 1-41 weeks). Median OS was 37 weeks (95% CI,
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31-42 weeks). No grade IV hematological toxicity or opportunistic infections occurred. Their data suggest that treatment with TMZ 7/14 is safe and effective in
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patients with recurrent or progressive HGG.[15]
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TMZ can be responsible for toxicities such as myelosuppression, and significant thrombocytopenia has been observed in 12–20% of patients.[16] Side effects occurred more frequently with early TMZ treatment (<6 cycles) in recent studies.[3, 17] Prolonged TMZ treatment has been investigated in several studies that suggested no significant
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increase in toxicity.[5-8, 18, 19] In our study, the prolonged TMZ treatment group (TMZ
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>6 cycles) experienced lower hematological toxicity, gastrointestinal toxicity, and opportunistic infections than the standard TMZ treatment group (TMZ ≤6 cycles) that
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was not significant. In a study by Malkoun et al., adjuvant TMZ was prescribed for a total
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of 24 cycles, unless there was progression or toxicities, and no treatment disruption for toxicity was necessary; however, 8 patients required dose adjustments because of side effects.[8] In our study, toxicity data were derived from detailed chart reviews performed by the treating physicians that corresponded well with the low incidence of toxicity
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reported in prospective clinical trials involving TMZ. However, because of the retrospective nature of this study, the true incidence of toxicities may have been
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underestimated.
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In glioblastoma, the promoter methylation status of the gene encoding for the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is undoubtedly with high impact on clinical practice.[20] MGMT is consumed when counteracting TMZ-induced DNA damage, and it has been predicted that the intracellular level of MGMT correlates
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with chemoresistance.[21] Because of the retrospective nature of this study, MGMT
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information is not provided. However, analysis of MGMT protein expression in glioblastoma tissue by immunohistochemistry failed to correlate with survival under
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chemoradiotherapy.[22]
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Conclusions
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Surgery remains the main treatment both to confirm the diagnosis of and to relieve symptoms related to an intracranial mass. During adjuvant TMZ treatment,
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the tumor volume was significantly decreased in patients with GBM and AA.
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Prolonged administration of TMZ improved OS, without increased toxicity was found in our study. Prospective studies in larger populations are needed to better
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define the population to whom it can be proposed, along with optimal duration.
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Disclosure
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in this study or the findings specified in this paper.
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The authors report no conflict of interest concerning the materials or methods used
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Preusser, M., et al., Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker.
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Brain Pathol, 2008. 18(4): p. 520-32.
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Figure Legends
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Patients Enrollment, Treatment and Outcomes.
2.
Kaplan–Meier plots indicating OS for patients with anaplastic astrocytoma (AA,
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n = 27) and glioblastoma multiforme (GBM, n = 76). The P value was obtained
3.
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using a log-rank comparison of data.
Relationship between OS and the surgical tumor resection rate (Spearman’s r = 0.241, P = .04).
Relationship between OS and total TMZ treatment cycles (Spearman’s r = 0.631, P ≤ .001).
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A 52 years-old male was diagnosed left parietal glioblastoma multiforme. A, E: Pre-OP MRI. B, F: MRI one week after surgery. C, G: MRI after 36 TMZ
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treatment cycles. D, H: MRI 20 months after stopping TMZ.
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patients with intracranial malignant glioma (n=103)
Age (y) , median (range)
%
60 (21 - 87) 20
19.4
50-59 y
30
29.1
60-69 y
25
24.3
≥70 y
28
27.2
Male
60
GCS at admission, median (range)
15 (7 - 15)
Clear consciousness (GCS = 15)
78
Disturbed consciousness (GCS < 15)
25
Clinical features at the time of admission Fever
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<50 y
Seizure Motor deficit
Papilledema Underlying diseases
75.7 24.3
4.9
19
18.4
15
14.6
5
4.9
6
5.8
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58.3
-
Hypertension Diabetes mellitus Chronic obstructive pulmonary disease Atrial fibrillation Coronary artery disease ESRD
Laboratory data at presentation, Median (IQR) WBC (x103/mL) Platelet counts (x103/mL) Surgical intervention
33.0
16
15.1
1
1.0
2
1.9
2
1.9
4
3.9
11
10.7
12.5 (3.6 - 27.7) 196 (78 - 473)
6
5.8
60
58.3
37
35.9
Glioblastoma multiforme
76
73.8
Anaplastic astrocytoma
27
26.2
Subtotal resection grossly total resection
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Pathology
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Biopsy
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Smoking
34
Time between surgery and CCRT treatment (days), median (range)
29 (17 - 66)
TMZ cycle, median (range)
10 (1 - 53)
Mortality
62
60.2
Before TMZ treatment
13
12.6
During TMZ treatment
4
3.9
45
43.7
After TMZ treatment Overall survival time (weeks), median (range)
78.4 (6 - 339.7)
Glioblastoma multiforme
72.3 (6 - 339.7)
Anaplastic astrocytoma
156.9 (15.6 – 322)
GCS=Glasgow coma score; SD=standard deviation; IQR= interquartile range CCRT=concomitant chemoradiotherapy; TMZ= temozolomide
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Age (y) , median (range)
TMZ treatment of ≤6 cycles (n=32)
TMZ treatment of >6 cycles (n=58)
59.5 (26 – 84)
58 (21 – 87)
Sex, n (%)
P value
0.373
Male
17 (53.1)
37 (63.8)
Female
15 (46.9)
21 (36.2)
Histology, n (%) 25 (78.1)
Anaplastic astrocytoma
7 (21.9)
Surgical intervention Biopsy
1 (3.1) 19 (59.4)
grossly total resection
12 (37.5)
TMZ cycles, median (range)
3 (1 – 6)
40 (69) 18 (31)
3 (5.2)
1.000
34 (58.6)
1.000
21 (36.2)
1.000
Grade III or IV thrombocytopenia
4 (12.5)
Leukopenia
3 (9.4)
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Subtotal resection
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0.463
Glioblastoma
2 (6.3)
Gastrointestinal toxicity Infection Overall survival time (weeks), median (range) Glioblastoma multiforme Anaplastic astrocytoma Mortality
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0.454
4 (6.9)
0.778
3 (5.2)
1.000
4 (12.5)
4 (6.9)
0.283
156.9 (31 – 339.7)
≤0.001
46.3 (6 – 155.1)
105.9 (31- 339.7)
≤0.001
66.3 (15.6 – 170.4)
156.9 (48.1 – 322)
0.025
25 (78.1)
24 (41.4)
0.001
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5 (8.6)
46.3 (6 – 170.4)
GCS=Glasgow coma score; SD=standard deviation; IQR= interquartile range CCRT=concomitant chemoradiotherapy; TMZ= temozolomide
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Table 3 Tumor Volume Change during and after Temozolomide Treatment Surgery (n=103)
During temozolomide treatment (n=90)
Preoperative tumor Postoperative tumor Tumor resection rate volume (mm3) volume (mm3) (%)
Tumor volume change (mm3)
After temozolomide treatment (n=86)
Average tumor change (mm3) (per week)
Tumor volume change (mm3)
Average tumor change (mm3) (per week)
10603
72.5
-2198
-340
11889
1043
55798.4
--
--
-22594.7
-800.6
32.8
12.5
Subtotal tumor resection (n=60)
37697.7
13510.6
60.8
-4368.5
Grossly total tumor resection (n=37)
45635.3
4053.2
95.2
33348.0
7583.3
65.3
726.4
--
--
Subtotal tumor resection (n=19)
25780.6
8083.6
58.3
Grossly total tumor resection (n=6)
65509.5
7289.4
93.4
43376.1
11801.2
Biopsy(n=2)
Glioblastoma multiforme(n=76)
55798.4
--
Subtotal tumor resection (n=41)
43325.1
16486.7
Grossly total tumor resection (n=31)
42455.4
3430.9
9829. 4
778.0
-183.45
16164.2
1515.2
-126.5
-370.7
13463.9
1234.6
-410.9
-10.1
1.15
0.01
2014.9
-206.1
20321.2
1713.6
-5637.3
-870.8
1951.5
585.3
75.0
-2940. 8
-329.4
11270.3
970.3
--
-44778.5
-1591.1
96
24. 9
61.6
-7134.6
-509.0
5091.1
362.2
95.4
4679.8
-27.2
19717.4
1763.1
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Biopsy(n=4)
-417.5
2769.2
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Anaplastic astrocytoma (n=27)
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Biopsy(n=6)
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Total (n=103)
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Parameter
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Table 4 Tumor Volume Changes in Response to Temozolomide 3
Average tumor volume change (mm )
Subtotal tumor resection (n=53) Grossly tumor resection (n=33)
-417.5 -183.45
778.0 1515.2
Anaplastic Astrocytoma (n=25) Biopsy(n=2) Subtotal tumor resection (n=17) Grossly tumor resection (n=6)
-370.7 -10.1 -206.1 -870.8
1234.6 0.01 1713.6 585.3
Glioblastoma multiforme(n=65) Biopsy(n=2) Subtotal tumor resection (n=36) Grossly tumor resection (n=27)
-329.4 -1591.1 -509.0 -27.2
-2364.9
-735.4
--
--
≤0.001 --
-2450.3 -3278.9
-384.5 -204.3
0.009 0.029
-3900.7 --4987.6 -5581.1
-86.0 --678.8 238.2
0.042 -0.015 0.067
970.3 24. 9 362.2 1763.1
-2306.5 --2094.8 -3712.8
-450.7 --46.5 -186.3
0.005 -0.042 0.022
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Total (n=90) Biopsy(n=4)
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After temozolomide treatment (n=86) 1043 12.5
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GCS=Glasgow coma score; SD=standard deviation; IQR= interquartile range CCRT=concomitant chemoradiotherapy
P value
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During temozolomide treatment (n=90) -340 -800.6
95% Confidence Interval Lower Upper
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Parameter
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ACCEPTED MANUSCRIPT Highlights > A significant decrease in tumor volume was observed during temozolomide treatment. > Median overall survival was significant regarding the surgical tumor resection rate (r = 0.241; P = .04) and total temozolomide treatment cycles (r = 0.631, P ≤ .001). > Prolonged temozolomide administration improved overall survival, without
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increased toxicity.
ACCEPTED MANUSCRIPT Abbreviations list: High-grade gliomas (HGG); concomitant radiochemotherapy (CCRT); temozolomide (TMZ), anaplastic astrocytoma (AA), glioblastoma multiforme
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(GBM), overall survival (OS); Glasgow Coma Score (GCS); magnetic resonance imaging (MRI); computer tomography (CT); outpatient department (OPD); regions of
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interest (ROI).
S1878-8750(18)30556-4
DOI:
10.1016/j.wneu.2018.03.078
Reference:
WNEU 7690
To appear in:
World Neurosurgery
Received Date: 23 October 2017 Accepted Date: 9 March 2018
Please cite this article as: Wang H-C, Lin Y-T, Lin W-C, Ho R-W, Lin Y-J, Tsai N-W, Ho J-T, Lu C-H, Tumor volume changes during and after temozolomide treatment for newly diagnosed higher-grade glioma (III and IV), World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.03.078. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Tumor volume changes during and after temozolomide treatment for newly diagnosed
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higher-grade glioma (III and IV)
Hung-Chen Wang, MD, PhD1; Yu-Tsai Lin, MD2; Wei-Che Lin, MD, PhD3; Ren-Wen Ho, MD4; Yu-Jun Lin, MD1; Nai-Wen Tsai, MD, PhD5; Jih-Tsun Ho, MD, PhD1*;
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Cheng-Hsien Lu, MD5 *()
Department of Neurosurgery1, Otolaryngology2, Neuroradiology3, Ophthalmology4 and
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Neurology5, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan Corresponding author: Jih-Tsun Ho and Cheng-Hsien Lu () Department of Neurology Chang Gung Memorial Hospital
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123, Ta Pei Road, Niao Sung District Kaohsiung, Taiwan TEL: +886-7-7317123 ext. 8011 FAX: +886-7-7902684
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E-mail: [email protected]
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Short title: Tumor volume changes in temozolomide treatment Funding: None of the authors have any commercial association, such as consultancies, stock ownership, or other equity interests or patent-licensing arrangements that may influence this study. E-mail address Hung-Chen Wang: [email protected] Yu-Tsai Lin: [email protected]
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Wei-Che Lin: [email protected] Ren-Wen Ho: [email protected] Yu-Jun Lin: [email protected]
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Nai-Wen Tsai: [email protected] Jih-Tsun Ho: [email protected] Cheng-Hsien Lu: [email protected]
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Abstract
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Background: A standard post-concomitant radiochemotherapy involving adjuvant temozolomide (TMZ) was stopped after 6 cycles for high-grade gliomas (HGG). Several
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studies demonstrated that prolonged TMZ treatment increased survival for these patients.
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Methods: This retrospective study aimed to compare changes in tumor volume during and after adjuvant TMZ treatment and overall survival (OS).
Results: There were 90 patients were administered adjuvant TMZ treatment. Comparing average tumor volume changes during TMZ treatment and after TMZ
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was stopped, a significant decrease in tumor volume was observed during TMZ treatment in the total patient population, the AA group, and the GBM group (P
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≤ .001, P = .042, and P = .005, respectively). Median OS was 78.4 weeks and was
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significant regarding the surgical tumor resection rate (r = 0.241; P = .04) and total TMZ treatment cycles (r = 0.631, P ≤ .001). Conclusions: During adjuvant TMZ treatment, tumor volume significantly decreased in patients with GBM and AA. Prolonged TMZ administration improved
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OS, without increased toxicity.
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Keywords: glioblastoma multiforme; anaplastic astrocytoma; temozolomide; tumor
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volume; overall survival
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Introduction
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High-grade gliomas (HGG) are the most frequent malignant primary brain tumor in adults and account for 80% of all gliomas in the United States.[1] The role of
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concomitant radiochemotherapy (CCRT) followed by adjuvant temozolomide (TMZ) has
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become the current standard of care for both anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). However, in a trial by Stupp et al., adjuvant TMZ was stopped after 6 cycles, but its optimal duration remains unknown.[2] Several institutions have studied the prolonged administration of TMZ and shown increased survival for
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these patients.[3-8] Canadian recommendations for the treatment of GBM suggest a longer duration may be considered in patients who experienced continuous improvement
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at the end of the sixth cycle.[9] Nevertheless, many questions remain, such as the best
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treatment choice for HGG, and there is a rationale for longer TMZ treatment cycles for the management of HGG. In this study, we evaluated the efficacy of prolonged TMZ treatment in patients with
HGG treated at a single institution. We aimed to compare changes in tumor volume
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during and after adjuvant TMZ treatment and overall survival (OS) with additional TMZ
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cycles.
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Materials and Methods
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Patients who were ≥20 years of age with newly diagnosed, histologically confirmed, supratentorial HGG were eligible for participation in the study (WHO grade III and IV
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astrocytoma). Additional eligibility criteria included adequate hematologic, renal, and
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hepatic function. Patients with histologically confirmed malignant gliomas who were initially treated at hospitals other than ours but who were subsequently transferred to our hospital for additional treatment were eligible.
From January 2009 to December 2014, there were 106 patients with newly
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diagnosed and histologically confirmed malignant HGG treated in our hospital. Three patients with histology consistent with AA who were administered RT only were excluded.
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There were 103 patients included in this study. The study protocol was approved by
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Institutional Review Committees on Human Research at the Chang Gung Memorial Hospital (Institutional Review Board numbers: 104-3909B). The demographic characteristics of these patients were documented, including length
of hospital stay, neurosurgical interventions, and underlying systemic diseases. The
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Glasgow Coma Score (GCS) was determined by neurosurgeons or a neurologist when
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patients arrived at our hospital.
After undergoing a surgical tumor resection or biopsy, patients were administered
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concurrent radiotherapy and CCRT. Radiotherapy consisted of fractionated focal
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irradiation administered at a dose of 180 cGy per fraction given once daily for 5 days a week for a total dose of 6660 cGy. Conformal therapy was delivered at an initial volume consisting of the area of enhancement or the postoperative cavity plus surrounding edema (or other abnormality as seen on fluid-attenuated inversion recovery [FLAIR] MRI scans)
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with a 2- to 3-cm margin for the clinical target volume. Radiotherapy was planned with dedicated CT and 3-dimensional planning systems.
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Chemotherapy treatment with TMZ, at a dose of 75 mg per square meter of body
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surface area (mg/m2), was started at the initiation of radiotherapy and continued daily until the completion of radiotherapy; then, 150 to 200 mg/m2 postirradiation on a 5-day schedule every 28 days if unacceptable toxic effects did not develop. Survivors obtained follow-up in the outpatient department (OPD) after discharge. Adverse effects of the TMZ
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therapy were regularly recorded.
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Each patient underwent an initial brain MRI scan during his or her first hospitalization. A repeat tumor-imaging study was performed as the following time points:
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1) approximately 4 weeks after surgical tumor excision or before radiotherapy; 2)
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approximately 4 weeks after completion of CCRT; 3) every 3 months for the first year; and 4) every 6 months annually. Emergency follow-up CT or MRI scans were performed in the event of clinical deterioration, including acute onset of focal neurologic deficits, seizures, or status epilepticus; and a progressive disturbance of consciousness.
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We measured tumor volumes using gadolinium-enhanced MRI scans. Changes in tumor volume during TMZ treatment were defined as follows: (the
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tumor volume in MRI most closed adjuvant TMZ was stopped) – (the tumor
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volume in MRI most closed adjuvant TMZ was started). The tumor volume changed after the TMZ treatment was stopped and was defined as follows: (tumor volume in a final MRI) – (the tumor volume in an MRI most closed adjuvant TMZ was stopped). A radiologist (W.-C. L.) experienced in MRI interpretation who was
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blinded to the patients’ clinical and biochemical data analyzed the MRIs so
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volumetric measurements of the tumor volumes could be determined. All images
were processed with image processing software (Vitrea version 3.9.0.1, Vital
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images, Minnesota, U.S.A) running on an offline workstation. The tumor volumes
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were calculated using a semiautomated process. The examiner manually drew regions of interest (ROI) in each slice throughout the tumor. Contiguous voxels were automatically summed to yield a tumor volume. The observer (W.-C. L.) drew the tumor twice at an interval of 1 month apart. Maps of the ROI that were used for
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measurement were stored and then confirmed by a neurosurgeon (H.-C. W.). Intraobserver and interobserver reproducibility of these measurements was
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evaluated using intraclass correlation coefficients. For tumor volume measurements,
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the intraobserver agreement (W.-C. L.) was r = 0.99, and the interobserver agreement (between W.-C. L. and H.-C. W.) was r = 0.99. Adverse events that occurred during treatment or after completion of therapy
were recorded and graded using the National Cancer Institute Common Toxicity
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Criteria (version 3). The follow-up period was terminated by death or the end of the
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study itself (August 15, 2015). Most patients obtained follow-up at an outpatient
department after discharge, and others were interviewed by telephone to identify
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neurological outcomes.
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The primary endpoint was OS, which was defined as the time until death from any cause. OS was calculated from date of diagnosis until death according to the Kaplan–Meier method.
Several separate statistical analyses were performed. First, a comparison
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clinical manifestations, histology, neurosurgical intervention, adverse events, and
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mortality between the 2 patient groups were analyzed using a χ2 or Fisher’s exact test. The mean ages and OS between the 2 patient groups were assessed using a Mann–Whitney test. Changes in tumor volume during and after TMZ treatment were analyzed using a paired t-test. Correlation among OS, the surgical tumor
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resection rate, and total TMZ treatment cycles was analyzed. All statistical analyses
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Statistical Institute, Cary, North Carolina).
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were conducted using the SAS software package, version 9.1 (2002, SAS
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Results
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Patient Characteristics
The 103 patients with HGGs included 60 men and 43 women (age range,
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21-87 years; median age, 60 years). Of these patients, 75.7% had clear
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consciousness upon admission, and the other 25 (24.3%) patients were unclear. Surgical intervention included 6 biopsies (5.8%), 60 partial resections (58.3%), and 37 complete resections (35.9%). Further, 73.8% had GBM, and the other 27 (26.2%) had AA. The median time between surgery and CCRT treatment was 29
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days, with a range of 17–66 days. The median follow-up was 56.7 weeks with a range of 8–339.7 weeks (Table 1).
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Drug Exposure
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Patients treated with adjuvant TMZ (n = 90) were administered a median of 10 cycles (range, 1-53 cycles) (Table 1). Thirty-two patients treated with standard TMZ (≤6 cycles) were administered a median of 3 cycles (range, 1-6 cycles), and 58 patients treated with prolonged TMZ treatment (>6 cycles) were administered a
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median of 13 cycles (range, 7-53 cycles) (Table 2).
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Safety
Toxicity data were derived from detailed chart reviews performed by the
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treating physicians. In patients in the standard TMZ treatment group (≤6 cycles),
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major adverse events included grade III or IV thrombocytopenia (n = 4, 12.5%), leukopenia (n = 3, 9.5%), gastrointestinal toxicity (n = 2, 6.3%), and infection (n = 4, 12.5%). In patients in the prolonged TMZ treatment group (>6 cycles), major adverse events included grade III or IV thrombocytopenia (n = 5, 8.6%),
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leukopenia (n = 4, 6.9%), gastrointestinal toxicity (n = 3, 5.2%), and infection (n =
2).
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4, 6.9%). There were no significant adverse events between these 2 groups (Table
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Mortality and Overall Survival
There were a total 62 patients who died during this period, including 13 who
died between surgery and CCRT (2, AA, and 11, GBM); 4 died during the adjuvant TMZ treatment (2, AA, and 2, GBM), and 45 died after the adjuvant TMZ
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treatment was stopped (11, AA, and 34, GBM). Forty-seven of these 62 patients
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had GBM, and the other 15 had AA based on pathology. Median OS was 78.4 weeks, with a range of 6-339.7 weeks (Table 1). Comparing AA and GBM, the
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median survival time was 170.4 weeks and 72.3 weeks, respectively (P = .039,
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Figure 1). Comparing the standard and prolonged TMZ treatment groups, median OS was 46.3 weeks (range, 6-170.4 weeks) and 156.9 weeks (range, 31-339.7 weeks), respectively (P ≤ .001, Table 2). For patients who had histology comprising GBM, median OS was 46.3 weeks (range, 6-155.1 weeks) and 105.9
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weeks (range, 31-339.7 weeks) in the standard TMZ and prolonged TMZ groups, respectively (P ≤ .001, Table 2). For patients who had histology comprising AA,
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median OS was 66.3 weeks (range, 15.6-170.4 weeks) and 156.9 weeks (range,
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48.1-322 weeks) in the standard and prolonged TMZ groups, respectively (P = .025, Table 2).
Changes in tumor volumes observed in the MRIs of these 103 patients are
listed in Table 3. The mean total tumor resection rate was 72.5%, including 60.8%
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in the subtotal tumor resection group and 95.2% in the total tumor resection group.
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The tumor resection rate was not significant between the AA and GBM groups. The mean total tumor volume changed during TMZ treatment and was -2198mm3,
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-126mm3 in the AA group and -2940mm3 in the GBM group (P = .595). The
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average total tumor volume change during TMZ treatment was -340mm3, -370mm3 in the AA group and -329 mm3 in the GBM group (P = .889). The mean total tumor volume change after TMZ treatment was 11889mm3, 13463mm3 in the AA group and 11270mm3 in the GBM group (P = .785). The average total tumor volume
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change after TMZ treatment was 1043mm3, 1234mm3 in the AA group and 970mm3 in the GBM group (P = .767).
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A comparison of average tumor volume change during and after TMZ
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treatment indicated a significant decrease in tumor volume during TMZ treatment in all patients, the AA group, and the GBM group (P ≤ .001, P = .042, and P = .005, respectively, Table 4).
OS was significantly correlated with the surgical tumor resection rate
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(Spearman’s r = 0.631, P ≤ .001, Figure 3).
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(Spearman’s r = 0.241, P = .04, Figure 2) and duration of all TMZ treatment cycles
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Discussion
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To our knowledge, this is the first study to evaluate changes in tumor volumes during and after adjuvant TMZ treatment based on enhanced MRI. We found that
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tumor volumes were significantly decreased during adjuvant TMZ treatment and
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then increased after the adjuvant TMZ treatment was stopped (P ≤ .001; Figure 4), and the difference was more significant in patients with GBM than in patients with AA (P = .005 and P = .042, respectively, Table 4). One recent case report by Liu et al. reported on a case of a 30-year-old man with GBM that affected his right
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thalamus, left lateral ventricle, and pineal region. The patient underwent treatment including an operation, concurrent radiochemotherapy, and 12-cycle adjuvant TMZ
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treatment. In their report, the masses in this patient nearly disappeared 15 months
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after the primary diagnosis, and no severe adverse events or neurological sequel occurred.[10] Temozolomide is an oral alkylating agent, and its main mechanism of action is methylation of O6-guanine, which causes breakage of DNA strands leading to apoptosis.[11] The enzyme O6-alkylguanine-DNA alkyltransferase removes the
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methyl group from O6-guanine, resulting in resistance of tumor cells to
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temozolomide. Prolonged use of temozolomide leads to a depletion of this enzyme, diminishing tumor resistance to the drug.[12] This might explain how the tumor
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volume decreased during adjuvant TMZ treatment; therefore, prolonged adjuvant
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TMZ treatment could extend OS.
In this study, OS was significantly and positively correlated with the surgical tumor resection rate and the duration of TMZ treatment (P = .04 and P ≤ .001, respectively). Prolonged TMZ use was associated with longer OS in our study and
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previous studies.[3-8] Median OS ranged from 24.6 months to 28 months and was reported if TMZ use was ≥6 cycles.[5-7] In our study, median OS was 78.4 weeks
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(19.6 months) in all patients: 46.3 weeks (11.8 months) in patients administered
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standard adjuvant TMZ (≤6 cycles) and 156.9 weeks (39.2 months) in patients administered prolonged adjuvant TMZ treatment (>6 cycles) (P ≤ .001, Table 2). The difference in OS between our results and previous studies might be because of histology; there were 27 (26.2%) patients with AA in our study, and previous studies
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included only patients who had GBM. For patients with GBM in our study, median
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OS was 46.3 weeks (11.8 months) in patients administered standard adjuvant TMZ (≤6 cycles) and 105.9 weeks (26.5 months) in patients administered prolonged
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adjuvant TMZ treatment (>6 cycles) (P ≤ .001, Table 2). Further, for patients with
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AA in our study, median OS was 66.3 weeks (16.6 months) in patients administered standard adjuvant TMZ (≤6 cycles) and 156.9 weeks (39.2 months) in patients administered prolonged adjuvant TMZ treatment (>6 cycles) (P = .025, Table 2). There have been several different adjuvant TMZ treatments investigated in
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previous studies. One similar study by Seiz et al. reported on 114 patients with GBM who were administered a median of 6 cycles of adjuvant temozolomide (range,
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1-57). Median OS for all patients was 15 months. OS directly correlated with the
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adjuvant TMZ cycles (each P < .0001).[3] In our study, OS was significantly correlated with the surgical tumor resection rate (r = 0.241, P = .04, Figure 2) and duration of all TMZ treatment cycles (r = 0.631, P ≤ .001, Figure 3). However, no significant influence from the extent of surgical treatment on OS (P = 0.4308) could
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be detected in Seiz et al. study.[3]
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In a study by Erpolat et al.,[4] the important prognostic factors were type of surgery and adjuvant temozolomide treatment for at least 4 cycles. However, they
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used adjuvant TMZ cycles of ≤3 and >3 to define patient groups and obtained
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differences (8.7 vs 20 months, respectively). A retrospective analysis was conducted of 37 patients with newly diagnosed GBM. Their results showed that patients treated with >6 TMZ cycles had an OS that was significantly longer than patients administered standard treatment (median OS, 28 months vs 8 months, respectively;
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P = .0001).[6] In a study by Darlix et al.,[7] 38 patients were administered 6 cycles, and 20 patients were administered ≥9 (median, 14) cycles. Prolonged treatment
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improved OS (P = .01).[7] Furthermore, the risk of recurrence was significantly
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higher in the group administered 6 cycles, as compared with the other group.[7] In a study by Urgoiti et al., adjuvant TMZ for >6 cycles was an independent prognostic factor for OS.[5]
Different TMZ treatment protocols have been investigated by several study
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groups. In a study by Mao et al.,[13] 52 patients were treated with a CCRT regimen
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plus early postsurgical TMZ (early TMZ group), and 47 patients were treated with a standard CCRT regimen (control group). In the early TMZ treatment group, 14 days
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after surgery, TMZ was administered orally at 75 mg/m2/d for 14 days. The median
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OS time in the early TMZ treatment group was 17.6 months, as compared with 13.2 months in the control group (P = .021). According to their results, the addition of TMZ during an early break from a standard CCRT regimen improved OS for patients with GBM, as compared with the standard CCRT regimen, but OS was
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shorter, as compared with other prolonged TMZ treatment studies. In a dose-dense TMZ study by Gilbert et al.,[14] patients were randomly assigned to standard TMZ
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(arm 1) or dose-dense (75-100 mg/m2 on days 1 to 21 every 28 days for a maximum
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of 12 cycles) TMZ (arm 2) for 6 to 12 cycles. A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1173 registered). No difference was observed between arms regarding median OS (16.6 vs 14.9 months, respectively). There was an increased incidence of grade ≥3 toxicities in arm 2 (34% vs 53%; P < .001). Their
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diagnosed GBM, regardless of methylation status.[14]
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study did not demonstrate improved efficacy for dose-dense TMZ in newly
In patients with recurrent or progressive HGGs, Galldiks et al. suggested that
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adjuvant TMZ at 150 mg/m²/day on days 1–7 and 15–21 of a 28-day cycle (1-week
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on/1-week off scheme; TMZ 7/14).[15] Fifty-four patients with recurrent or progressive HGGs were treated with a 1-week on/1-week off scheme (TMZ 7/14) with individual dose adjustments depending on toxicity. The median number of treatment weeks was 7 (range, 1-41 weeks). Median OS was 37 weeks (95% CI,
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31-42 weeks). No grade IV hematological toxicity or opportunistic infections occurred. Their data suggest that treatment with TMZ 7/14 is safe and effective in
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patients with recurrent or progressive HGG.[15]
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TMZ can be responsible for toxicities such as myelosuppression, and significant thrombocytopenia has been observed in 12–20% of patients.[16] Side effects occurred more frequently with early TMZ treatment (<6 cycles) in recent studies.[3, 17] Prolonged TMZ treatment has been investigated in several studies that suggested no significant
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increase in toxicity.[5-8, 18, 19] In our study, the prolonged TMZ treatment group (TMZ
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>6 cycles) experienced lower hematological toxicity, gastrointestinal toxicity, and opportunistic infections than the standard TMZ treatment group (TMZ ≤6 cycles) that
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was not significant. In a study by Malkoun et al., adjuvant TMZ was prescribed for a total
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of 24 cycles, unless there was progression or toxicities, and no treatment disruption for toxicity was necessary; however, 8 patients required dose adjustments because of side effects.[8] In our study, toxicity data were derived from detailed chart reviews performed by the treating physicians that corresponded well with the low incidence of toxicity
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reported in prospective clinical trials involving TMZ. However, because of the retrospective nature of this study, the true incidence of toxicities may have been
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underestimated.
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In glioblastoma, the promoter methylation status of the gene encoding for the repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is undoubtedly with high impact on clinical practice.[20] MGMT is consumed when counteracting TMZ-induced DNA damage, and it has been predicted that the intracellular level of MGMT correlates
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with chemoresistance.[21] Because of the retrospective nature of this study, MGMT
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information is not provided. However, analysis of MGMT protein expression in glioblastoma tissue by immunohistochemistry failed to correlate with survival under
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chemoradiotherapy.[22]
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Conclusions
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Surgery remains the main treatment both to confirm the diagnosis of and to relieve symptoms related to an intracranial mass. During adjuvant TMZ treatment,
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the tumor volume was significantly decreased in patients with GBM and AA.
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Prolonged administration of TMZ improved OS, without increased toxicity was found in our study. Prospective studies in larger populations are needed to better
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define the population to whom it can be proposed, along with optimal duration.
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Disclosure
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in this study or the findings specified in this paper.
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The authors report no conflict of interest concerning the materials or methods used
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References Dolecek, T.A., et al., CBTRUS statistical report: primary brain and central
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1.
nervous system tumors diagnosed in the United States in 2005-2009. Neuro
Oncol, 2012. 14 Suppl 5: p. v1-49. Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide
2.
4.
Cancer Res Clin Oncol, 2010. 136(11): p. 1691-5. Erpolat, O.P., et al., Outcome of newly diagnosed glioblastoma patients treated by radiotherapy plus concomitant and adjuvant temozolomide: a
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SC
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for glioblastoma. N Engl J Med, 2005. 352(10): p. 987-96. Seiz, M., et al., Long-term adjuvant administration of temozolomide in patients with glioblastoma multiforme: experience of a single institution. J
long-term analysis. Tumori, 2009. 95(2): p. 191-7. Roldan Urgoiti, G.B., A.D. Singh, and J.C. Easaw, Extended adjuvant
5.
temozolomide for treatment of newly diagnosed glioblastoma multiforme. J Neurooncol, 2012. 108(1): p. 173-7. Barbagallo, G.M., et al., Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience
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6.
with as many as 101 temozolomide cycles. Neurosurg Focus, 2014. 37(6): p. E4. Darlix, A., et al., Prolonged administration of adjuvant temozolomide improves survival in adult patients with glioblastoma. Anticancer Res, 2013.
9.
33(8): p. 3467-74. Malkoun, N., et al., Prolonged temozolomide for treatment of glioblastoma: preliminary clinical results and prognostic value of p53 overexpression. J
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8.
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7.
10.
Neurooncol, 2012. 106(1): p. 127-33. Mason, W.P., et al., Canadian recommendations for the treatment of glioblastoma multiforme. Curr Oncol, 2007. 14(3): p. 110-7. Liu, Y., et al., Long-term temozolomide might be an optimal choice for patient with multifocal glioblastoma, especially with deep-seated structure involvement: a case report and literature review. World J Surg Oncol, 2015.
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12.
malignant glioma. J Clin Oncol, 1998. 16(12): p. 3851-7. Tolcher, A.W., et al., Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J
Cancer, 2003. 88(7): p. 1004-11. Mao, Y., et al., Does Early Postsurgical Temozolomide Plus Concomitant Radiochemotherapy Regimen Have Any Benefit in Newly-diagnosed Glioblastoma Patients? A Multi-center, Randomized, Parallel, Open-label,
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13.
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11.
13: p. 142. Friedman, H.S., et al., DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed
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31(32): p. 4085-91. Galldiks, N., et al., "One week on-one week off": efficacy and side effects of dose-intensified temozolomide chemotherapy: experiences of a single center. J Neurooncol, 2013. 112(2): p. 209-15. Gerber, D.E., et al., The impact of thrombocytopenia from temozolomide and
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16.
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14.
Phase II Clinical Trial. Chin Med J (Engl), 2015. 128(20): p. 2751-8. Gilbert, M.R., et al., Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol, 2013.
radiation in newly diagnosed adults with high-grade gliomas. Neuro Oncol,
18.
temozolomide. Cancer Chemother Pharmacol, 2012. 69(1): p. 107-13. Khasraw, M., D. Bell, and H. Wheeler, Long-term use of temozolomide:
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17.
2007. 9(1): p. 47-52. Villano, J.L., et al., Hematologic adverse events associated with
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could you use temozolomide safely for life in gliomas? J Clin Neurosci, 2009.
19.
16(6): p. 854-5. Hau, P., et al., Safety and feasibility of long-term temozolomide treatment in
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patients with high-grade glioma. Neurology, 2007. 68(9): p. 688-90. Pegg, A.E., Repair of O(6)-alkylguanine by alkyltransferases. Mutat Res,
21.
2000. 462(2-3): p. 83-100. Gerson, S.L., MGMT: its role in cancer aetiology and cancer therapeutics. Nat Rev Cancer, 2004. 4(4): p. 296-307.
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Preusser, M., et al., Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker.
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Brain Pathol, 2008. 18(4): p. 520-32.
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Figure Legends
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Patients Enrollment, Treatment and Outcomes.
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Kaplan–Meier plots indicating OS for patients with anaplastic astrocytoma (AA,
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n = 27) and glioblastoma multiforme (GBM, n = 76). The P value was obtained
3.
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using a log-rank comparison of data.
Relationship between OS and the surgical tumor resection rate (Spearman’s r = 0.241, P = .04).
Relationship between OS and total TMZ treatment cycles (Spearman’s r = 0.631, P ≤ .001).
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A 52 years-old male was diagnosed left parietal glioblastoma multiforme. A, E: Pre-OP MRI. B, F: MRI one week after surgery. C, G: MRI after 36 TMZ
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5.
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treatment cycles. D, H: MRI 20 months after stopping TMZ.
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patients with intracranial malignant glioma (n=103)
Age (y) , median (range)
%
60 (21 - 87) 20
19.4
50-59 y
30
29.1
60-69 y
25
24.3
≥70 y
28
27.2
Male
60
GCS at admission, median (range)
15 (7 - 15)
Clear consciousness (GCS = 15)
78
Disturbed consciousness (GCS < 15)
25
Clinical features at the time of admission Fever
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5
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<50 y
Seizure Motor deficit
Papilledema Underlying diseases
75.7 24.3
4.9
19
18.4
15
14.6
5
4.9
6
5.8
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Visual disturbance
58.3
-
Hypertension Diabetes mellitus Chronic obstructive pulmonary disease Atrial fibrillation Coronary artery disease ESRD
Laboratory data at presentation, Median (IQR) WBC (x103/mL) Platelet counts (x103/mL) Surgical intervention
33.0
16
15.1
1
1.0
2
1.9
2
1.9
4
3.9
11
10.7
12.5 (3.6 - 27.7) 196 (78 - 473)
6
5.8
60
58.3
37
35.9
Glioblastoma multiforme
76
73.8
Anaplastic astrocytoma
27
26.2
Subtotal resection grossly total resection
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Pathology
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Biopsy
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Smoking
34
Time between surgery and CCRT treatment (days), median (range)
29 (17 - 66)
TMZ cycle, median (range)
10 (1 - 53)
Mortality
62
60.2
Before TMZ treatment
13
12.6
During TMZ treatment
4
3.9
45
43.7
After TMZ treatment Overall survival time (weeks), median (range)
78.4 (6 - 339.7)
Glioblastoma multiforme
72.3 (6 - 339.7)
Anaplastic astrocytoma
156.9 (15.6 – 322)
GCS=Glasgow coma score; SD=standard deviation; IQR= interquartile range CCRT=concomitant chemoradiotherapy; TMZ= temozolomide
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Age (y) , median (range)
TMZ treatment of ≤6 cycles (n=32)
TMZ treatment of >6 cycles (n=58)
59.5 (26 – 84)
58 (21 – 87)
Sex, n (%)
P value
0.373
Male
17 (53.1)
37 (63.8)
Female
15 (46.9)
21 (36.2)
Histology, n (%) 25 (78.1)
Anaplastic astrocytoma
7 (21.9)
Surgical intervention Biopsy
1 (3.1) 19 (59.4)
grossly total resection
12 (37.5)
TMZ cycles, median (range)
3 (1 – 6)
40 (69) 18 (31)
3 (5.2)
1.000
34 (58.6)
1.000
21 (36.2)
1.000
Grade III or IV thrombocytopenia
4 (12.5)
Leukopenia
3 (9.4)
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Subtotal resection
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0.463
Glioblastoma
2 (6.3)
Gastrointestinal toxicity Infection Overall survival time (weeks), median (range) Glioblastoma multiforme Anaplastic astrocytoma Mortality
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Adverse events, n (%)
0.454
4 (6.9)
0.778
3 (5.2)
1.000
4 (12.5)
4 (6.9)
0.283
156.9 (31 – 339.7)
≤0.001
46.3 (6 – 155.1)
105.9 (31- 339.7)
≤0.001
66.3 (15.6 – 170.4)
156.9 (48.1 – 322)
0.025
25 (78.1)
24 (41.4)
0.001
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5 (8.6)
46.3 (6 – 170.4)
GCS=Glasgow coma score; SD=standard deviation; IQR= interquartile range CCRT=concomitant chemoradiotherapy; TMZ= temozolomide
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Table 3 Tumor Volume Change during and after Temozolomide Treatment Surgery (n=103)
During temozolomide treatment (n=90)
Preoperative tumor Postoperative tumor Tumor resection rate volume (mm3) volume (mm3) (%)
Tumor volume change (mm3)
After temozolomide treatment (n=86)
Average tumor change (mm3) (per week)
Tumor volume change (mm3)
Average tumor change (mm3) (per week)
10603
72.5
-2198
-340
11889
1043
55798.4
--
--
-22594.7
-800.6
32.8
12.5
Subtotal tumor resection (n=60)
37697.7
13510.6
60.8
-4368.5
Grossly total tumor resection (n=37)
45635.3
4053.2
95.2
33348.0
7583.3
65.3
726.4
--
--
Subtotal tumor resection (n=19)
25780.6
8083.6
58.3
Grossly total tumor resection (n=6)
65509.5
7289.4
93.4
43376.1
11801.2
Biopsy(n=2)
Glioblastoma multiforme(n=76)
55798.4
--
Subtotal tumor resection (n=41)
43325.1
16486.7
Grossly total tumor resection (n=31)
42455.4
3430.9
9829. 4
778.0
-183.45
16164.2
1515.2
-126.5
-370.7
13463.9
1234.6
-410.9
-10.1
1.15
0.01
2014.9
-206.1
20321.2
1713.6
-5637.3
-870.8
1951.5
585.3
75.0
-2940. 8
-329.4
11270.3
970.3
--
-44778.5
-1591.1
96
24. 9
61.6
-7134.6
-509.0
5091.1
362.2
95.4
4679.8
-27.2
19717.4
1763.1
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Biopsy(n=4)
-417.5
2769.2
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Anaplastic astrocytoma (n=27)
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Biopsy(n=6)
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Table 4 Tumor Volume Changes in Response to Temozolomide 3
Average tumor volume change (mm )
Subtotal tumor resection (n=53) Grossly tumor resection (n=33)
-417.5 -183.45
778.0 1515.2
Anaplastic Astrocytoma (n=25) Biopsy(n=2) Subtotal tumor resection (n=17) Grossly tumor resection (n=6)
-370.7 -10.1 -206.1 -870.8
1234.6 0.01 1713.6 585.3
Glioblastoma multiforme(n=65) Biopsy(n=2) Subtotal tumor resection (n=36) Grossly tumor resection (n=27)
-329.4 -1591.1 -509.0 -27.2
-2364.9
-735.4
--
--
≤0.001 --
-2450.3 -3278.9
-384.5 -204.3
0.009 0.029
-3900.7 --4987.6 -5581.1
-86.0 --678.8 238.2
0.042 -0.015 0.067
970.3 24. 9 362.2 1763.1
-2306.5 --2094.8 -3712.8
-450.7 --46.5 -186.3
0.005 -0.042 0.022
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Total (n=90) Biopsy(n=4)
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After temozolomide treatment (n=86) 1043 12.5
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GCS=Glasgow coma score; SD=standard deviation; IQR= interquartile range CCRT=concomitant chemoradiotherapy
P value
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During temozolomide treatment (n=90) -340 -800.6
95% Confidence Interval Lower Upper
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ACCEPTED MANUSCRIPT Highlights > A significant decrease in tumor volume was observed during temozolomide treatment. > Median overall survival was significant regarding the surgical tumor resection rate (r = 0.241; P = .04) and total temozolomide treatment cycles (r = 0.631, P ≤ .001). > Prolonged temozolomide administration improved overall survival, without
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ACCEPTED MANUSCRIPT Abbreviations list: High-grade gliomas (HGG); concomitant radiochemotherapy (CCRT); temozolomide (TMZ), anaplastic astrocytoma (AA), glioblastoma multiforme
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(GBM), overall survival (OS); Glasgow Coma Score (GCS); magnetic resonance imaging (MRI); computer tomography (CT); outpatient department (OPD); regions of
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interest (ROI).