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Accelerated Hypofractionated Intensity-Modulated Radiotherapy With Concurrent and Adjuvant Temozolomide for Patients With Glioblastoma Multiforme: A Safety and Efficacy Analysis
Int. J. Radiation Oncology Biol. Phys., Vol. 73, No. 2, pp. 473–478, 2009 Copyright Ó 2009 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2008.04.030
CLINICAL INVESTIGATION
Brain
ACCELERATED HYPOFRACTIONATED INTENSITY-MODULATED RADIOTHERAPY WITH CONCURRENT AND ADJUVANT TEMOZOLOMIDE FOR PATIENTS WITH GLIOBLASTOMA MULTIFORME: A SAFETY AND EFFICACY ANALYSIS VALERIE PANET-RAYMOND, M.D.,* LUIS SOUHAMI, M.D.,* DAVID ROBERGE, M.D.,* PETR KAVAN, M.D.,y LILY SHAKIBNIA, M.D.,* THIERRY MUANZA, M.D.,* CHRISTINE LAMBERT, M.D.,* RICHARD LEBLANC, M.D.,z ROLANDO DEL MAESTRO, M.D.,z MARIE-CHRISTINE GUIOT, M.D.,x AND GEORGE SHENOUDA, M.D.* Departments of *Oncology, Division of Radiation Oncology, y Medicine, z Neurosurgery, and x Pathology, McGill University, Montre´al, QC, Canada Purpose: Despite multimodality treatments, the outcome of patients with glioblastoma multiforme remains poor. In an attempt to improve results, we have begun a program of accelerated hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concomitant and adjuvant temozolomide (TMZ). Methods and Materials: Between March 2004 and June 2006, 35 unselected patients with glioblastoma multiforme were treated with hypo-IMRT. During a 4-week period, using a concomitant boost technique, a dose of 60 Gy and 40 Gy were delivered in 20 fractions prescribed to the periphery of the gross tumor volume and planning target volume, respectively. TMZ was administered according to the regimen of Stupp et al. Results: The median follow-up was 12.6 months. Of the 35 patients, 29 (82.8%) completed the combined modality treatment, and 25 (71.4%) received a median of four cycles of adjuvant TMZ. The median overall survival was 14.4 months, and the median disease-free survival was 7.7 months. The median survival time differed significantly between patients who underwent biopsy and those who underwent partial or total resection (7.1 vs. 16.1 months, p = 0.035). The median survival was also significantly different between patients with methylated vs. unmethylated 0-6-methylguanine-DNA methyltransferase promoters (14.4 vs. 8.7 months, p = 0.049). The pattern of failure was predominantly central, within 2 cm of the initial gross tumor volume. Grade 3-4 toxicity was limited to 1 patient with nausea and emesis during adjuvant TMZ administration. Conclusion: The results of our study have shown that hypo-IMRT with concomitant and adjuvant TMZ is well tolerated with a useful 2-week shortening of radiotherapy. Despite a high number of patients with poor prognostic features (74.3% recursive partitioning analysis class V or VI), the median survival was comparable to that after standard radiotherapy fractionation schedules plus TMZ. Ó 2009 Elsevier Inc. Glioblastoma multiforme, Radiotherapy, Hypofractionation, Intensity-modulated radiotherapy, IMRT, Temozolomide.
INTRODUCTION Glioblastoma multiforme (GBM) is associated with a notoriously poor prognosis. Early trials established the utility of postoperative whole brain radiotherapy (RT) in improving overall survival compared with surgery alone (1). Despite RT to a dose of 60 Gy in 30 fractions, administered during a 6-week period, a pattern of central failure is still seen, with >90% of patients developing failure within 2 cm of the gross target volume (GTV) (2, 3). Hypofractionated RT allows for effective treatment to be administered with a useful shortening of the overall treatment
time. The radiobiologic rationale behind hypofractionation is twofold. First, it decreases the treatment duration, thus limiting the repopulation of tumor cells as documented by in vitro studies in malignant astrocytoma cell lines (4), and, second, it might increase cell killing because of the use of a greater dose per fraction, instead of the 1.8–2 Gy/fraction used in conventional fractionation schedules. Several investigators have used hypofractionated schedules in an attempt to overcome the natural resistance of GBM to RT. Although no obvious improvement in survival has been demonstrated, treatment has generally been well tolerated, with similar survival
Reprint requests to: George Shenouda, M.D., Department of Radiation Oncology, Montreal General Hospital, 1650 Cedar Ave., D5-400, Montreal, QC H3G 1A4 Canada. Tel: (514) 934-8040; Fax: (514) 934-8280; E-mail: [email protected] Presented in poster form at the 49th Annual Meeting of the
American Society for Therapeutic Radiology and Oncology (ASTRO), October 28–November 1, 2007, Los Angeles, CA. Conflict of interest: none. Received Feb 27, 2008, and in revised form April 24, 2008. Accepted for publication April 24, 2008. 473
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outcomes and an important shortening of treatment duration. In a trial by Floyd et al. (5), 50 Gy was administered in 5-Gy daily fractions during a 2-week period to the primary disease with a concomitant treatment of 30 Gy in 10 fractions to the surrounding edema. The treatment was well tolerated but no improvement was seen in disease-free survival (DFS). A Phase I-II trial was conducted by Shenouda et al. (6) using a concomitant boost technique. A dose of 44 Gy in 22 fractions was delivered to the planning target volume (PTV) with a concomitant boost of 16 Gy in eight fractions to the GTV. The treatment was equivalent to that of published series with respect to toxicity and outcome. Our center has previously published results using accelerated hypofractionation delivered using an intensity-modulated RT (hypo-IMRT) technique (7). A total of 25 patients received 60 Gy in 20 fractions to the GTV, with concurrent administration of 40 Gy in 20 fractions to the PTV (7). The use of this shortened regimen resulted in equivalent survival to that seen with standard fractionation schemes without additional toxicity. Increasingly, chemotherapeutic agents are being used in the concurrent and adjuvant setting for the treatment of high-grade glioma. In 2004, a European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada (EORTC/NCIC) trial established the utility of concomitant and adjuvant temozolomide (TMZ) in the treatment of GBM (8). In this randomized trial, overall survival was significantly improved with the addition of chemotherapy. In 2004, we began using hypo-IMRT combined with concomitant and adjuvant TMZ. The objective of this study is to report on the results of this regimen in a group of unselected GBM patients. METHODS AND MATERIALS
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available postoperative imaging findings. The GTV was defined as the surgical cavity and/or postoperative contrast-enhancing lesion on MRI fusion. The PTV was taken as the GTV plus a 1.5-cm margin. Visible edema outside the PTV margin was not included in the volume. Treatment planning was done using a forward or inverse IMRT technique. Treatments were delivered with an isocentric technique, often with three or more noncoplanar beams. A total dose of 60 Gy in 20 daily 3-Gy fractions was delivered to the GTV. Through IMRT, it was ensured that the 95–100% isodose line covered the GTV, and the 65–70% line encompassed the PTV. The critical structures, including the brainstem, optic chiasm, lens, optic nerves, and cerebral cortex, were outlined, and dose–volume histograms for each structure were obtained to ensure the doses to the critical structures were within tolerance. The doses were limited to <46 Gy to the spinal cord, <52 Gy to the optic chiasm, and <54 Gy to the brainstem and optic nerves.
Chemotherapy Patients received concomitant TMZ at a dose of 75 mg/m2 daily during hypo-IMRT, followed by adjuvant TMZ at a dose of 150– 200 mg/m2 daily for 5 days every 28 days, according to the EORTC/NCIC regimen (8), for #1 year starting 1 month after RT completion. In the case of progression, patients were considered for second-line treatment on a case-by-case basis.
Surveillance Patients were assessed weekly during RT with clinical examination, complete blood counts, blood chemistry, and liver enzymes tests. After completion of the concomitant treatment, patients were followed on a monthly basis with repeat serologic assessments at each visit. Typically, MRI was requested at 3 months after completion of the combined modality treatment, or earlier if patients developed progressive symptoms. Tumor progression was defined by neurologic deterioration and/or an increased need for corticosteroids and was confirmed by serial imaging denoting new or progressive lesions. Toxicities for both RT and chemotherapy were graded according to the Radiation Therapy Oncology Group (RTOG) criteria.
Eligibility The patients included in this study were unselected. As of 2004, hypo-IMRT was adopted as our treatment regimen for patients who were otherwise ineligible or did not wish to participate in ongoing protocols. No limitations were placed on performance status, age, resection extent, or lesion size. Patients whose tumors were within 1.5 cm of either the optic chiasm or the brainstem were not included. All patients had histologically proven GBM. 0-6-methylguanineDNA methyltransferase promoter methylation (MGMT) status was available in 30 patients. This was a retrospective analysis, and the institutional ethics committee provided written consent to review patient information.
Assessment and treatment technique All patients were initially evaluated with a complete history and physical examination, including a full neurologic assessment. Patients underwent contrast-enhanced computed tomography simulation with 3-mm-thick slices. The patients were immobilized with a thermoplastic mask for simulation and treatment. The computed tomography images were then co-registered with a postoperative magnetic resonance imaging (MRI) scan if available. All patients underwent preoperative MRI, and 6 patients underwent postoperative MRI. The remaining patients underwent postoperative computed tomography. Volume delineation was determined from the
DNA extraction and methylation-specific polymerase chain reaction Genomic DNA was isolated from 15-mm-thick paraffin sections using the QIAamp DNA mini kit (Qiagen Sciences, Germantown, MD). Bisulfite treatment of 2 mg of DNA was performed using the EZ DNA Methylation Gold Kit (Zymo Research, Orange, CA). The methylation-specific polymerase chain reaction was performed using the specific primers to distinguish methylated and unmethylated DNA (9). The primer sequences used were as follows: UM forward: 50 -TTTGTGTTTTGATGTTTGTAGGTTTTTGT-30 ; UM reverse: 50 -AACTCCACACTCTTCCAAAAACAAAACA30 ; M forward: 50 -TTTCGACGTTCGTAGGTTTTCGC-30 ; and M reverse: 50 -GCACTCTTCCGAAAACGAAACG-30 . Methylated and unmethylated polymerase chain reaction products were visualized on a Criterion precast gel 10% TBE (Bio-Rad, Hercules, CA). Control DNA samples were treated concomitantly and consisted of genomic DNA isolated from the Hela cell line for the methylated form and from placental DNA for the unmethylated form.
Statistical analysis A univariate analysis using the log–rank test was used to assess the effect of different prognostic factors on overall survival and DFS. These factors included methylation status at the MGMT
Hypofractionated IMRT and temozolomide in GBM d V. PANET-RAYMOND et al.
promoter site, RTOG recursive partitioning analysis class, and the extent of surgical resection. The principal endpoints were the toxicity evaluation and median survival and DFS, measured from the date of the pathologic diagnosis. Median and DFS were actuarially calculated using the life table method of Kaplan and Meier.
RESULTS Between March 2004 and June 2006, 35 patients with histologically proven GBM were treated. The patient characteristics are listed in Table 1. The median patient age was 63 years (range, 31–78). The patients were grouped according to the RTOG recursive partitioning analysis (RPA) class (10). Most patients were in RPA class V (n = 20, 57.1%), with a smaller number in class III (n = 2, 5.7%), IV (n = 7, 20%), and VI (n = 6, 17.1%). The methylation status at the MGMT promoter site was determined for 30 of the 35 patients. Of the 30 patients, 20 (66.7%) had methylated promoters and 10 had unmethylated promoters (33.3%). The average GTV was 63.5 cm3 (standard deviation, 41.3) and the average PTV was 218.8 cm3 (standard deviation, 81.8). Of the 35 patients, 2 did not complete the prescribed RT course. One patient had a large intracranial bleed 3 days into treatment, necessitating admission for supportive care. This complication was thought to be postoperative in nature. The patient ultimately completed a palliative course of 30 Gy Table 1. Patient characteristics Parameter Age (y) Median Range Gender (n) Male Female RPA class III IV V VI Resection Biopsy only Subtotal Gross total MGMT methylation status Methylated Unmethylated Multicentricity Present Absent Concomitant chemotherapy Yes No Adjuvant chemotherapy Yes No Unknown
Value 63 31-78 20 (57) 15 (43) 2 (5.7) 7 (20.0) 20 (57.1) 6 (17.1) 9 (25.8) 13 (37.1) 13 (37.1) 20 (66.7) 10 (33.3) 4 (11.4) 31 (88.6) 29 (82.4) 6 (17.1) 25 (71.4) 6 (17.1) 4 (11.4)
Abbreviations: RPA = recursive partitioning analysis; MGMT = 0-6-methylguanine DNA methyltransferase promoter methylation. Data presented as number of patients, with percentages in parentheses.
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in 10 fractions. A second patient developed progressive neurologic symptoms thought to be secondary to disease progression. The patient required a second surgical intervention for decompression and insertion of an Omaya reservoir. Her course was further complicated by recurrent pulmonary emboli. The patient ultimately underwent palliative-intent RT. In all, 6 patients (17%) did not complete the prescribed course of concomitant chemotherapy. For 3 patients, administrative difficulty occurred in obtaining the TMZ in a timely manner, and 3 patients discontinued the medication because of patient refusal in 1 patient or clinical deterioration in 2. Of the patients with deterioration, 1 patient improved after an increase in corticosteroids and completed her prescribed treatment after having missed four TMZ doses. The other patient required insertion of an Omaya reservoir to treat rapidly evolving hydrocephalus and was able to receive concomitant treatment after the surgical intervention. Toxicity assessment Acute toxicity was minimal for both the concomitant and the adjuvant courses of TMZ. The most common acute toxicity reported was moderate fatigue. Toxicities are listed in Table 2. No Grade 3 or 4 toxicities were reported during concomitant chemoradiotherapy. Myelotoxicity, although common, was not severe, with 38% of patients having Grade 1 toxicity. During RT, 1 patient had urosepsis without any evidence of myelosuppression. The occurrence of Grade 3-4 toxicity was limited to 1 patient who had nausea and emesis during adjuvant TMZ administration requiring hospitalization. No late toxicity with respect to treatment was seen in our cohort. Outcomes At a median follow-up of 12.6 months (range, 3.2–26.5), the median survival was 14.4 months (range, 3.2–26.5). Table 2. Acute toxicity Grade Toxicity Gastrointestinal Nausea Vomiting Myelotoxicity Thrombocytopenia Leukopenia Anemia Hepatotoxicity AST/ALT Other Dermatitis Fatigue
1
2
3
4
6 (21) 5 (17)
2 (7) 1 (3)
0 (0) 0 (0)
0 (0) 0 (0)
1 (3) 2 (7) 11 (38)
0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0)
6 (21)
2 (7)
0 (0)
0 (0)
4 (14) 14 (48)
7 (24) 4 (14)
0 (0) 0 (0)
0 (0) 0 (0)
Abbreviations: AST/ALT = aspartate aminotransferase/alanine aminotransferase. Data presented as number of patients, with percentages in parentheses.
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Fig. 1. (A) Median survival for all patients. Median survival rates among different subgroups by (B) extent of surgical resection, (C) recursive partitioning analysis (RPA) subclass, and (D) methylation of 0-6-methylguanine-DNA methyltransferase promoter methylation status.
Figure 1A shows the median survival for all patients. The survival rates for the extent of surgical resection, different RPA classes, and MGMT promoter methylation status are shown in Fig. 1B–D, respectively. Surgery limited to biopsy was associated with a median survival of 7.1 months and partial or complete resection was associated with a median survival of 16.1 months (p = 0.035). The median survival for those with RPA class III-IV was 17.9 months and was 12.9 months for those with class V-VI. The median DFS, taken as the period between the pathologic diagnosis and evidence of clinical deterioration, was 7.7 months (Fig. 2). The median DFS intervals were also determined for the different RPA classes, MGMT promoter methylation status, and extent of surgical resection. The DFS for RPA class III-IV was 7.0 months and was 8.0 months for RPA class V-VI (p = 0.81). Similarly,
Fig. 2. Disease-free survival for all patients.
the DFS was 5.6 months for the biopsy-alone group and 8.0 months for those who underwent partial or gross total resection (p = 0.04). MGMT promoter methylation status was a significant prognostic indicator for median survival (14.4 months for methylated vs. 8.7 months for unmethylated, p = 0.05) but not for DFS (7.7 months for methylated vs. 4.4 months for unmethylated, p = 0.09). The treatment volumes (GTVs and PTVs) were also assessed using a continuous analysis to determine whether these parameters affected the outcome. We found no correlation between treatment volume and median survival or DFS in our study population. Patterns of failure Of 23 documented cases of disease progression on MRI, 21 were central. Only 2 patients developed failure >2 cm from their initial GTV. Two other patients developed pseudoprogression (11). Both developed evidence of solid tumor enlargement within weeks of completing combined modality treatment in the absence of clinical deterioration. Both patients’ subsequent imaging reflected improvement or stabilization of disease for more than 1 year. Treatment at failure Seven patients with relapse underwent additional treatment. Of the 7 patients, 3 were RPA class III-IV and 4 were class V-VI. Two patients underwent debulking surgery before second-line chemotherapy and two underwent additional RT. Of the 7 patients, 6 received a procarbazine/temozolomide regimen that was halted after disease progression (12). One patient started dose-dense TMZ, 21 days on and 7 days off.
Hypofractionated IMRT and temozolomide in GBM d V. PANET-RAYMOND et al.
DISCUSSION Although much work has been performed on various hypofractionation regimens and dose escalation for malignant astrocytomas, none has convincingly demonstrated a survival advantage compared with conventional RT (13–18). Much of the work addressing the utility of increasing the dose to the primary tumor in GBM was performed before the EORTC/ NCIC trial (8). Hypofractionation has three purported benefits compared with conventional fractionation (5). It allows a shortening of overall treatment time, it may reduce the cost of treatment and, because of increasing the dose per fraction from 2 to 3 Gy, it may increase cell kill and reduce accelerated repopulation. In a nonrandomized prospectively analyzed study by Hulshof et al. (17), different hypofractionated regimens were compared among patients with malignant astrocytomas. All schemas of fractionation were well tolerated, with no detrimental effects on survival. A retrospective review of three Brain Tumor Study Group randomized trials identified a dose response with an increasing radiation dose from <45 Gy to 60 Gy (19). However, trials escalating the dose to >60 Gy have repeatedly failed to demonstrate a clinical benefit (3). In an RTOG randomized controlled trial by Souhami et al. (20), the utility of a stereotactic radiosurgical boost was assessed in patients with GBM. The trial failed to show a survival benefit with the addition of a radiosurgical boost compared with conventional RT alone. Others have used brachytherapy to deliver a greater dose to the GTV in malignant astrocytomas. In a trial by Laperriere et al. (21), patients with malignant astrocytomas were randomized between external beam RT and standard RT with a brachytherapy boost. No improvement in overall survival was seen with the brachytherapy boost compared with standard treatment. Thus, the body of evidence to date has indicated that although GBMs show a repeated pattern of central failure, RT dose escalation, regardless of method, does not appear to lead to improvement in patient outcomes. Our present regimen has laid the groundwork to perhaps challenge the way RT is routinely given for patients with GBM. Despite an unselected patient population, with 74% of our patients in RPA class V or VI, we found that our treatment results, with a median survival of 14.4 months, appear to be comparable to published results using standard fractionation RT combined with TMZ. In the EORTC/NCIC trial, the median survival
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was 14.6 months for the combined modality treatment arm after selecting for patients <70 years and with an Eastern Cooperative Oncology Group performance status of #2 (8). Direct comparisons to historical controls or to other studies should be viewed with caution, however, and only a properly designed randomized trial can firmly establish whether our regimen is comparable or superior to the standard treatment. Despite a greater daily radiation dose, the toxicity in our present study was minimal, and tolerance to the concomitant TMZ and hypofractionated RT was excellent. No late toxicities have been seen using this regimen. The most common acute toxicity was fatigue, which largely resolved during adjuvant treatment. Two patients required an interruption in their RT, in the first patient, the toxicity was thought to be secondary to a postoperative complication and in the other patient, it was thought to be secondary to disease progression. Neither complication was thought to be related to treatment. The results of our present study support our initial work and further establish the safety of our regimen when combined with TMZ. Our data support the biologic concept introduced by Hegi et al. (22) that the methylation status of the MGMT promoter can be used as a clinically relevant prognostic factor. The median overall survival was significantly different between our patients with methylated MGMT promoters and those with unmethylated promoters (14.4 vs. 8.8 months, p = 0.049). Future efforts in GBM research might best be spent investigating new systemic agents and strategies to overcome MGMT-mediated treatment resistance rather than dose escalation or changes in RT targeting.
CONCLUSION Hypo-IMRT with concurrent and adjuvant TMZ appears to be a safe and effective regimen for GBM. We have found it to be well tolerated and associated with a low risk of significant acute or long-term toxicity. Despite an unfavorable patient population with a high proportion of RPA class V and VI patients, the median survival and DFS were encouraging and similar to published survival rates using conventionally fractionated RT and TMZ. This treatment schedule results in a 2-week shortening of the overall treatment time, which might be useful, especially for patients with a more guarded prognosis.
REFERENCES 1. Walker MD, Green SB, Byar DP. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980;303:1323–1329. 2. Hochberg FH, Pruitt A. Assumptions in the radiotherapy of glioblastoma. Neurology 1980;30:907–911. 3. Lee SW, Fraass BA, Marsh LH, et al. Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: A quantitative dosimetric study. Int J Radiat Oncol Biol Phys 1999;43:79–88. 4. Budach W, Gioioso D, Taghian A, et al. Repopulation capacity during fractionated irradiation of squamous cell carcinomas and
glioblastomas in vitro. Int J Radiat Oncol Biol Phys 1997;39: 743–750. 5. Floyd NS, Woo SY, Teh BS, et al. Hypofractionated intensitymodulated radiotherapy for primary glioblastoma multiforme. Int J Radiat Oncol Biol Phys 2004;58:721–726. 6. Shenouda G, Souhami L, Freeman CR, et al. Accelerated fractionation for high-grade cerebral astrocytomas: Preliminary treatment results. Cancer 1991;67:2247–2252. 7. Sultanem K, Patrocinio H, Lambert C, et al. The use of hypofractionated intensity-modulated irradiation in the treatment of glioblastoma multiforme: Preliminary results of
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a prospective trial. Int J Radiat Oncol Biol Phys 2004;58: 247–252. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–996. Esteller M, Hamilton SR, Burger PC, et al. Inactivation of the DNA repair gene 0-6-methylguanine DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999;59:793–797. Curran WJ Jr., Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85: 704–710. de Wit MC, de Bruin HG, Eijkenboom W, et al. Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression. Neurology 2004;63:535–537. Huang F, Kavan P, Guiot MC, et al. When temozolomide alone fails: Adding procarbazine in salvage therapy of glioma. Can J Neurol Sci 2008;35:192–197. Bleehen NM, Stenning SP. A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. Br J Cancer 1991;64:769–774. Thomas R. Hypofractionated radiotherapy as palliative treatment in poor prognosis patients with high grade glioma. Radiother Oncol 1994;33:113–116. Bauman GS, Gaspar LE, Fisher BJ, et al. A prospective study of short-course radiotherapy in poor prognosis glioblastoma multiforme. Int J Radiat Oncol Biol Phys 1994;29:835–839.
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16. Slotman BJ, Kralendonk JH, van Alphen HAM, et al. Hypofractionated radiation therapy in patients with glioblastoma multiforme: Results of treatment and impact of prognostic factors. Int J Radiat Oncol Biol Phys 1996;34:895–898. 17. Hulshof MCCM, Schimmel EC, Bosch DA, et al. Hypofractionation in glioblastoma multiforme. Radiother Oncol 2000;54: 143–148. 18. Kleinberg LR, Slick T, Enger C, et al. Short course radiotherapy is an appropriate option for most malignant glioma patients. Int J Radiat Oncol Biol Phys 1997;38:31–36. 19. Walker MD, Strike TA, Sheline GE. An analysis of dose–effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 1979;5:1725–1731. 20. Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: Report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 2004;60:853–860. 21. Laperriere NJ, Leung PMK, McKenzie S, et al. Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma. Int J Radiat Oncol Biol Phys 1998;41:1005–1011. 22. Hegi ME, Diserens A-C, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003.
doi:10.1016/j.ijrobp.2008.04.030
CLINICAL INVESTIGATION
Brain
ACCELERATED HYPOFRACTIONATED INTENSITY-MODULATED RADIOTHERAPY WITH CONCURRENT AND ADJUVANT TEMOZOLOMIDE FOR PATIENTS WITH GLIOBLASTOMA MULTIFORME: A SAFETY AND EFFICACY ANALYSIS VALERIE PANET-RAYMOND, M.D.,* LUIS SOUHAMI, M.D.,* DAVID ROBERGE, M.D.,* PETR KAVAN, M.D.,y LILY SHAKIBNIA, M.D.,* THIERRY MUANZA, M.D.,* CHRISTINE LAMBERT, M.D.,* RICHARD LEBLANC, M.D.,z ROLANDO DEL MAESTRO, M.D.,z MARIE-CHRISTINE GUIOT, M.D.,x AND GEORGE SHENOUDA, M.D.* Departments of *Oncology, Division of Radiation Oncology, y Medicine, z Neurosurgery, and x Pathology, McGill University, Montre´al, QC, Canada Purpose: Despite multimodality treatments, the outcome of patients with glioblastoma multiforme remains poor. In an attempt to improve results, we have begun a program of accelerated hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with concomitant and adjuvant temozolomide (TMZ). Methods and Materials: Between March 2004 and June 2006, 35 unselected patients with glioblastoma multiforme were treated with hypo-IMRT. During a 4-week period, using a concomitant boost technique, a dose of 60 Gy and 40 Gy were delivered in 20 fractions prescribed to the periphery of the gross tumor volume and planning target volume, respectively. TMZ was administered according to the regimen of Stupp et al. Results: The median follow-up was 12.6 months. Of the 35 patients, 29 (82.8%) completed the combined modality treatment, and 25 (71.4%) received a median of four cycles of adjuvant TMZ. The median overall survival was 14.4 months, and the median disease-free survival was 7.7 months. The median survival time differed significantly between patients who underwent biopsy and those who underwent partial or total resection (7.1 vs. 16.1 months, p = 0.035). The median survival was also significantly different between patients with methylated vs. unmethylated 0-6-methylguanine-DNA methyltransferase promoters (14.4 vs. 8.7 months, p = 0.049). The pattern of failure was predominantly central, within 2 cm of the initial gross tumor volume. Grade 3-4 toxicity was limited to 1 patient with nausea and emesis during adjuvant TMZ administration. Conclusion: The results of our study have shown that hypo-IMRT with concomitant and adjuvant TMZ is well tolerated with a useful 2-week shortening of radiotherapy. Despite a high number of patients with poor prognostic features (74.3% recursive partitioning analysis class V or VI), the median survival was comparable to that after standard radiotherapy fractionation schedules plus TMZ. Ó 2009 Elsevier Inc. Glioblastoma multiforme, Radiotherapy, Hypofractionation, Intensity-modulated radiotherapy, IMRT, Temozolomide.
INTRODUCTION Glioblastoma multiforme (GBM) is associated with a notoriously poor prognosis. Early trials established the utility of postoperative whole brain radiotherapy (RT) in improving overall survival compared with surgery alone (1). Despite RT to a dose of 60 Gy in 30 fractions, administered during a 6-week period, a pattern of central failure is still seen, with >90% of patients developing failure within 2 cm of the gross target volume (GTV) (2, 3). Hypofractionated RT allows for effective treatment to be administered with a useful shortening of the overall treatment
time. The radiobiologic rationale behind hypofractionation is twofold. First, it decreases the treatment duration, thus limiting the repopulation of tumor cells as documented by in vitro studies in malignant astrocytoma cell lines (4), and, second, it might increase cell killing because of the use of a greater dose per fraction, instead of the 1.8–2 Gy/fraction used in conventional fractionation schedules. Several investigators have used hypofractionated schedules in an attempt to overcome the natural resistance of GBM to RT. Although no obvious improvement in survival has been demonstrated, treatment has generally been well tolerated, with similar survival
Reprint requests to: George Shenouda, M.D., Department of Radiation Oncology, Montreal General Hospital, 1650 Cedar Ave., D5-400, Montreal, QC H3G 1A4 Canada. Tel: (514) 934-8040; Fax: (514) 934-8280; E-mail: [email protected] Presented in poster form at the 49th Annual Meeting of the
American Society for Therapeutic Radiology and Oncology (ASTRO), October 28–November 1, 2007, Los Angeles, CA. Conflict of interest: none. Received Feb 27, 2008, and in revised form April 24, 2008. Accepted for publication April 24, 2008. 473
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outcomes and an important shortening of treatment duration. In a trial by Floyd et al. (5), 50 Gy was administered in 5-Gy daily fractions during a 2-week period to the primary disease with a concomitant treatment of 30 Gy in 10 fractions to the surrounding edema. The treatment was well tolerated but no improvement was seen in disease-free survival (DFS). A Phase I-II trial was conducted by Shenouda et al. (6) using a concomitant boost technique. A dose of 44 Gy in 22 fractions was delivered to the planning target volume (PTV) with a concomitant boost of 16 Gy in eight fractions to the GTV. The treatment was equivalent to that of published series with respect to toxicity and outcome. Our center has previously published results using accelerated hypofractionation delivered using an intensity-modulated RT (hypo-IMRT) technique (7). A total of 25 patients received 60 Gy in 20 fractions to the GTV, with concurrent administration of 40 Gy in 20 fractions to the PTV (7). The use of this shortened regimen resulted in equivalent survival to that seen with standard fractionation schemes without additional toxicity. Increasingly, chemotherapeutic agents are being used in the concurrent and adjuvant setting for the treatment of high-grade glioma. In 2004, a European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada (EORTC/NCIC) trial established the utility of concomitant and adjuvant temozolomide (TMZ) in the treatment of GBM (8). In this randomized trial, overall survival was significantly improved with the addition of chemotherapy. In 2004, we began using hypo-IMRT combined with concomitant and adjuvant TMZ. The objective of this study is to report on the results of this regimen in a group of unselected GBM patients. METHODS AND MATERIALS
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available postoperative imaging findings. The GTV was defined as the surgical cavity and/or postoperative contrast-enhancing lesion on MRI fusion. The PTV was taken as the GTV plus a 1.5-cm margin. Visible edema outside the PTV margin was not included in the volume. Treatment planning was done using a forward or inverse IMRT technique. Treatments were delivered with an isocentric technique, often with three or more noncoplanar beams. A total dose of 60 Gy in 20 daily 3-Gy fractions was delivered to the GTV. Through IMRT, it was ensured that the 95–100% isodose line covered the GTV, and the 65–70% line encompassed the PTV. The critical structures, including the brainstem, optic chiasm, lens, optic nerves, and cerebral cortex, were outlined, and dose–volume histograms for each structure were obtained to ensure the doses to the critical structures were within tolerance. The doses were limited to <46 Gy to the spinal cord, <52 Gy to the optic chiasm, and <54 Gy to the brainstem and optic nerves.
Chemotherapy Patients received concomitant TMZ at a dose of 75 mg/m2 daily during hypo-IMRT, followed by adjuvant TMZ at a dose of 150– 200 mg/m2 daily for 5 days every 28 days, according to the EORTC/NCIC regimen (8), for #1 year starting 1 month after RT completion. In the case of progression, patients were considered for second-line treatment on a case-by-case basis.
Surveillance Patients were assessed weekly during RT with clinical examination, complete blood counts, blood chemistry, and liver enzymes tests. After completion of the concomitant treatment, patients were followed on a monthly basis with repeat serologic assessments at each visit. Typically, MRI was requested at 3 months after completion of the combined modality treatment, or earlier if patients developed progressive symptoms. Tumor progression was defined by neurologic deterioration and/or an increased need for corticosteroids and was confirmed by serial imaging denoting new or progressive lesions. Toxicities for both RT and chemotherapy were graded according to the Radiation Therapy Oncology Group (RTOG) criteria.
Eligibility The patients included in this study were unselected. As of 2004, hypo-IMRT was adopted as our treatment regimen for patients who were otherwise ineligible or did not wish to participate in ongoing protocols. No limitations were placed on performance status, age, resection extent, or lesion size. Patients whose tumors were within 1.5 cm of either the optic chiasm or the brainstem were not included. All patients had histologically proven GBM. 0-6-methylguanineDNA methyltransferase promoter methylation (MGMT) status was available in 30 patients. This was a retrospective analysis, and the institutional ethics committee provided written consent to review patient information.
Assessment and treatment technique All patients were initially evaluated with a complete history and physical examination, including a full neurologic assessment. Patients underwent contrast-enhanced computed tomography simulation with 3-mm-thick slices. The patients were immobilized with a thermoplastic mask for simulation and treatment. The computed tomography images were then co-registered with a postoperative magnetic resonance imaging (MRI) scan if available. All patients underwent preoperative MRI, and 6 patients underwent postoperative MRI. The remaining patients underwent postoperative computed tomography. Volume delineation was determined from the
DNA extraction and methylation-specific polymerase chain reaction Genomic DNA was isolated from 15-mm-thick paraffin sections using the QIAamp DNA mini kit (Qiagen Sciences, Germantown, MD). Bisulfite treatment of 2 mg of DNA was performed using the EZ DNA Methylation Gold Kit (Zymo Research, Orange, CA). The methylation-specific polymerase chain reaction was performed using the specific primers to distinguish methylated and unmethylated DNA (9). The primer sequences used were as follows: UM forward: 50 -TTTGTGTTTTGATGTTTGTAGGTTTTTGT-30 ; UM reverse: 50 -AACTCCACACTCTTCCAAAAACAAAACA30 ; M forward: 50 -TTTCGACGTTCGTAGGTTTTCGC-30 ; and M reverse: 50 -GCACTCTTCCGAAAACGAAACG-30 . Methylated and unmethylated polymerase chain reaction products were visualized on a Criterion precast gel 10% TBE (Bio-Rad, Hercules, CA). Control DNA samples were treated concomitantly and consisted of genomic DNA isolated from the Hela cell line for the methylated form and from placental DNA for the unmethylated form.
Statistical analysis A univariate analysis using the log–rank test was used to assess the effect of different prognostic factors on overall survival and DFS. These factors included methylation status at the MGMT
Hypofractionated IMRT and temozolomide in GBM d V. PANET-RAYMOND et al.
promoter site, RTOG recursive partitioning analysis class, and the extent of surgical resection. The principal endpoints were the toxicity evaluation and median survival and DFS, measured from the date of the pathologic diagnosis. Median and DFS were actuarially calculated using the life table method of Kaplan and Meier.
RESULTS Between March 2004 and June 2006, 35 patients with histologically proven GBM were treated. The patient characteristics are listed in Table 1. The median patient age was 63 years (range, 31–78). The patients were grouped according to the RTOG recursive partitioning analysis (RPA) class (10). Most patients were in RPA class V (n = 20, 57.1%), with a smaller number in class III (n = 2, 5.7%), IV (n = 7, 20%), and VI (n = 6, 17.1%). The methylation status at the MGMT promoter site was determined for 30 of the 35 patients. Of the 30 patients, 20 (66.7%) had methylated promoters and 10 had unmethylated promoters (33.3%). The average GTV was 63.5 cm3 (standard deviation, 41.3) and the average PTV was 218.8 cm3 (standard deviation, 81.8). Of the 35 patients, 2 did not complete the prescribed RT course. One patient had a large intracranial bleed 3 days into treatment, necessitating admission for supportive care. This complication was thought to be postoperative in nature. The patient ultimately completed a palliative course of 30 Gy Table 1. Patient characteristics Parameter Age (y) Median Range Gender (n) Male Female RPA class III IV V VI Resection Biopsy only Subtotal Gross total MGMT methylation status Methylated Unmethylated Multicentricity Present Absent Concomitant chemotherapy Yes No Adjuvant chemotherapy Yes No Unknown
Value 63 31-78 20 (57) 15 (43) 2 (5.7) 7 (20.0) 20 (57.1) 6 (17.1) 9 (25.8) 13 (37.1) 13 (37.1) 20 (66.7) 10 (33.3) 4 (11.4) 31 (88.6) 29 (82.4) 6 (17.1) 25 (71.4) 6 (17.1) 4 (11.4)
Abbreviations: RPA = recursive partitioning analysis; MGMT = 0-6-methylguanine DNA methyltransferase promoter methylation. Data presented as number of patients, with percentages in parentheses.
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in 10 fractions. A second patient developed progressive neurologic symptoms thought to be secondary to disease progression. The patient required a second surgical intervention for decompression and insertion of an Omaya reservoir. Her course was further complicated by recurrent pulmonary emboli. The patient ultimately underwent palliative-intent RT. In all, 6 patients (17%) did not complete the prescribed course of concomitant chemotherapy. For 3 patients, administrative difficulty occurred in obtaining the TMZ in a timely manner, and 3 patients discontinued the medication because of patient refusal in 1 patient or clinical deterioration in 2. Of the patients with deterioration, 1 patient improved after an increase in corticosteroids and completed her prescribed treatment after having missed four TMZ doses. The other patient required insertion of an Omaya reservoir to treat rapidly evolving hydrocephalus and was able to receive concomitant treatment after the surgical intervention. Toxicity assessment Acute toxicity was minimal for both the concomitant and the adjuvant courses of TMZ. The most common acute toxicity reported was moderate fatigue. Toxicities are listed in Table 2. No Grade 3 or 4 toxicities were reported during concomitant chemoradiotherapy. Myelotoxicity, although common, was not severe, with 38% of patients having Grade 1 toxicity. During RT, 1 patient had urosepsis without any evidence of myelosuppression. The occurrence of Grade 3-4 toxicity was limited to 1 patient who had nausea and emesis during adjuvant TMZ administration requiring hospitalization. No late toxicity with respect to treatment was seen in our cohort. Outcomes At a median follow-up of 12.6 months (range, 3.2–26.5), the median survival was 14.4 months (range, 3.2–26.5). Table 2. Acute toxicity Grade Toxicity Gastrointestinal Nausea Vomiting Myelotoxicity Thrombocytopenia Leukopenia Anemia Hepatotoxicity AST/ALT Other Dermatitis Fatigue
1
2
3
4
6 (21) 5 (17)
2 (7) 1 (3)
0 (0) 0 (0)
0 (0) 0 (0)
1 (3) 2 (7) 11 (38)
0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0)
0 (0) 0 (0) 0 (0)
6 (21)
2 (7)
0 (0)
0 (0)
4 (14) 14 (48)
7 (24) 4 (14)
0 (0) 0 (0)
0 (0) 0 (0)
Abbreviations: AST/ALT = aspartate aminotransferase/alanine aminotransferase. Data presented as number of patients, with percentages in parentheses.
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Fig. 1. (A) Median survival for all patients. Median survival rates among different subgroups by (B) extent of surgical resection, (C) recursive partitioning analysis (RPA) subclass, and (D) methylation of 0-6-methylguanine-DNA methyltransferase promoter methylation status.
Figure 1A shows the median survival for all patients. The survival rates for the extent of surgical resection, different RPA classes, and MGMT promoter methylation status are shown in Fig. 1B–D, respectively. Surgery limited to biopsy was associated with a median survival of 7.1 months and partial or complete resection was associated with a median survival of 16.1 months (p = 0.035). The median survival for those with RPA class III-IV was 17.9 months and was 12.9 months for those with class V-VI. The median DFS, taken as the period between the pathologic diagnosis and evidence of clinical deterioration, was 7.7 months (Fig. 2). The median DFS intervals were also determined for the different RPA classes, MGMT promoter methylation status, and extent of surgical resection. The DFS for RPA class III-IV was 7.0 months and was 8.0 months for RPA class V-VI (p = 0.81). Similarly,
Fig. 2. Disease-free survival for all patients.
the DFS was 5.6 months for the biopsy-alone group and 8.0 months for those who underwent partial or gross total resection (p = 0.04). MGMT promoter methylation status was a significant prognostic indicator for median survival (14.4 months for methylated vs. 8.7 months for unmethylated, p = 0.05) but not for DFS (7.7 months for methylated vs. 4.4 months for unmethylated, p = 0.09). The treatment volumes (GTVs and PTVs) were also assessed using a continuous analysis to determine whether these parameters affected the outcome. We found no correlation between treatment volume and median survival or DFS in our study population. Patterns of failure Of 23 documented cases of disease progression on MRI, 21 were central. Only 2 patients developed failure >2 cm from their initial GTV. Two other patients developed pseudoprogression (11). Both developed evidence of solid tumor enlargement within weeks of completing combined modality treatment in the absence of clinical deterioration. Both patients’ subsequent imaging reflected improvement or stabilization of disease for more than 1 year. Treatment at failure Seven patients with relapse underwent additional treatment. Of the 7 patients, 3 were RPA class III-IV and 4 were class V-VI. Two patients underwent debulking surgery before second-line chemotherapy and two underwent additional RT. Of the 7 patients, 6 received a procarbazine/temozolomide regimen that was halted after disease progression (12). One patient started dose-dense TMZ, 21 days on and 7 days off.
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DISCUSSION Although much work has been performed on various hypofractionation regimens and dose escalation for malignant astrocytomas, none has convincingly demonstrated a survival advantage compared with conventional RT (13–18). Much of the work addressing the utility of increasing the dose to the primary tumor in GBM was performed before the EORTC/ NCIC trial (8). Hypofractionation has three purported benefits compared with conventional fractionation (5). It allows a shortening of overall treatment time, it may reduce the cost of treatment and, because of increasing the dose per fraction from 2 to 3 Gy, it may increase cell kill and reduce accelerated repopulation. In a nonrandomized prospectively analyzed study by Hulshof et al. (17), different hypofractionated regimens were compared among patients with malignant astrocytomas. All schemas of fractionation were well tolerated, with no detrimental effects on survival. A retrospective review of three Brain Tumor Study Group randomized trials identified a dose response with an increasing radiation dose from <45 Gy to 60 Gy (19). However, trials escalating the dose to >60 Gy have repeatedly failed to demonstrate a clinical benefit (3). In an RTOG randomized controlled trial by Souhami et al. (20), the utility of a stereotactic radiosurgical boost was assessed in patients with GBM. The trial failed to show a survival benefit with the addition of a radiosurgical boost compared with conventional RT alone. Others have used brachytherapy to deliver a greater dose to the GTV in malignant astrocytomas. In a trial by Laperriere et al. (21), patients with malignant astrocytomas were randomized between external beam RT and standard RT with a brachytherapy boost. No improvement in overall survival was seen with the brachytherapy boost compared with standard treatment. Thus, the body of evidence to date has indicated that although GBMs show a repeated pattern of central failure, RT dose escalation, regardless of method, does not appear to lead to improvement in patient outcomes. Our present regimen has laid the groundwork to perhaps challenge the way RT is routinely given for patients with GBM. Despite an unselected patient population, with 74% of our patients in RPA class V or VI, we found that our treatment results, with a median survival of 14.4 months, appear to be comparable to published results using standard fractionation RT combined with TMZ. In the EORTC/NCIC trial, the median survival
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was 14.6 months for the combined modality treatment arm after selecting for patients <70 years and with an Eastern Cooperative Oncology Group performance status of #2 (8). Direct comparisons to historical controls or to other studies should be viewed with caution, however, and only a properly designed randomized trial can firmly establish whether our regimen is comparable or superior to the standard treatment. Despite a greater daily radiation dose, the toxicity in our present study was minimal, and tolerance to the concomitant TMZ and hypofractionated RT was excellent. No late toxicities have been seen using this regimen. The most common acute toxicity was fatigue, which largely resolved during adjuvant treatment. Two patients required an interruption in their RT, in the first patient, the toxicity was thought to be secondary to a postoperative complication and in the other patient, it was thought to be secondary to disease progression. Neither complication was thought to be related to treatment. The results of our present study support our initial work and further establish the safety of our regimen when combined with TMZ. Our data support the biologic concept introduced by Hegi et al. (22) that the methylation status of the MGMT promoter can be used as a clinically relevant prognostic factor. The median overall survival was significantly different between our patients with methylated MGMT promoters and those with unmethylated promoters (14.4 vs. 8.8 months, p = 0.049). Future efforts in GBM research might best be spent investigating new systemic agents and strategies to overcome MGMT-mediated treatment resistance rather than dose escalation or changes in RT targeting.
CONCLUSION Hypo-IMRT with concurrent and adjuvant TMZ appears to be a safe and effective regimen for GBM. We have found it to be well tolerated and associated with a low risk of significant acute or long-term toxicity. Despite an unfavorable patient population with a high proportion of RPA class V and VI patients, the median survival and DFS were encouraging and similar to published survival rates using conventionally fractionated RT and TMZ. This treatment schedule results in a 2-week shortening of the overall treatment time, which might be useful, especially for patients with a more guarded prognosis.
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