Quantification of Tumor Growth Kinetics in Patients Showing Progression From Low-grade to High-grade Gliomas

Volume 84  Number 3S  Supplement 2012

2143 Is There a Role for Concomitant Low-dose Fractionated Radiation Therapy and Chemotherapy in Recurrent or Progressive Glioblastoma? B. Diletto, M. Balducci, S. Chiesa, L. De Filippo, S. Gaudino, G. Mantini, F. Micciche´, G. D’ Agostino, C. Anile, and V. Valentini; Catholic University of the Sacred Heart, Rome, Italy Purposes/Objective(s): Standardized salvage treatment for recurrent or progressive glioblastoma multiforme (GBM) patients, who previously received radiation therapy plus concomitant and adjuvant temozolomide (TMZ), has not yet been defined. Several in vitro and preclinical studies have demonstrated the hyper-radiosensitivity of human malignant glioma cell lines to low radiation doses and a synergism between low dose fractionated radiation therapy (LD-FRT) and chemotherapy. To evaluate the feasibility and efficacy of this approach in recurrent or progressive GBM, we performed a prospective analysis of concurrent chemotherapy and LD-FRT. Material and Methods: Patients with radiological diagnosis of recurrent or progressive GBM, previously treated by surgical resection followed by 3DCRT (total dose 59.4 Gy) plus concomitant and adjuvant TMZ were enrolled. Patients with disease progressing during TMZ received 30 cGy twice a day on days 1-2,8-9,15-16, q42, concurrently with cisplatin (30 mg/ m2 on days 1, 8, 15) and fotemustine (40 mg/m2 on days 2, 9, 16), whereas patients with recurrent disease 4-6 months after the end of adjuvant TMZ were treated by 40 cGy twice a day, over consecutive 5 days, q28, concurrently with TMZ (150/200 mg/m2). Primary endpoints were safety and toxicity (CTCAE v4.0); we also evaluated clinical response (RECIST criteria), Progression Free Survival (PFS) and Overall Survival (OS). Results: From November 2007 to August 2011, 32 patients were enrolled in the analysis. Twenty-one (65.6%) patients received LD-FRT and TMZ, 11 patients (34.4%) received LD-FRT with cisplatin and fotemustine. The median total dose of LD-FRT delivered was 800 cGy (range, 240-2160). A grade 1-2 hematologic toxicity was observed in 18.7% of patients, while a grade 3-4 toxicity (leucopenia) was experienced by 9.4% of patients. One patient (3.1%) showed a complete response, 3 patients (9.4%) a partial response (PR), 8 patients (25%) had a stable disease (SD) for at least 8 weeks, while 20 patients (62.5%) experienced progressive disease, with a median time to progression of 14.5 months (range, 2 - 86). The Clinical Benefit was 37.5%. At a median follow-up of 22.5 months from the diagnosis of recurrent/progressive disease (range, 3 - 48), the median PFS was 5 months, the median OS was 8 months, with a survival rate at 6 months of 60.4% and a 1-year OS of 28.6%. Conclusion: Our data demonstrate that concurrent LD-FRT and chemotherapy regimen as second-line treatment in recurrent or progressive GBM was safe and well tolerated, and they support the development of further studies exploring the optimal level of low dose for fraction. Author Disclosure: B. Diletto: None. M. Balducci: None. S. Chiesa: None. L. De Filippo: None. S. Gaudino: None. G. Mantini: None. F. Micciche´: None. G. D’ Agostino: None. C. Anile: None. V. Valentini: None.

2144 Patterns of Failure in Patients With Glioblastoma Treated With Surgery and Intensity Modulated Radiation Therapy and Temozolomide M. Rodriguez-Ruiz, I. San Miguel, M. Moreno-Jimenez, J. Espinos, E. Arevalo, P. Dominguez, S. Tejada, J. Arbizu, M.A. Idoate, and J. Aristu; University of Navarra Clinic, Pamplona, Spain Purpose/Objective(s): To evaluate the patterns of recurrence in patients with newly diagnosed GBM treated with concurrent temozolomide intensity-modulated radiation therapy (TMZ-IMRT), and adjuvant temozolomide (TMZ). Materials/Methods: Patients with pathologically diagnosed of GBM were included in a prospective study. All patients were treated with maximal surgical resection using fluorescence-5ALA-guided surgery followed IMRT and concomitant-adjuvant TMZ. Target volumes were outline on the treatment-planning CT images fused with PET-methionine images. The

Poster Viewing Abstracts S273 gross tumor volume (GTV) was defined as the surgical cavity plus macroscopic residual disease observed in MR-PET-CT images. Clinical target volume (CTV) included GTV plus 2-cm margins and the PTV was generated after a 0.5-cm symmetrical expansion of the CTV. Prescription dose were 70 Gy, 65 Gy and 60 Gy to the 95% of the GTV, CTV and PTV, respectively. MRI images showing tumor recurrences were fused with the planning-CT, and the patterns of failure were defined according to the location of recurrence respect the isodose lines (IDL). Central recurrences was considered if the tumor recurrence was located within the 65 Gy IDL, local recurrence from 60 Gy to 55 Gy IDL, marginal recurrence within 30 to 50 Gy IDL and distal failure when the recurrence was located outside of the 30 Gy IDL. Results: From January 2007 to august 2010, 46 patients (26 men and 20 women, 59 median age years, range 43-77) were analyzed with a median follow-up of 31.89 months (10-62 months).Twenty one patients (45.7%), 2 patients (4.3%), 0 patients (0%), 4patients (8.7%) and 7 patients (15.2%) had central, local, marginal, central plus local and distal recurrences, respectively. In 38 patients (82%) O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status were analyzed and 19 patients (50%) with unmethylated MGMT compared with 9 patients (23%) with methylated MGMT status had tumor recurrence. Central recurrences were more frequently observed in patients with methylated MGMT (5 patients [27%]) than in patients with unmethylated-MGMT (13 patients [72%]). This difference was not statistically significant. The median overall survival and progression-free survival were 23 months and 17 months, respectively. Conclusions: The patterns of failure in GBM patients treated with highly conformal dose distribution (IMRT) are predominantly local-central without increasing the marginal recurrence rate. We have observed that unmethylated-MGMT tumors could be a predictive factor for local-central recurrences. Author Disclosure: M. Rodriguez-Ruiz: None. I. San Miguel: None. M. Moreno-Jimenez: None. J. Espinos: None. E. Arevalo: None. P. Dominguez: None. S. Tejada: None. J. Arbizu: None. M.A. Idoate: None. J. Aristu: None.

2145 Quantification of Tumor Growth Kinetics in Patients Showing Progression From Low-grade to High-grade Gliomas R. Munbodh,1 R.J. Young,2 H. Tagare,3 N.T. Nguyen,4 L. Friguglietti,2 and K. Beal2; 1University of Pennsylvania School of Medicine, Philadelphia, PA, 2Memorial Sloan Kettering Cancer Center, New York, NY, 3Yale University School of Medicine, New Haven, CT, 4University of the Sciences, Philadelphia, PA Purpose/Objective(s): Nearly all Grade II low-grade gliomas (LGGs) will progress to high-grade gliomas (HGGs), although the time interval for malignant transformation may vary from months to years. High-grade (HG) disease is typically assessed by monitoring tumor size and contrast enhancement over time in magnetic resonance images (MRI). Early, reliable diagnosis of malignant transformation in patients with LGGs prior to the development of contrast enhancement is desirable to facilitate appropriate treatment decisions. In this study, we seek to characterize the growth kinetics of LGGs that progress to HG using an automated levelset based segmentation method that allows volumetric quantification of tumors from MRI. Materials/Methods: The patient cohort consisted of 8 patients with LGG histopathology and subsequent HGG histopathology with a mean of 22 MRI T2/FLAIR scans each (range, 13 to 42) over 2.3 to 11 years. A complete clinical and histopathological history was available for all patients. We segmented the tumors in the longitudinal MRI scans for each patient. The segmentation methods used account for the variable spatial sensitivity of MR receiver coils and also accurately capture the infiltrative shape of gliomas. Absolute tumor volume, relative change in tumor volume, and absolute and relative tumor growth rates over time were quantified. The mean values of these parameters were then calculated from successive scans at two points: (1) when the tumor was diagnosed as being

S274

International Journal of Radiation Oncology  Biology  Physics

low-grade and (2) prior to histopathological confirmation of a transformation to HG. A paired t-test analysis was performed to detect increases in tumor volume and growth rate between these two time points. Results: We detected significant increases in tumor volumes and growth rates within a mean of 210 days from malignant transformation. The mean absolute tumor volume increased from 15.6 cm3 to 26.4 cm3, the mean absolute growth rate increased from 6.6 mm3 per day to 152.2 mm3 per day, the mean relative change in tumor volume between consecutive scans increased from 6.6% to 84.5%, and the mean relative growth rate increased from 0.08% per day to 0.9% per day with respect to the previous scan (p < 0.05). In a few patients, we observed an increase in tumor volume and growth rate up to 1.5 years prior to definite transformation to HG indicating that transformation to HG may occur over several months to years. Conclusion: We were able to accurately quantify changes in the growth kinetics of gliomas transforming from low- to high-grade in a longitudinal study of MRI data. These findings indicate the usefulness of quantitative volumetric measures in monitoring the status of patients with LGGs. Application of these techniques may help improve our understanding of tumor growth and direct treatment options. Author Disclosure: R. Munbodh: None. R.J. Young: None. H. Tagare: None. N.T. Nguyen: None. L. Friguglietti: None. K. Beal: None.

Author Disclosure: A. Paulsson: None. A.M. Peiffer: None. K.P. McMullen: None. W.H. Hinson: None. G.J. Lesser: None. T.L. Ellis: None. S.B. Tatter: None. E.G. Shaw: None. M.D. Chan: None.

2146 Comparison of Clinical Outcomes for Single Focus and Multifocal Glioblastoma A. Paulsson,1 A.M. Peiffer,1 K.P. McMullen,2 W.H. Hinson,1 G.J. Lesser,1 T.L. Ellis,1 S.B. Tatter,1 E.G. Shaw,1 and M.D. Chan1; 1Wake Forest University School of Medicine, Winston-Salem, NC, 2Indiana University School of Medicine, Indianapolis, IN Purpose/Objective(s): We investigate the differences in failure patterns and survival between multifocal and multicentric glioblastoma (GBM) and single focus GBM in the modern treatment era of 3D conformal radiation therapy and temozolomide-based chemotherapy. Materials/Methods: Between August 2000 and May 2010, 161 patients with GBM were treated with radiation therapy using modern treatment planning techniques. Of this group, 33 were considered to have either multifocal (25) or multicentric (8) GBM. Patients were treated with nonwhole brain radiation therapy fields using a shrinking field technique. Patients were followed clinically and with serial MRI. Electronic medical records and imaging review were used to retrospectively determine date of initial failure using the Response Assessment in Neuro-Oncology (RANO) criteria. Treatment planning data were fused to MRI at date of failure using the treatment planning system. Location of treatment failure was categorized as within the 60 or 46 Gy volume, and distant (beyond the 46 Gy volume). Patterns of failure, time to progression and overall survival were compared based on whether the patient was considered a multifocal, multicentric, or single focus GBM. Kaplan-Meier analysis was used to generate survival curves and Chi Square contingency analysis was used to determine differences between failure patterns between single focus and multiple foci populations. Results: Median survival was equivalent between multicentric GBM (8.2 months) and multifocal GBM (8.2 months). Furthermore, the difference in overall survival between the multiple focus tumors (8.2 months) and single focus GBM (11.1 months) was not statistically significant (p Z 0.28). However, progression free survival was superior in the single focus tumors (7.1 months) as compared to multi-focal (5.6 months, p Z 0.02). Failure patterns were not significantly different between single focus, multifocal and multicentric GBM. For patients with single focus, multifocal and multicentric GBM, 81%, 76% and 88% of treatment failures occurred in the 60 Gy volume (p Z 0.49), while 54%, 72%, and 38% of treatment failures occurred in the 46 Gy volume (p Z 0.35). Out of field failures were rare in both single focus and multiple foci GBM (7% vs 3%). Conclusions: Patterns of failure for multifocal and multicentric GBM do not appreciably differ when compared to single focus tumors. Time to progression may be worse in these patients, suggesting a difference in tumor biology.

2147 Prospective Trial Evaluating Difference in Radiation Target Volume on 3T Versus 1.5T MR for Patients With Malignant Gliomas J.N. Guarnaschelli, A. Vagal, J. Breneman, R. Warnick, C. Mcpherson, W. Barrett, and M. Lamba; University of Cincinnati, Cincinnati, OH Purpose/Objective(s): It is hypothesized that there is a difference in the peritumoral and tumor related signal abnormality detected by 1.5 tesla (T) versus 3T T2 FLAIR magnet resonance imaging (MRIs). We assessed the difference in radiation treatment gross tumor volumes (GTVs) defined by four investigators for high-grade gliomas as determined using 1.5T vs. 3T MRIs. Materials/Methods: A total of 23 patients with newly diagnosed, high grade-gliomas were enrolled in this IRB approved prospective trial. All patients underwent a 1.5T and 3T MR scans within a 24-hour period, with no treatment or steroid dose change between scans. The 1.5T study was part of the clinical standard of care and hence was the MR imaging with intravenous gadolinium administration and was used for radiation treatment planning. Gadolinium was not given at 3T imaging. The imaging parameters for T1, T2, and FLAIR sequences were those that are clinically employed at this institution. Image processing and radiation planning was performed using radiation oncology software. MRIs were fused by a designated physicist and were reviewed by a radiation oncologist. GTV delineation was independently performed by 4 experienced investigators: 2 radiation oncologists and 2 neurosurgeons. To decrease inherent biases, investigators contoured 1.5T and 3T MRs separately, with a minimum of 72 hours between contours, blinded to other contours. GTV was defined by the extent of peritumoral edema depicted by high T2 FLAIR signal abnormality. For each patient and investigator the volumes defined by FLAIR images at 1.5 and 3T were determined and the ratio of the volumes (GTV3T/GTV1.5T) were calculated. The mean volume ratios were calculated for each investigator as well as an overall average. To assess the consistency of contours from investigator to investigator, the standard deviations and range of the volumes amongst all investigators were determined for each patient at each field strength. Results: The volumes ratios for each investigator (GTV3T/GTV1.5T) were 0.86  0.20 (range, 0.37-1.03), 0.90  0.20 (range, 0.19-1.08), 0.94  0.18 (range, 0.37-1.14), and 0.98  0.14 (range, 0.66-1.18). One patient was clearly an outlier, with 3T volumes 0.19 to 0.66 that of the 1.5T volumes. The overall GTV3T/GTV1.5Tratio was 0.95  0.19. Excluding the outlier produced an overall GTV3T/GTV1.5T ratio 0.94  0.13 (range, 0.57-1.18). The 1.5T studies produced less variability from investigator to investigator. Thirty-nine percent of contoured volumes were different by greater than 10%. Conclusions: At this institution, it was found that flair defined GTVs for high grade gliomas were on average smaller that at 3T. There was increased volume variability on 3T MR. Author Disclosure: J.N. Guarnaschelli: None. A. Vagal: None. J. Breneman: None. R. Warnick: None. C. Mcpherson: None. W. Barrett: None. M. Lamba: None.

2148 Smaller Margins in the Treatment of Glioblastoma Multiforme A. Morris, M. TenNapel, C. Anderson, M. Smith, and J. Buatti; University of Iowa Hospitals and Clinics, Iowa City, IA Purpose/Objective(s): Malignant glioma is the most common primary brain tumor in adults. Diagnosed in over 9,000 Americans per year, highgrade gliomas are highly aggressive and diffusely infiltrative tumors. Given their poorly defined borders, generous CTV and PTV margins have historically been used in order to cover the entire scope of microscopic disease. Current RTOG protocols use a 2 cm margin around the clinical treatment volume. Despite these generous margins, however, outcomes