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1 Neuro-Oncology XX(XX), 1 11, 2018 doi: /neuonc/noy049 Advance Access date 26 March Prognostic value of contrast enhancement and FLAIR for survival in newly diagnosed glioblastoma treated with and without bevacizumab: results from ACRIN 6686 Jerrold L. Boxerman, Zheng Zhang, Yair Safriel, Jeffrey M. Rogg, Ronald L. Wolf, Suyash Mohan, Helga Marques, A. Gregory Sorensen, Mark R. Gilbert, and Daniel P. Barboriak Department of Diagnostic Imaging, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island (J.L.B., J.M.R.); Center for Statistical Sciences, Brown University, Providence, Rhode Island (Z.Z., H.M.); Pharmascan Clinical Trials and Radiology Associates of Clearwater University of South Florida, Clearwater, Florida (Y.S.); Department of Radiology, Neuroradiology Division, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania (R.L.W., S.M.); Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts (A.G.S.); Department of Neuro-oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (M.R.G.); Department of Radiology, Duke University Medical Center, Durham, North Carolina (D.P.B.); IMRIS, Deerfield Imaging, Inc, Minnetonka, Minnesota (A.G.S.); Neuro-Oncology Branch of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland (M.R.G.) Corresponding Author: Jerrold L. Boxerman, MD, PhD, FACR, Rhode Island Hospital, Department of Diagnostic Imaging, 593 Eddy Street, Providence, RI (jboxerman@lifespan.org). Abstract Background. ACRIN 6686/RTOG 0825 was a phase III trial of conventional chemoradiation plus adjuvant temozolomide with bevacizumab or without (placebo) in newly diagnosed glioblastoma. This study investigated whether changes in contrast-enhancing and fluid attenuated inversion recovery (FLAIR) hyperintense tumor assessed by central reading prognosticate overall survival (OS). Methods. Two hundred eighty-four patients (171 men; median age 57 y, range 19 79; 159 on bevacizumab) had MRI at post-op (baseline) and pre-cycle 4 of adjuvant temozolomide (22 wk post chemoradiation initiation). Four central readers measured bidimensional lesion enhancement (2D-T1) and FLAIR hyperintensity at both time points. Changes from baseline to pre-cycle 4 for both markers were dichotomized (increasing vs non-increasing). Cox proportional hazards model and Kaplan Meier survival estimates were used for inference. Results. Adjusting for treatment, increasing 2D-T1 (n = 262, hazard ratio [HR] = 2.07, 95% CI: , P < 001) and FLAIR (n = 273, HR = 1.75, 95% CI: , P = 008) significantly predicted worse OS. Median OS (days) was significantly shorter for patients with increasing versus non-increasing 2D-T1 for both bevacizumab (443 vs 535, P = 04) and placebo (526 vs 887, P = 01). Median OS was significantly shorter for patients with increasing versus non-increasing FLAIR for placebo (595 vs 872, P = 01), and trended similarly for bevacizumab (499 vs 535, P = 935). Adjusting for 2D-T1 and treatment, increasing FLAIR represented significantly higher risk for death (HR = 1.59 [ ], P = 1). Conclusion. Increased 2D-T1 significantly predicts worse OS in both treatment groups, implying absence of a substantial proportion of pseudoprogression 22 weeks after initiation of standard therapy. FLAIR adds value beyond 2D-T1 in predicting OS, potentially addressing the pseudoresponse effect by substratifying bevacizumab-treated patients with non-increasing 2D-T1. Keywords contrast-enhanced MRI fluid-attenuated inversion recovery (FLAIR) glioblastoma pseudoprogression pseudoresponse The Author(s) Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please journals.permissions@oup.com

2 2 Boxerman et al. Results from the ACRIN 6686 Central Reader Study Importance of the study This study establishes that changes in tumor enhancement and FLAIR from baseline to pre-cycle 4 of adjuvant temozolomide are prognostic imaging markers for OS. Increased enhancement at pre-cycle 4 in patients on standard therapy was strongly associated with poor OS, implying absence of substantial pseudoprogression at this time (22 wk following treatment initiation) and helping define the period during which pseudoprogression must be considered using Response Assessment in Neuro-Oncology (RANO) criteria. FLAIR had independent prognostic value for OS, and added value beyond 2D-T1 in predicting OS, supporting its inclusion in RANO. On the basis of a 0% threshold for progression (increasing vs non-increasing), FLAIR further substratified bevacizumab-treated patients with improving contrast enhancement, addressing the issue of pseudoresponse and helping to further refine T1-based OS assessment for standard therapy. Because literature results vary greatly for alternative FLAIR thresholds, our results suggest that FLAIR thresholds must be judiciously selected for RANO. Glioblastoma, the most common and aggressive primary brain tumor, has a dismal prognosis, with median survival of months 1 and 5-year survival rate of 9.8%. 2 Surgical resection followed by chemoradiation with concomitant and adjuvant temozolomide (TMZ) is the standard of care, offering prolonged overall survival (OS), 3 but progressive glioblastoma is uniformly fatal, with median survival under 30 weeks. 4 Glioblastoma stem cells promote tumor angiogenesis, 5 prompting use of anti-angiogenic drugs in clinical treatment trials. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, 6 is FDA approved for second-line treatment of recurrent glioblastoma, 7 appearing to confer a clinical benefit in early phase II clinical trials 8 compared with historic controls. 3 However, not all recurrent glioblastomas respond to bevacizumab, and response in this setting is poorly defined. 9 Radiologic markers providing early indication of treatment failure for standard and anti-angiogenic therapy and timely opportunity to select alternative treatments or trials are therefore important. However, posttreatment image interpretation is challenging because of 2 confounders. 10 Pseudoprogression is transient increased contrast enhancement mimicking tumor progression 11 that commonly follows radiotherapy and TMZ within 1 6 months 12 and stabilizes or resolves without further intervention, potentially conferring improved survival. 13,14 Its mechanism likely involves pro-inflammatory mediators and cytokines 15 producing edema and contrast enhancement that are difficult to distinguish from progressive disease on conventional MRI, 16 prompting modification of response assessment criteria to allow for the possibility of pseudoprogression within 12 weeks, and possibly up to 6 months after completion of radiation. 17 Pseudoresponse reflects decreased contrast enhancement independent of antitumor effect, typically in the setting of anti-angiogenic therapy. Bevacizumab yields high response rates and prolonged progressionfree survival (PFS) without improved OS, 1 illustrating how pseudoresponse limits early response assessment and motivating the inclusion of non-enhancing tumor (fluid attenuated inversion recovery [FLAIR]) in response assessment criteria. 17 The ability of changes in contrast enhancement and FLAIR to predict OS is therefore uncertain and controversial. Radiation Therapy Oncology Group (RTOG) 0825, a multicenter randomized phase III trial of conventional concurrent chemoradiation and adjuvant TMZ with or without bevacizumab in newly diagnosed glioblastoma, provided the opportunity to evaluate posttreatment conventional MRI metrics for predicting OS using controlled, retrospective central reader methodology. ACRIN 6686 is the companion study that evolved to investigate the association between changes in tumor size measured by postcontrast T1-weighted or FLAIR images prior to cycle 4 of adjuvant TMZ and OS in both treatment arms. Specifically, we analyzed the RTOG 0825 image set to determine: (i) the relationship between OS and change in tumor size on contrast-enhanced T1-weighted and FLAIR images; (ii) the ability of change in enhancement and FLAIR to independently prognosticate OS in each treatment arm with attention to possible pseudoprogression and pseudoresponse; and (iii) the added value of FLAIR beyond contrast-enhanced T1 in prognosticating OS and distinguishing pseudoresponse from true response for bevacizumab therapy. Materials and Methods RTOG, in collaboration with the American College of Radiology Imaging Network (ACRIN), both funded by the National Cancer Institute, conducted a prospective phase III double-blind placebo-controlled multicenter trial comparing conventional concurrent chemoradiation and adjuvant TMZ without versus with bevacizumab in patients with newly diagnosed glioblastoma (RTOG 0825/ACRIN 6686). Each participating institution obtained institutional review board approval before subject accrual and conducted the trial with Health Insurance Portability and Accountability Act compliance. Informed consent was obtained for all subjects. Study Subjects and Treatment All patients had newly diagnosed, histologically proven glioblastoma or gliosarcoma (World Health Organization grade IV astrocytoma) confirmed on central review. Detailed inclusion and exclusion criteria are available at RTOG0825-ACRIN6686_Amend4_ _ForOnline.pdf

3 Boxerman et al. Results from the ACRIN 6686 Central Reader Study 3 (Section 3.0). Fractionated, conformal radiotherapy or intensity-modulated radiotherapy (2 Gy/d, 5 d/wk for 6 wk) was delivered to the postoperative cavity, marginating enhancement, and surrounding FLAIR signal abnormality plus a 2 cm margin (46 Gy in 23 fractions, followed by a boost of 14 Gy in 7 fractions). Temozolomide treatment (75 mg/m 2 p.o. daily) coincided with radiotherapy (maximum of 49 doses). Patients were randomly assigned to receive standard therapy plus bevacizumab or standard therapy alone (referred to as the placebo arm); stratification factors included methylation status of O 6 -methylguanine DNA methyl-transferase and a 9-gene tumor-based molecular profile. Bevacizumab (for the bevacizumab arm) was administered (10 mg/kg i.v., days 1 and 15 of a 28-d cycle) starting at week 4 of radiotherapy, until disease progression, severe treatment-related toxicity, or completion of adjuvant therapy (24 doses over 12 cycles, maximum). Maintenance TMZ began 4 weeks after completion of radiotherapy (150 mg/m 2 p.o. for 5 consecutive days of a 28-day cycle, increased to 200 mg/m 2 p.o. for subsequent cycles in the absence of treatment-related adverse events of grade 2 or higher). 1 Imaging Timeline MRI exams occurred at postoperative baseline; approximately 4 weeks after completion of radiotherapy prior to cycle 1 of maintenance TMZ; prior to cycle 4 of maintenance TMZ (typically occurring 22 wk following initiation of chemoradiation, and referred to herein as the pre-cycle 4 time point); and before initiation of cycles 7 and 10 of maintenance TMZ, if administered. Patients completing adjuvant treatment had follow-up MRIs every 3 months until tumor progression. MRI Protocol Conventional MRI included precontrast T1-weighted, T2-weighted, FLAIR, and diffusion-weighted imaging. After intravenous injection of 0.1 mmol/kg of standard gadolinium-based contrast agent, axial 2D spin-echo postcontrast T1-weighted images (herein referred to as 2D-T1 for simplicity) with or without 3D volumetric T1-weighted images were acquired. Patients participating in the optional advanced component of the trial (ACRIN 6686, to be reported separately) also had dynamic contrast-enhanced and/or dynamic susceptibility contrast perfusion-weighted MRI at up to 4 additional time points: 0 5 days pre-chemoradiation, 0 3 days pre-bevacizumab/ placebo cycle 1, 0 1 day post-bevacizumab/placebo cycle 1 initiation, and post-chemoradiation. The complete MRI protocol is documented online at Portals/0/Protocols/6686/Protocol-RTOG0825-ACRIN6686_ Amend4_ _ForOnline.pdf (Appendix XII). Central Reader Methods All local imaging was transmitted to ACRIN for central review. Four primary readers, each with neuroradiology certificates of added qualification and 26, 14, 10, and 8 years of post-fellowship experience, were trained at ACRIN headquarters regarding 2D measurement techniques. Each primary reader, blinded to clinical outcome data, then conducted independent image assessments remotely using XenApp (Citrix Systems) desktop virtualization software. Image analysis in 2D was performed using MIM analysis software. For each distinct contrastenhancing target lesion ( 1 cm diameter, 1 cm from other enhancing lesions), the largest diameter of contrast enhancement and its maximum co-planar perpendicular diameter were measured on the spin-echo postcontrast T1-weighted images following RANO guidelines, 17 with similar measurements made on corresponding FLAIR images. Readers were instructed to identify tumor-related FLAIR hyperintensity, although it is acknowledged that objective tumor-related FLAIR measures are difficult to prescribe. 17 Tumor areas in 2D-T1 and FLAIR were computed by summing over all lesions the product of maximum perpendicular diameters. Pre- and postcontrast images were reviewed simultaneously to exclude blood products from 2D areas. Two standard imaging exams were evaluated for each patient: the baseline postoperative MRI and the MRI performed before cycle 4 of adjuvant TMZ (pre-cycle 4). For all evaluable patients with imaging available at both time points, one (190 patients) or two (94 patients) central readers independently made 2D-T1 and FLAIR measurements. For patients evaluated by 2 central readers, the measurements from 1 reader were randomly selected for statistical analysis. Study Cohort Six hundred twenty-one patients were randomized in RTOG 0825 and included in the main study publication. 1 Of those, patients were discounted who lacked baseline imaging (n = 16), pre-cycle 4 imaging (n = 206, including 98 who died before pre-cycle 4), or complete and interpretable 2D-T1 or FLAIR datasets at baseline and pre-cycle 4 (n = 48), or for whom pre-cycle 4 MRI fell outside the week range (n = 67), leaving 284 analyzable datasets (2D- T1 and/or FLAIR) with post-op baseline and pre-cycle 4 imaging. There were 148 and 114 interpretable 2D-T1 datasets for the bevacizumab and placebo arms, respectively (262 total). There were 153 and 120 interpretable FLAIR datasets for the bevacizumab and placebo arms, respectively (273 total). Statistical Methods Hazard ratio (HR) from the multivariate Cox proportional hazards model with or without treatment and marker interaction terms was used to detect the association between changes in 2D-T1 and FLAIR imaging markers and OS. Kaplan Meier survival curves and log-rank tests were used to compare OS between patients with increasing versus non-increasing markers. All tests were 2-sided with significance level of 5 and were performed using SAS 9.4. The Biomarker, Imaging and Quality of Life Studies Funding Program (BIQSFP) of the National Cancer Institute supported image processing and statistical analysis. Neuro- Oncology

4 4 Boxerman et al. Results from the ACRIN 6686 Central Reader Study Eastern Cooperative Oncology Group ACRIN and NRG Oncology approved the manuscript prior to submission. Results Patient Demographics Table 1 compares the patient demographics for the main RTOG 0825 cohort and our analyzable subset. There were 284 evaluable patients from 134 sites, including 171 (6%) men and 113 (39.8%) women, with a median age of 57 years (range 19 79). The bevacizumab arm contained 159 patients (56%). Relationship Between OS and Change in 2D-T1 and FLAIR for All Patients By the time of outcomes data collection, 177/284 patients (62%) had died. The median OS was 606 days (19.9 mo), Table 1. Comparison of patient demographics for the RTOG 0825 parent trial and the analyzable cohort for ACRIN 6686 RTOG (n = 621) ACRIN 6686 (n = 284) Age Mean (SD) 57.7 (11.1) 56.2 (1) Median (range) 58 (19 82) 57.0 (19 79) Dichotomized age, n (%) <50 y 122 (19.6) 65 (22.9) 50 y 499 (8) 219 (77.1) Race, n (%) Caucasian 591 (95.2) 272 (95.8) Asian 7 (1.1) 4 (1.4) Black or African American 11 (1.8) 4 (1.4) American Indian/Alaska Native 2 (0.3) 1 () More than one race 1 () 0 () Unknown 9 (1.4) 3 (1.1) Sex, n (%) Female 249 (40.1) 113 (39.8) Male 372 (59.9) 171 (6) Ethnicity, n (%) Hispanic or Latino 25 (4.0) 9 (3.2) Not Hispanic or Latino 563 (90.7) 262 (92.3) Unknown 33 (5.3) 13 (4.6) Treatment arm, n (%) Bevacizumab 312 (5) 159 (56.0) Placebo 309 (49.8) 125 (44.0) Survival status, n (%) Overall Died 413 (66.5) 177 (62.3) Alive 208 (33.5) 107 (37.7) Bevacizumab Died 215 (68.9) 112 (7) Alive 97 (31.1) 47 (29.6) OS (days [95% CI]) 478 [ ] * 532 [ ] ** Placebo Died 198 (64.1) 65 (52.0) Alive 111 (35.9) 60 (48.0) OS (days [95% CI]) 490 [ ] * 715 [ ] ** *OS measured from randomization; P = 1. **OS measured from baseline scan; P < 001.

5 Boxerman et al. Results from the ACRIN 6686 Central Reader Study 5 95% CI: days ( mo). Adjusting for treatment arm, tumor growth between baseline and pre-cycle 4 was significantly associated with shortened OS (for each 1 cm 3 of additive tumor volume, HR = 27, 95% CI: 07 47, P = 08 for 2D-T1 and HR = 11, 95% CI: 02 21, P = 2 for FLAIR). These results confirm that changes in tumor enhancement and FLAIR from baseline to pre-cycle 4 (typically 22 wk post chemoradiation initiation) are prognostic imaging markers for OS. We subsequently evaluated the effect of change in tumor size on OS by dichotomizing patients based upon whether their tumor grew from baseline to pre-cycle 4. Of 262 patients, 75 with complete 2D-T1 measurements had increased 2D-T1 from baseline to pre-cycle 4, whereas 83/273 patients with complete FLAIR measurements had increased FLAIR. Median OS (days [95% CI]) was significantly shorter for patients with increasing versus non-increasing 2D-T1 (487 [ ] vs 649 [ ], P = 011) and FLAIR (541 [ ] vs 655 [ ], P = 078). Adjusting for treatment, increasing 2D-T1 (HR = 2.07, 95% CI: , P < 001) and FLAIR (HR = 1.75, 95% CI: , P = 008) were significantly associated with worse survival (Table 2 and Fig. 1). Subgroup Analysis of the Relationship Between Change in 2D-T1 and OS Of the 262 patients with baseline and pre-cycle 4 2D-T1 measurements, 142 had measurable enhancement at pre-cycle 4 (79/114 in the placebo group, and 63/148 in the bevacizumab group). Median survival (days [95% CI]) differed significantly between patients with increasing versus non-increasing 2D-T1 for both the bevacizumab (443 [ ] vs 535 [ ], respectively; P = 042; n = 148) and the placebo arms (526 [ ] vs 887 [684 undefined], respectively; P = 01; n = 114) (Fig. 2). For both the patients on bevacizumab (HR = 1.92, 95% CI: , P = 049) and placebo (HR = 2.33, 95% CI: , P = 014), increasing 2D-T1 was strongly associated with Neuro- Oncology Table 2. Association between changes in tumor size on 2D-T1 and FLAIR from baseline to pre-cycle 4 of adjuvant TMZ (increasing vs non-increasing) and OS Group n Median OS [95% CI] (days) All [ ] 2D-T1 262 Comparison, median OS (P-value) HR [95% CI] (P-value) [ ] [ ] * Non-increasing [ ] (<001) FLAIR [ ] [ ] * Non-increasing [ ] (008) Bevacizumab 2D-T [ ] [ ] Non-increasing [ ] (049) FLAIR [ ] [ ] Non-increasing [ ] (96) A: 2D-T1( )/FLAIR( ) [ ] A vs B: B: 2D-T1( )/FLAIR(+) [ ] B vs C: C: 2D-T1(+) [ ] A vs C: 015 Placebo 2D-T [ ] [ ] Non-increasing [684 ###] (014) FLAIR [ ] [ ] Non-increasing [684 ###] (019) A: 2D-T1( )/FLAIR( ) [745 ###] A vs B: 512 B: 2D-T1( )/FLAIR(+) [303 ###] B vs C: C: 2D-T1(+) [ ] A vs C: 004 * Adjusted for treatment arm. ### = Undefined. (+) =. ( ) = Non-increasing.

6 6 Boxerman et al. Results from the ACRIN 6686 Central Reader Study A 2D-T1 487 vs. 649 days p = 011 (n = 262) Non- B FLAIR 541 vs. 655 days p = 078 (n = 273) Non- Fig. 1 Kaplan Meier survival curves stratified by change in 2D-T1 (A) and FLAIR (B) from baseline to pre-cycle 4 of adjuvant TMZ (typically 22 wk post treatment initiation) for both treatment arms combined. There is statistically significant difference in median survival for patients with increasing versus non-increasing 2D-T1 and FLAIR. A 2D-T1 443 vs. 535 days Bevacizumab p = 042 (n = 148) Non- 2D-T1 B Placebo (Standard Rx) 2D-T1 526 vs. 887 days p = 01 (n = 114) Non- 2D-T1 Fig. 2 Kaplan Meier survival curves stratified by change in 2D-T1 from baseline to pre-cycle 4 of adjuvant TMZ for patients in the bevacizumab (A) and placebo (B) arms separately. In both treatment arms, there is statistically significant difference in median survival for patients with increasing versus non-increasing 2D-T1. worse survival (Table 2). These findings suggest that there is no substantial pseudoprogression effect at pre-cycle 4 (typically 22 wk after initiation of chemoradiation). Subgroup Analysis of the Relationship Between Change in FLAIR and OS Median survival (days [95% CI]) differed significantly between patients with increasing versus non-increasing FLAIR for the placebo arm (595 [ ] vs 872 [684 undefined], respectively; P = 014; n = 120), and increasing FLAIR was strongly associated with worse survival (HR = 2.21, 95% CI: , P = 019). Similar trends were observed in the bevacizumab arm for differences in median survival (499 [ ] vs 535 [ ], respectively; P = 935; n = 153) and association with worse survival (HR = 1.45, 95% CI: , P = 96), but without reaching statistical significance (Table 2 and Fig. 3). Multivariate Modeling of the Additive Value of FLAIR for Predicting OS Of the 254 patients with both 2D-T1 and FLAIR measurements, 40 had increased 2D-T1 and FLAIR from baseline to pre-cycle 4, 143 had decreased 2D-T1 and FLAIR, and 71 had increased value for one but not both. In a multivariate

7 Boxerman et al. Results from the ACRIN 6686 Central Reader Study 7 Cox regression model including 2D-T1, FLAIR, and treatment variables, increased FLAIR represented a 59% higher risk for death (HR = 1.59, 95% CI: , P = 1) when adjusting for 2D-T1 change and treatment. There were no statistically significant interactions between 2D-T1, FLAIR, and treatment in the multivariate model, suggesting that this association between FLAIR and survival is independent of treatment assignment and change in 2D-T1. For bevacizumab therapy, FLAIR may help distinguish pseudoresponders from true responders. In Fig. 4A, patients with non-increasing 2D-T1 (black survival curve in Fig. 2A) are substratified into patients with increasing (curve B) versus non-increasing (curve A) FLAIR. Median survival (days [95% CI]) for patients with non-increasing FLAIR (581 [ ]) remains significantly greater than that for patients with increasing 2D-T1 (443 [ ]). Patients with increasing FLAIR have poorer survival (474 [ ]), with a survival curve visually approaching and median survival not significantly different than that for patients with increasing 2D-T1 (curve C), suggesting that the non-increasing enhancement for these patients reflects pseudoresponse. Similarly, FLAIR may potentially Neuro- Oncology A FLAIR Bevacizumab 499 vs. 535 days p = 935 (n = 153) Non- FLAIR B Placebo (Standard Rx) FLAIR 595 vs. 872 days p = 14 (n = 120) Non- FLAIR Fig. 3 Kaplan Meier survival curves stratified by change in FLAIR from baseline to pre-cycle 4 of adjuvant TMZ for patients in the bevacizumab (A) and placebo (B) arms separately. Median survival differed significantly between patients with increasing versus non-increasing FLAIR for the placebo arm. A similar trend in median survival was observed in the bevacizumab arm, without reaching statistical significance. A Bevacizumab Median OS (days): (A) 581 vs. (C) 443, p < 1 (B) 474 vs. (C) 443, p < 0.33 (A) 581 vs. (B) 443, p = 0.11 (C) 2D-T1 (n = 145) (A) 2D-T1, FLAIR (B) 2D-T1, FLAIR B Placebo (Standard Rx) (n = 111) (C) 2D-T1 Median OS (days): (A) 887 vs. (C) 526, p < 1 (B) 628 vs. (C) 526, p < 0.56 (A) 887 vs. (B) 628, p = 5 (A) 2D-T1, FLAIR (B) 2D-T1, FLAIR Fig. 4 Substratification of patients with non-increasing 2D-T1 by increasing versus non-increasing FLAIR (intermediate gray and black survival curves, respectively) for (A) bevacizumab arm and (B) placebo arm. In both arms, survival for patients with non-increasing FLAIR remains significantly greater than that for patients with increasing 2D-T1. (A) Median survival for patients with increasing FLAIR is not significantly different than that for patients with increasing 2D-T1, reflecting pseudoresponse. (B) Median survival for patients with increasing FLAIR is more similar to that for patients with increasing 2D-T1 than patients with non-increasing FLAIR, illustrating the importance of FLAIR when prognosticating survival based on 2D-T1 for standard therapy.

8 8 Boxerman et al. Results from the ACRIN 6686 Central Reader Study further refine 2D-T1 based prognostication of OS for standard therapy illustrated in Fig. 2B. In Fig. 4B, patients with non-increasing 2D-T1 (black survival curve in Fig. 2B) are substratified into patients with increasing (curve B) versus non-increasing (curve A) FLAIR. Median survival (days [95% CI]) for patients with increasing FLAIR (628 [303 undefined]) is more similar to that for patients with increasing 2D-T1 (526 [ ]) than patients with nonincreasing FLAIR (887 [745 undefined]), further emphasizing the importance of FLAIR when prognosticating survival based on 2D-T1 for standard therapy. Survival curves for patients with non-increasing 2D-T1 substratified by increasing (curve B) versus non-increasing (curve A) FLAIR differ significantly for standard therapy, and are visually distinct without reaching significance for bevacizumab therapy. Discussion Pseudoprogression is a common 18 local inflammatory reaction 15 following radiotherapy and TMZ, marked by progressive enhancement and subsequent radiologic improvement or stabilization without modified therapy. 11,12,19 The modified RANO criteria recognize the possibility of pseudoprogression within 6 months (60% of the time within 3 mo) after completion of chemoradiation. 12,14,19 21 Precycle 4 MRI typically occurred approximately 22 weeks after initiation of chemoradiation (16 weeks after completion of chemoradiation). There was strong correlation of 2D-T1 with OS in the standard therapy arm at pre-cycle 4 (Fig. 2B), implying the absence of a strong pseudoprogression effect. This suggests that progressive enhancement beyond 16 weeks post-chemoradiation is likely to be real, placing an upper bound on the time frame during which pseudoprogression should be considered in RANO. Assuming similar absence of pseudoprogression at precycle 4 in the bevacizumab arm, the strong correlation between increased 2D-T1 and OS (Fig. 2A) demonstrates that worsened enhancement implicates true tumor progression and a failure of treatment to inhibit tumor growth. These findings recapitulate results for recurrent glioblastoma from ACRIN 6677, a phase II trial of bevacizumab with or without irinotecan in recurrent glioblastoma, reaffirming the significance of progressive enhancement in glioblastomas on anti-angiogenic therapy. 22 Pseudoresponse occurs with anti-angiogenic agents like bevacizumab that reduce contrast agent extravasation and discernible tumor enhancement independent of cytotoxic or cytostatic effect, 23 thereby limiting early response assessment 10 and prompting inclusion of non-enhancing tumor in modified response assessment criteria. 17 FLAIR hyperintensity may progress after anti-angiogenic therapy despite decreased tumor-related contrast enhancement, 24 explaining why enhancement-based response may be incongruous with and a poor predictor of OS. 25 RTOG 0825 illustrated this concept. For 637 newly diagnosed glioblastomas, OS did not differ significantly between patients on bevacizumab and placebo, despite significantly longer PFS, as primarily assessed by imaging, in the bevacizumab group. 1 Furthermore, bevacizumab has been shown to reduce imaging changes associated with radiation-related necrosis 26 and thus will likely reduce the incidence of pseudoprogression. Therefore, a lower incidence of pseudoprogression on the bevacizumab arm likely contributed to the discordance between the PFS and OS results for the trial. FLAIR was added to the RANO criteria in order to identify non-enhancing tumor progression, particularly for anti-angiogenic therapies. 27 Retrospective analysis found that FLAIR helps identify progression approximately one month earlier than contrast enhancement alone, but without significant differences in predicted OS. 28 Use of FLAIR has been controversial due to the subjective nature of its interpretation, as evidenced by the dependence of OS prediction upon nuances of FLAIR segmentation, including demarcation of circumscribed versus infiltrative patterns. 29 The utility of FLAIR also depends upon the threshold used for declaring progression, which is not specified by RANO. For instance, Huang evaluated recurrent glioblastomas from the AVF3708g trial and found that RANO inclusion of subjective FLAIR progression yielded statistically significant differences in median PFS and objective response rate compared with Macdonald criteria, although objective response rate and PFS determined by both RANO and Macdonald criteria correlated with OS. 28 Radbruch also found that addition of FLAIR to RANO increases the sensitivity for glioblastoma progression, with a 15% threshold for FLAIR progression having far superior performance to a 25% threshold. 30 Concordantly, for recurrent glioblastomas in ACRIN 6677, a 25% threshold for FLAIR progression was not helpful for substratifying by OS the 2D-T1 nonprogressors at 8 or 16 weeks after bevacizumab initiation. 22 In our study that uses a 0% threshold, OS differed significantly between patients with increasing versus non-increasing FLAIR for the placebo arm, and increasing FLAIR was strongly associated with worse survival. We observed similar trends in the bevacizumab arm for differences in median survival and association with worse survival (Fig. 3). Therefore, the additive value of FLAIR appears to depend strongly upon the criteria for declaring FLAIR progression, which must seemingly be carefully defined before FLAIR can provide consistent benefit in response assessment. 31 Our results confirm the presence of pseudoresponse in the bevacizumab arm at pre-cycle 4 and demonstrate that FLAIR may help distinguish true responders from pseudoresponders. Of the patients with non-increasing 2D-T1, the subgroup with increasing FLAIR had significantly shorter survival than the subgroup with non-increasing FLAIR, with median survival not significantly different than that for patients with increasing 2D-T1 (Fig. 4A). These results imply the presence of pseudoresponse, with an artifactual absence of worsened 2D-T1 in the setting of worsened FLAIR-delineated tumor burden. Substratification by FLAIR of 2D-T1 non-increasers in this study differs from the findings in ACRIN 6677, 22 where for the 2D-T1 nonprogressors, there was no statistically significant OS reduction among FLAIR progressors compared with nonprogressors at 8 and 16 weeks after bevacizumab initiation. An important difference between these studies, in addition to the timing interval between bevacizumab initiation and imaging, is the selected FLAIR thresholds. Whereas ACRIN 6677 required a 25% increase in FLAIR for progression, for this

9 Boxerman et al. Results from the ACRIN 6686 Central Reader Study 9 study we imposed a 0% threshold. A threshold for lesion progression on FLAIR is not quantified by RANO, and our results support previous evidence that lower thresholds are more sensitive for isolated FLAIR progression. 30 In the standard therapy arm, our results analogously show that FLAIR may help further refine 2D-T1 based prognostication of OS. Of the patients with non-increasing 2D-T1, the subgroup with increasing FLAIR had survival more similar to that for patients with increasing 2D-T1 than patients with non-increasing FLAIR (Fig. 4B), further emphasizing the importance of FLAIR when prognosticating survival based on 2D-T1 for standard therapy. Although OS is the standard endpoint for glioblastoma therapy trials, it may not be suitable when high crossover rates exist in the control arm. For instance, a large percentage of patients in the placebo arms for RTOG 0825 (48%) and AVAglio (31%), another phase III study of bevacizumab efficacy, eventually received bevacizumab. 1,32 There is therefore interest in determining whether 6-month PFS (PFS6), for instance, is a meaningful surrogate for OS in clinical trials. 33 Of the prescribed imaging time points in RTOG 0825, pre-cycle 4, typically occurring 22 weeks after initiation of chemoradiation, was closest to the 6-month time point without exceeding it. We therefore used precycle 4 to determine the relationship between OS and PFS6 based on 2D-T1 and FLAIR, using a 0% threshold for progression. Adjusting for treatment, both increasing 2D-T1 and FLAIR were significantly associated with worse survival (Fig. 1). Therefore, analogous to conventional measures of PFS in other trials, simple measures of change for these markers approximately 6 months after initiation of chemoradiation were highly predictive of OS. Furthermore, adjusting for treatment across all patients, every unit of additive difference in 2D-T1 or FLAIR between baseline and pre-cycle 4 corresponded to a significant increased risk of death, establishing 2D-T1 and FLAIR as predictive imaging markers for survival. Use of PFS has challenges, including measurement variability and discordance in interpretation between radiologists, 36 although a 0% threshold is simple and may reduce discrepancies due to scaling biases. When assessing the relationship between tumor growth and OS, we dichotomized patients based upon increasing versus non-increasing 2D-T1 or FLAIR at pre-cycle 4 compared with baseline. This essentially uses a 0% threshold for progression, compared with the 25% threshold for 2D-T1 progression imposed by the Macdonald and RANO criteria. The Macdonald and RANO thresholds defining response and progression are arbitrary without scientific basis for optimized correlation with OS or PFS. Thresholds based on percentage change with respect to baseline tumor size are greatly biased toward diminutive tumors where relatively small changes in tumor size yield large percentage changes. 37 This is particularly relevant for newly diagnosed glioblastomas, where either small initial tumors or those with minimal residual postoperative enhancement often progress early when non-measurable disease reaches the measurable threshold or small growth produces substantial percentage change in size. Among our 94 patients evaluated by 2 readers, the kappa statistic for classification as increasing versus non-increasing on 2D-T1 was 0 (88 patients), and 4 on FLAIR (92 patients), both at the boundary between moderate and substantial agreement. In ACRIN 6677, the adjudication rate for 2 central readers identifying time of progression (25% threshold) was approximately 40% (39%, FLAIR; 43%, 2D-T1). 22 These results illustrate the challenges associated with reproducible implementation of response assessment criteria. Volumetric response evaluation has been theorized to improve the RANO criteria. 31 We used conventional 2D bidirectional measures of contrast-enhancing tumor, as specified currently by RANO, and similarly used 2D measures of FLAIR. Central readers also made 3D segmentations of enhancement and FLAIR, with qualitatively similar performance of 2D and 3D measures of enhancement and FLAIR (results not shown). Bidirectional measurements may overestimate tumor volume 38 and yield higher reader discordance. 39 However, several studies 37,40 have demonstrated concordance between 2D-T1 and 3D-T1 methods for determining radiologic response of newly diagnosed and recurrent high-grade gliomas, including ACRIN and the recently published BELOB trial for recurrent glioblastoma, where volumetric methods did not significantly improve upon RANO for prognosis. 41 Bidirectional assessment may provide a quicker, more practical alternative to volumetric segmentation, although given the geometric complexity of contrast enhancement and FLAIR hyperintensity in treated glioblastomas, volumetric segmentations facilitated by 3D-T1 difference maps obtained with a newly standardized brain tumor imaging protocol 42 may ultimately improve accuracy, and computerization of such measures may lessen interobserver variability. 43 Other modifications to the RANO criteria have been proposed 31 that differ from the methodology of our study. Contrast-enhanced T1-weighted subtraction maps increase lesion conspicuity 44 but are facilitated by acquisition of pre- and postcontrast volumetric T1-weighted images using identical pulse sequence parameters (for example, as prescribed by a consensus brain tumor imaging protocol 42 ) but not included in ACRIN Use of the postradiation time point as baseline for response assessment has also been proposed. The first posttherapy MRI prescribed in ACRIN 6686 was at pre-cycle 1 (4 wk after completion of initial chemoradiation), and to maintain consistency with the methodology of prior investigations, as well as the original aims of the BIQSFP grant funding this trial, we used the postoperative, pretherapy scan as baseline. According to the World Health Organization 2016 diagnostic criteria, glioblastoma is not a formally complete diagnosis, and is further classified by isocitrate dehydrogenase (IDH) mutation status. The parent RTOG 0825 trial pre-dated this classification, and IDH mutational data are unavailable. It is likely that our cohort contains both IDH wildtype and mutant patients. However, 219/284 (77%) patients in our cohort were at least 50 years old (in proportion to RTOG 0825), a cohort that should be nearly completely wildtype. It is therefore likely that our results are generally applicable to IDH-wildtype glioblastomas. In conclusion, changes in tumor enhancement and FLAIR from baseline to pre-cycle 4 of adjuvant TMZ are prognostic imaging markers for OS. Increased enhancement at pre-cycle 4 in patients on standard therapy is strongly associated with poor OS, implying absence of substantial pseudoprogression at this time (approximately 22 wk after Neuro- Oncology

10 10 Boxerman et al. Results from the ACRIN 6686 Central Reader Study treatment initiation) and helping define the period when pseudoprogression must be considered using RANO criteria. Similar results in the bevacizumab arm recapitulate the findings from ACRIN FLAIR has independent prognostic value for OS overall, and added value beyond 2D-T1 in predicting OS. For bevacizumab therapies, FLAIR can substratify T1 non-increasers (helping to identify pseudoresponse), and for standard therapy, FLAIR may help further refine T1-based OS assessment. Funding This work was supported by National Cancer Institute grants CA021661, CA079778, CA080098, CA180794, CA180820, CA180822, CA180868, and the Biomarker, Imaging and Quality of Life Studies Funding Program (BIQSFP). Acknowledgments Portions of this material were presented at RSNA We thank Bernadine Dunning, Donna Hartfeil, Dunstan Horng, James Gimpel, Cynthia Price, Lisa Cimino, and Sandy Toland-Cary from ACRIN for administrative, data management, and image processing support, and all study patients for their cooperation. Conflict of interest statement. Financial: A. Gregory Sorensen: IMRIS, Deerfield Imaging, Inc, stock equity. Advisory affiliations: Daniel Barboriak: GE Medical Systems, neuro MRI advisory board. Management affiliations: A. Gregory Sorensen: DeepHealth, Inc, CEO. Paid consulting: A. Gregory Sorensen: Hitachi Medical and Konica Minolta. References 1. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8): Stupp R, Hegi ME, Mason WP, et al; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. 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Trends Mol Med. 2007;13(6): Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009;14(11): Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009;27(28): Norden AD, Drappatz J, Wen PY. Novel anti-angiogenic therapies for malignant gliomas. Lancet Neurol. 2008;7(12): Hygino da Cruz LC Jr, Rodriguez I, Domingues RC, Gasparetto EL, Sorensen AG. Pseudoprogression and pseudoresponse: imaging challenges in the assessment of posttreatment glioma. AJNR Am J Neuroradiol. 2011;32(11): Brandes AA, Tosoni A, Spagnolli F, et al. Disease progression or pseudoprogression after concomitant radiochemotherapy treatment: pitfalls in neurooncology. Neuro Oncol. 2008;10(3): Gerstner ER, McNamara MB, Norden AD, Lafrankie D, Wen PY. Effect of adding temozolomide to radiation therapy on the incidence of pseudoprogression. 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J Clin Oncol. 2010;28(11): Fink J, Born D, Chamberlain MC. Pseudoprogression: relevance with respect to treatment of high-grade gliomas. Curr Treat Options Oncol. 2011;12(3): Taal W, Brandsma D, de Bruin HG, et al. Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer. 2008;113(2): Roldán GB, Scott JN, McIntyre JB, et al. Population-based study of pseudoprogression after chemoradiotherapy in GBM. Can J Neurol Sci. 2009;36(5): Pope WB, Hessel C. Response assessment in neuro-oncology criteria: implementation challenges in multicenter neuro-oncology trials. AJNR Am J Neuroradiol. 2011;32(5): Boxerman JL, Zhang Z, Safriel Y, et al. Early post-bevacizumab progression on contrast-enhanced MRI as a prognostic marker for overall survival in recurrent glioblastoma: results from the ACRIN 6677/RTOG 0625 central reader study. Neuro Oncol. 2013;15(7): Brandsma D, van den Bent MJ. Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol. 2009;22(6): Zuniga RM, Torcuator R, Jain R, et al. Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J Neurooncol. 2009;91(3):

11 Boxerman et al. Results from the ACRIN 6686 Central Reader Study van den Bent MJ, Vogelbaum MA, Wen PY, Macdonald DR, Chang SM. End point assessment in gliomas: novel treatments limit usefulness of classical Macdonald s criteria. J Clin Oncol. 2009;27(18): Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys. 2011;79(5): Chinot OL, Macdonald DR, Abrey LE, Zahlmann G, Kerloëguen Y, Cloughesy TF. Response assessment criteria for glioblastoma: practical adaptation and implementation in clinical trials of antiangiogenic therapy. Curr Neurol Neurosci Rep. 2013;13(5): Huang RY, Rahman R, Ballman KV, et al. The impact of T2/FLAIR evaluation per RANO criteria on response assessment of recurrent glioblastoma patients treated with bevacizumab. Clin Cancer Res. 2016;22(3): Nowosielski M, Wiestler B, Goebel G, et al. Progression types after antiangiogenic therapy are related to outcome in recurrent glioblastoma. Neurology. 2014;82(19): Radbruch A, Lutz K, Wiestler B, et al. Relevance of T2 signal changes in the assessment of progression of glioblastoma according to the Response Assessment in Neurooncology criteria. Neuro Oncol. 2012;14(2): Ellingson BM, Wen PY, Cloughesy TF. Modified criteria for radiographic response assessment in glioblastoma clinical trials. Neurotherapeutics. 2017;14(2): Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapytemozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8): Lamborn KR, Yung WK, Chang SM, et al; North American Brain Tumor Consortium. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008;10(2): Prados M, Cloughesy T, Samant M, et al. Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab. Neuro Oncol. 2011;13(1): Han K, Ren M, Wick W, et al. Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based metaanalysis from 91 trials. Neuro Oncol. 2014;16(5): Provenzale JM, Ison C, Delong D. Bidimensional measurements in brain tumors: assessment of interobserver variability. AJR Am J Roentgenol. 2009;193(6):W515 W Ellingson BM, Nguyen HN, Lai A, et al. Contrast-enhancing tumor growth dynamics of preoperative, treatment-naive human glioblastoma. Cancer. 2016;122(11): Dempsey MF, Condon BR, Hadley DM. Measurement of tumor size in recurrent malignant glioma: 1D, 2D, or 3D? AJNR Am J Neuroradiol. 2005;26(4): Shah GD, Kesari S, Xu R, et al. Comparison of linear and volumetric criteria in assessing tumor response in adult high-grade gliomas. Neuro Oncol. 2006;8(1): Galanis E, Buckner JC, Maurer MJ, et al. Validation of neuroradiologic response assessment in gliomas: measurement by RECIST, two-dimensional, computer-assisted tumor area, and computer-assisted tumor volume methods. Neuro Oncol. 2006;8(2): Gahrmann R, van den Bent M, van der Holt B, et al. Comparison of 2D (RANO) and volumetric methods for assessment of recurrent glioblastoma treated with bevacizumab a report from the BELOB trial. Neuro Oncol. 2017;19(6): Ellingson BM, Bendszus M, Boxerman J, et al; Jumpstarting Brain Tumor Drug Development Coalition Imaging Standardization Steering Committee. Consensus recommendations for a standardized brain tumor imaging protocol in clinical trials. Neuro Oncol. 2015;17(9): Sorensen AG, Batchelor TT, Wen PY, Zhang WT, Jain RK. Response criteria for glioma. Nat Clin Pract Oncol. 2008;5(11): Ellingson BM, Kim HJ, Woodworth DC, et al. Recurrent glioblastoma treated with bevacizumab: contrast-enhanced T1-weighted subtraction maps improve tumor delineation and aid prediction of survival in a multicenter clinical trial. Radiology. 2014;271(1): Neuro- Oncology

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