Patterns of management and outcomes of unifocal versus multifocal glioblastoma

Journal of Clinical Neuroscience xxx (xxxx) xxx

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Clinical study

Patterns of management and outcomes of unifocal versus multifocal glioblastoma Waqar Haque a,⇑, Yvonne Thong b, Vivek Verma c, Robert Rostomily d, E. Brian Butler a, Bin S. Teh a a

Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX, USA Department of Psychology, University of Texas at Dallas, Richardson, TX, USA c Department of Radiation Oncology, Allegheny General Health, Pittsburgh, PA, USA d Department of Neurosurgery, Houston Methodist Hospital, Houston, TX, USA b

a r t i c l e

i n f o

Article history: Received 25 November 2019 Accepted 27 January 2020 Available online xxxx Keywords: Unifocal GBM Multifocal GBM Glioblastoma Radiation therapy

a b s t r a c t Background: Glioblastoma (GBM) presents as a solitary lesion (unifocal), or as multiple discrete lesions (multifocal). Multifocal GBM may have a worse prognosis as compared to unifocal GBM, but existing data are limited to small institutional series. The purpose of the present study was to evaluate demographic and clinical characteristics of patients with unifocal versus multifocal GBM to highlight demographic differences and clinical outcomes for two groups of patients. Methods: The National Cancer Database (NCDB) was queried (2004–2016) for patients newly diagnosed with either unifocal or multifocal GBM. Statistics included Kaplan-Meier overall survival (OS) analysis, along with Cox proportional hazards modeling. Results: Of 45,268 total patients, 37,483 (82.8%) had unifocal GBM and 7,785 (17.2%) had multifocal GBM. Patients with unifocal GBM more frequently received gross total resection (GTR) (41.2% versus 25.8%, p < 0.001) and conventionally fractionated radiation therapy (RT) (48.2% versus 42.7%, p < 0.001). Patients with multifocal GBM had a higher rate of surgery with biopsy only (34.0% compared to 24.1%, p < 0.001). Median OS was 12.8 months versus 8.3 months (p < 0.001) for patients with unifocal GBM or multifocal GBM, respectively. On multivariate analysis, factors associated with improved OS included unifocal disease, MGMT methylation, RT use, and chemotherapy use. Conclusions: This is the largest study to date describing outcomes for patients with multifocal GBM, and it shows that multifocal GBM is associated with a decreased use both of GTR and conventionally fractionated RT, as well as worse median OS. Further research is needed to improve clinical outcomes for patients with multifocal GBM. Ó 2020 Elsevier Ltd. All rights reserved.

1. Introduction Glioblastoma (GBM) is the most common primary brain tumor, with an estimated 13,000 new cases diagnosed in the United States in 2019 [1]. The current standard of care includes maximal safe resection followed by conventionally fractionated radiation therapy (RT), delivered with concurrent and adjuvant temozolomide (TMZ) [2,3]. Elderly patients, or those with a poor performance status, may be treated with hypofractionated RT (HFRT) [4,5], and concurrent chemotherapy has also been associated with improved OS amongst patients receiving HFRT [6,7]. The use of tumor treating fields following chemoradiation has also been

⇑ Corresponding author at: Department of Radiation Oncology, Houston Methodist Hospital, 18400 Katy Freeway, Houston, TX 77094, USA. E-mail address: [email protected] (W. Haque).

associated with improvements in OS and has become a standard of care [8]. Multifocal GBM occurs in about 12% of patients with GBM [8]. While the above cited studies included patients with multifocal disease [2–7], the outcomes of patients specifically with multifocal disease was not reported separately, and consequently there is currently no difference in the standard of care for multifocal patients when compared to unifocal patients. The existing literature describing multifocal GBM is primarily limited to small series, the largest of which consists of 63 patients [9–13]. As such, more data is required regarding current practice patterns and clinical outcomes for patients with multifocal disease. The purpose of the present trial was to use the National Cancer Database (NCDB) to describe utilization rates of surgery, RT (HFRT as well as conventional), and chemotherapy for both unifocal and multifocal GBM patients as well as to describe clinical outcomes for the two groups of patients.

https://doi.org/10.1016/j.jocn.2020.01.086 0967-5868/Ó 2020 Elsevier Ltd. All rights reserved.

Please cite this article as: W. Haque, Y. Thong, V. Verma et al., Patterns of management and outcomes of unifocal versus multifocal glioblastoma, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.086

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W. Haque et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx

2. Materials and methods The NCDB is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society, which consists of de-identified information regarding tumor characteristics, demographics, and survival for approximately 70% of the US population [14]. All pertinent cases are reported regularly from CoC-accredited centers and compiled into a unified dataset, which is then validated. The data used in the study were derived from a de-identified NCDB file (2004–2016). The American College of Surgeons and the CoC have not verified and are neither responsible for the analytic or statistical methodology employed nor the conclusions drawn from these data by the investigators. As all patient information in the NCDB database is de-identified, this study was exempt from institutional review board evaluation. Inclusion criteria for this study were patients aged 18 years who were diagnosed with glioblastoma from 2004 to 2016. Furthermore, in order for inclusion, patients required a record of whether the tumor was either unifocal or multifocal (based on the CS Site-Specific Factor 8), and a record of the surgical status. Statistics, performed using STATA (version 14, College Station, TX), were two-sided, with a threshold of p < 0.05 for statistical significance. Multivariable logistic regression modeling determined characteristics predictive for delivery of chemotherapy or RT. Survival analysis was performed by the Kaplan-Meier method, and group comparisons done with the log-rank test. Survival was compared between unifocal and multifocal GBM amongst all patients, and then between unifocal and multifocal GBM after stratifying by surgery type. Following this, in order to further characterize the optimal treatment paradigm for the multifocal GBM population, survival was compared comparing by extent of resection amongst patients with multifocal GBM. Finally, survival rates were compared amongst people multifocal GBM treated with biopsy only by use of chemotherapy and by use of RT. OS referred to the interval between the date of diagnosis and the date of death, or censored at last contact. Univariate analysis ascertained factors associated with OS; subsequently, Cox multivariate analysis included variables that were either significant or showed a strong trend to statistical significance on univariate analysis. 3. Results A complete flow diagram of patient selection is provided in Fig. 1. In total, 45,268 patients met study criteria, and of these, 37,483 (82.8%) had unifocal GBM and 7,785 (17.2%) had multifocal GBM. Table 1 displays clinical and demographic characteristics of

Fig. 1. Patient selection criteria.

Table 1 Clinical and demographic characteristics for all patients. Characteristic

Multifocal, n = 7785

Age 50 1022 (13.1%) 51–65 3360 (43.2%) 66–79 2814 (36.2%) 80+ 589 (7.6%) Sex Female 3380 (43.4%) Male 4405 (56.6%) Race White 7092 (91.1%) African American 388 (5.0%) Other/not recorded 305 (3.9%) Charlson-Deyo comorbidity score 0 5407 (69.5%) 1 1397 (17.9%) 2 626 (8.0%) 3 355 (4.6%) MGMT Status Methylated 731 (9.4%) Unmethylated 1080 (13.9%) Not recorded 5974 (76.7%) Practice type Academic 3350 (43.0%) Non Academic 4186 (53.8%) Not recorded 249 (3.2%) Insurance status Medicare 3375 (43.4%) Private 3424 (44.0%) Medicaid 480 (6.2%) Not insured 241 (3.1%) Other governemnt/not 265 (3.4%) recorded Surgery type Biopsy only 2647 (34.0%) Subtotal resection 2731 (35.1%) Gross todal resection 2005 (25.8%) Surgery NOS 402 (5.2%) Radiation therapy Hypofractionation 370 (4.8%) Conventional fractionation 3323 (42.7%) Non-standard/ not 2265 (29.1%) reported No radiation 1827 (23.5%) Chemotherapy Concurrent 4190 (53.8%) Yes, non- concurrent 718 (9.2%) No 2877 (37.0%)

Unifocal, n = 37483

Pvalue

5981 (16.0%) 15,474 (41.3%) 13,117 (35.0%) 2911 (7.8%)

<0.001

15,443 (41.2%) 33,040 (58.8%)

<0.001

33,749 (90.0%) 2176 (5.8%) 1558 (4.2%)

0.009

26,501 (70.7%) 6536 (17.4%) 2937 (7.8%) 1509 (4.0%)

0.066

3396 (9.1%) 4844 (12.9%) 29,243 (78.0%)

0.037

16,434 (43.8%) 19,094 (50.9%) 1955 (5.2%)

<0.001

15,634 (41.7%) 16,799 (44.8%) 2499 (6.7%) 1375 (3.7%) 1176 (3.1%)

0.005

9034 (24.1%) 11,233 (30.0%) 15,444 (41.2%) 1772 (4.7%)

<0.001

1412 (3.8%) 18,068 (48.2%) 9498 (25.3%)

<0.001

8505 (22.7%) 20,680 (55.2%) 3972 (10.6%) 12,831 (34.2%)

<0.001

the analyzed patients. Charlson-Deyo comorbidities were similar between the two patient cohorts. A higher percentage of patients with unifocal GBM underwent gross total resection (GTR) (41.2% versus 25.8%), whereas a higher proportion of multifocal GBM patients underwent biopsy only (34.0% versus 24.1%). Conventionally fractionated radiation therapy was more common in the unifocal GBM cohort (48.2% versus 42.7%) Tables 1 and 2. Multifocal disease was associated with worse OS in both univariate and multivariate analysis (p < 0.001 for both). Additionally, MGMT unmethylated disease status was associated with worse OS when compared to patients with MGMT methylation, and surgery of any extent was associated with superior OS when compared to patients treated with biopsy only. On multivariate analysis, (Table 2) when compared to HFRT, use of conventionally fractionated RT (CFRT) was associated with improved OS (p < 0.001), while omission of radiation therapy was associated with worse OS (p = 0.001). Use of concurrent chemotherapy was associated with improved OS when compared to treatment with no chemotherapy (p < 0.001). Kaplan Meier curves depicting median OS outcomes comparing unifocal and multifocal GBM are displayed in Fig. 2. Patients diag-

Please cite this article as: W. Haque, Y. Thong, V. Verma et al., Patterns of management and outcomes of unifocal versus multifocal glioblastoma, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.086

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W. Haque et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 2 Univariate and multivariate analysis for factors predictive of overall survival. Univariate analysis Characteristic Tumor type Unifocal Multifocal Age 50 51–65 66–79 80+ Sex Female Male Race White African American Other/ not recorded Charlson-Deyo comorbidity score 0 1 2 3 MGMT Status Methylated Unmethylated Not recorded Practice type Academic Non Academic Not recorded Insurance status Medicare Private Medicaid Not insured Other governemnt/not recorded Surgery type Biopsy only Subtotal resection Gross todal resection S urgery NOS Radiation therapy Hypofractionation Conventional fractionation Non-standard/ not reported No radiation Chemotherapy Concurrent Yes, non-concurrent No

Multivariate analysis

Hazard ratio

95% Confidence interval

P-value

Hazard ratio

95% Confidence interval

P-value

1 (reference) 1.448

1.408–1.489

<0.001

1 (reference) 1.396

1.357–1.437

<0.001

1 (reference) 1.489 2.261 4.069

1.440–1.541 2.184–2.340 3.880–4.267

<0.001 <0.001 <0.001

1 (reference) 1.301 1.659 2.602

1.252–1.352 1.584–1.738 2.454–2.760

<0.001 <0.001 <0.001

1 (reference) 1.033

1.010–1.055

0.004

1 (reference) 1.062

1.039–1.085

<0.001

1 (reference) 0.881 0.739

0.840–0.924 0.697–0.784

<0.001 <0.001

1 (reference) 0.903 0.733

0.861–0.948 0.691–0.778

<0.001 <0.001

1 (reference) 1.325 1.407 1.701

1.288–1.362 1.352–1.465 1.611–1.796

<0.001 <0.001 <0.001

1 (reference) 1.206 1.345 1.468

1.172–1.240 1.196–1.296 1.390–1.550

<0.001 <0.001 <0.001

1 (reference) 1.381 1.42

1.310–1.455 1.360–1.483

<0.001 <0.001

1 (reference) 1.416 1.306

1.343–1.492 1.250–1.365

<0.001 <0.001

1 (reference) 1.192 0.494

1.166–1.219 0.465–0.524

<0.001 <0.001

1 (reference) 1.135 0.755

1.110–1.161 0.705–0.807

<0.001 <0.001

1 (reference) 0.560 0.608 0.563 0.702

0.547–0.573 0.580–0.638 0.529–0.599 0.659–0.748

<0.001 <0.001 <0.001 <0.001

1 (reference) 0.836 0.945 0.810 0.913

0.808–0.864 0.896–0.996 0.758–0.866 0.854–0.975

<0.001 0.036 <0.001 0.007

1 (reference) 0.862 0.669 0.841

0.838–0.887 0.651–0.687 0.798–0.885

<0.001 <0.001 <0.001

1 (reference) 0.938 0.746 0.880

0.911–0.965 0.725–0.766 0.835–0.926

<0.001 <0.001 <0.001

1 (reference) 0.540 0.782 1.147

0.509–0.573 0.736–0.830 1.080–1.219

<0.001 <0.001 <0.001

1 (reference) 0.736 0.979 1.115

0.693–0.782 0.921–1.040 1.044–1.191

<0.001 0.495 0.001

1 (reference) 0.995 1.771

0.959–1.032 1.730–1.813

0.797 <0.001

1 (reference) 0.967 1.291

0.932–1.003 1.248–1.336

0.076 <0.001

Fig. 2. Kaplan meier curves comparing overall survival for (A) All patients; (B) patients undergoing biopsy only; (C) patients undergoing subtotal resection; and (D) patients undergoing gross total resection.

nosed with unifocal GBM were observed to have superior median OS than patients with multifocal GBM (Fig. 2A, 12.8 months versus 8.3 months, p < 0.001). Improved median OS for patients with unifocal GBM remained when stratifying patients by surgery type (biopsy only, 9.9 months versus 5.8 months, p < 0.001, Fig. 2B; subtotal resection, 11.8 months versus 9.0 months, p < 0.001, Fig. 2C; gross total resection, 15.4 months versus 11.5 months, p < 0.001, Fig. 2D). Amongst patients with multifocal GBM, extent of resection predicted for overall survival (Fig. 3A), as patients with GTR were found to have the greatest median OS (11.5 months), and patients with STR were shown to have a statistically greater median OS than patients receiving biopsy only (9.0 vs 5.8 months, p < 0.001). Subest analysis performed in patients with multifocal GBM received biopsy only revealed improved OS with use of chemotherapy (Fig. 3B, 8.8 vs 2.9 months, p < 0.001). Additionally, improved median OS was observed with use CFRT when compared to HFRT (Fig. 3C, 11.0 vs 4.7 months, p < 0.001) and with use of HFRT compared to no RT (4.7 vs 2.5 months, p = 0.008).

Please cite this article as: W. Haque, Y. Thong, V. Verma et al., Patterns of management and outcomes of unifocal versus multifocal glioblastoma, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.086

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W. Haque et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx

Fig. 3. Kaplan meier curves comparing overall survival for multifocal GBM amongst (A) patients stratified by surgical type; (B) patients treated with biopsy only stratified by chemotherapy use; (C); patients treated with biopsy only stratified by radiation therapy use.

4. Discussion With a total of 7,785 multifocal GBM patients, the present study is the largest to date describing outcomes in patients with multifocal GBM. These results from this analysis of a contemporary national database suggest that patients with multifocal GBM experience worse OS outcomes compared to patients with unifocal GBM. This is independent of surgical type, as patients the improved OS observed amongst patients with unifocal GBM remained constant when stratifying patients by surgical type. Furthermore, these results suggest that there is a benefit to both RT use and chemotherapy use in all patients and in the multifocal GBM population, even in patients treated with biopsy alone, and that greater extent of resection is associated with improved OS in the multifocal GBM population. The major goal of this study was to evaluate management of multifocal GBM patients who received treatment methods such as surgery, HFRT and CFRT, and chemotherapy. These results can help physicians and care teams decide on the most effective treatment(s) to administer to these patients. Previously published reports have conflicting outcomes regarding the prognostic importance of multifocal GBM. Investigators from UCLA performed a retrospective review of 368 patients with GBM, 47 (12.8%) of whom had multifocal GBM (9), and described significantly worse OS in patients with multifocal GBM (median OS of 11 months vs 6 months, p = 0.02). A retrospective review from University Hospital Heidelberg (11) conducted on 265 patients with GBM, 63 (24%) of whom had multifocal disease, also reported worse OS in the multifocal cohort (14.8 months vs 11.5 months, p = 0.032). However, a study from Wake Forest University conducted in 161 patients, of whom 33 (20.5%) had multifocal disease, demonstrated no differences in median OS when comparing unifocal and multifocal disease (11 vs 8.2 months, p = 0.3). The present study reported improved median OS in patients with multifocal disease (12.8 vs 8.3 months, p < 0.001). The reason for the lack of OS difference in the Wake Forest study are unclear, but given the relatively small number of patients with multifofcal disease, it is possible that this study was not adequately powered to detect a survival difference. The findings of independently higher OS with GTR compared to subtotal resection (STR) are noteworthy. The results found herein suggest that GTR is more feasible and widely used for unifocal compared to multifocal GBM (41.2% versus 25.8%, respectively). STR was used to treat a higher percentage of multifocal GBM patients than unifocal GBM patients (35.1% versus 30.0%, p < 0.001). Furthermore, this is the first study to report that similar

to the unifocal GBM population [15], greater extent of resection in the multifocal population is associated with improved OS, and that GTR should be attempted, if it can be safely achieved, and STR should be regarded as the preferred intervention for multifocal GBM when GTR is not possible. CFRT was used in a plurality of patients with either type of GBM (48.2% of unifocal GBM patients and 42.7% of multifocal GBM patients). HFRT was used in a minority of patients (4.8% of multifocal GBM patients and 3.8% of unifocal patients). On multivariate analysis, use of conventionally fractionated RT was associated with improved OS when compared to HFRT, while no RT was associated with worse OS when compared to HFRT. This study also demonstrated that in patients with multifocal GBM treated with biopsy only, CFRT was associated with an OS benefit when compared to HFRT, as has previously been demonstrated in the general GBM population [16], and that HFRT was associated with improved OS when compared to no RT, suggesting that there may be a role for HFRT even in patients with poor performance status. Chemotherapy was used in a majority of patients, but a substantial proportion of patients (36%) did not receive any chemotherapy. This is despite data demonstrating improved OS in patients receiving chemotherapy in addition to RT in the setting of both CFRT and HFRT (2–3, 6). On subset analysis, the present study demonstrates a significant OS benefit with the use of chemotherapy amongst patients with multifocal GBM treated with biopsy alone, suggesting that chemotherapy should be used if it is deemed that it can be safely tolerated by patients. This finding is in line with previously published reports demonstrating improved OS with use of chemotherapy in the general GBM population treated with biopsy alone [17]. Also in line with previously published reports [18], MGMT methylation status was associated with improved OS on both univariate and multivariate analysis, suggesting that this can be a prognostic indicator in the multifocal GBM population. As this is retrospective study, this study had several limitations, in addition to those mentioned elsewhere [19–21]. First, while the NCDB has information regarding the treatment delivered, it does not report the rationale behind the delivery of a specific treatment. Therefore, there may be selection biases in which patients with multifocal GBM deemed to have a poor prognosis were offered less aggressive therapy. Furthermore, there is likely significant heterogeneity in the multiofocal GBM group. Furthermore, the data on certain demographics, such as race, may not be representative. Some groups may experience disparities in social determinants of health that prevent them from getting proper treatment. As a result, groups may contain patients who have not been accounted for in the NCDB, and racial minorities may be at greater risk for GBM than what is reported based on the sample.

5. Conclusions The results of this study suggest that multifocal GBM results in worse OS as compared to unifocal GBM. Various treatment options may be used to improve OS outcomes, including maximal safe surgical resection, use of RT, an use of chemotherapy. Understanding the demographic and clinical characteristics of patients with multifocal and unifocal GBM is crucial to predicting OS outcomes for patients as they begin treatment for disease. Other investigations are recommended to improve treatments, prolong survival, and lower risks for patients with both unifocal and multifocal disease. Disclaimers None. This has never been presented/published before in any form. All authors declare that conflicts of interest do not exist. Funding There was no research support for this study.

Please cite this article as: W. Haque, Y. Thong, V. Verma et al., Patterns of management and outcomes of unifocal versus multifocal glioblastoma, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.086

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Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Appendix A. Supplementary data [12]

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Please cite this article as: W. Haque, Y. Thong, V. Verma et al., Patterns of management and outcomes of unifocal versus multifocal glioblastoma, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2020.01.086