Glioblastoma (GBM) is an aggressive, infiltrative, primary brain malignancy with a poor prognosis [
We reviewed the treatment and survival of adult patients consecutively diagnosed with GBM at one rural tertiary healthcare practice between 1995 and 2012, a time period that includes several years before and after TMZ was introduced for newly diagnosed GBM and bevacizumab was approved for the treatment of recurrent GBM. To determine whether these treatments were translated into clinical practice in a rural healthcare setting, we compared treatment type before and after TMZ was introduced and examined the details of GBM treatment in patients who received bevacizumab. To assess whether the treatments showed evidence of a survival benefit, we compared overall survival according to use of the standard-of-care regimen at diagnosis or use of bevacizumab at first GBM recurrence and also evaluated the treatments for independent associations with overall survival. Because many GBM patients are elderly [
Patients were identified retrospectively from medical records at Marshfield Clinic, a multispecialty clinic with affiliated hospitals in Wisconsin, USA, that serves a predominantly rural population. Patients were included in the study if they were newly diagnosed with GBM between 1995 and 2012 and at least 18 years of age at the time of diagnosis. Pathology reports and available histopathological material were reviewed by a neuropathologist to confirm the diagnosis of GBM (World Health Organization grade IV astrocytoma) for each patient. Patients without histological confirmation of GBM or who were diagnosed with GBM at autopsy only were excluded. The research was carried out according to the principles outlined in the Declaration of Helsinki (1964) and all subsequent revisions, and the Institutional Review Board of the Marshfield Clinic Research Institute approved the study.
The primary service area of Marshfield Clinic comprises 28 counties in central and northern Wisconsin and Gogebic county in Michigan. In 20 of the 29 counties, ≥ 60% of the population lives in a rural area (city or town with < 2,500 people), according to the 2010 United States Census [
Medical records were reviewed to obtain data on patient age at GBM diagnosis, sex, race, year of GBM diagnosis, presenting symptoms, comorbidities, extent of surgery, tumor location and size, use of radiotherapy and chemotherapy, tumor recurrence, and date of death. Comorbidities were represented in this study by the Charlson comorbidity score, a weighted sum of comorbid conditions based on the risk of mortality for each condition [
Data were summarized as mean ± standard deviation for parametric variables and median (interquartile range) for nonparametric variables. Groups were compared using the chi-squared test for categorical data and the Wilcoxon rank sum test for continuous data.
No patients were lost to follow-up and data were censored for patients alive on December 31, 2015. For bivariate analyses, survival curves were generated using the Kaplan-Meier method and were compared using the log-rank test. Cox proportional hazards regression analysis was used to determine whether TMZ and bevacizumab therapies were independently associated with survival in a multiple regression model. All variables associated with survival in bivariate analyses (
Between 1995 and 2012, 307 adult patients were newly diagnosed with GBM. The mean age at diagnosis was 64.9 ± 13.9 years; 59% of patients were male, 96% were Caucasian, and approximately 50% had comorbid conditions (Table
Characteristics of patients diagnosed with glioblastoma.
Characteristic | |
---|---|
Age at diagnosis (years) | |
18-39 | 15 (4.9) |
40-49 | 29 (9.4) |
50-59 | 58 (18.9) |
60-69 | 85 (27.7) |
70-79 | 75 (24.4) |
≥ 80 | 45 (14.7) |
Year of diagnosis | |
1995-1999 | 89 (29.0) |
2000-2004 | 74 (24.1) |
2005-2009 | 89 (29.0) |
2010-2012 | 55 (17.9) |
Male | 181 (59.0) |
Race | |
White | 295 (96.0) |
African-American | 1 (0.3) |
Asian | 2 (0.7) |
American Indian or Alaska native | 2 (0.7) |
Unknown | 7 (2.3) |
Charlson comorbidity score | |
0 | 155 (50.5) |
1 | 29 (9.5) |
2 | 60 (19.5) |
≥ 3 | 63 (20.5) |
Presenting symptoms | |
Headaches | 160 (52.1) |
Seizures | 75 (24.4) |
Nausea/vomiting | 48 (15.6) |
Sensory deficit1 | 56 (18.2) |
Motor deficit2 | 137 (44.6) |
Confusion/memory loss | 175 (57.0) |
Extent of surgery | |
Resection | 180 (58.6) |
Biopsy | 113 (36.8) |
Unknown | 14 (4.6) |
Radiation dose | |
60 Gy | 147 (47.9) |
< 60 Gy | 47 (15.3) |
Unknown dose | 24 (7.8) |
No radiotherapy | 89 (29.0) |
Chemotherapy | |
Temozolomide only | 44 (14.3) |
Temozolomide and other agents | 86 (28.0) |
Non-temozolomide agents only | 46 (15.0) |
No chemotherapy | 131 (42.7) |
Tumor location - supratentorial | |
Frontal | 124 (40.4) |
Parietal | 105 (34.2) |
Temporal | 136 (44.3) |
Occipital | 43 (14.0) |
Corpus callosum | 42 (13.7) |
Thalamus | 13 (4.2) |
Tumor location - infratentorial | |
Cerebellum | 11 (3.6) |
Brainstem | 6 (2.0) |
Tumor location - unknown | 4 (1.3) |
We defined standard treatment as maximal safe surgery followed by standard radiotherapy (60 Gy), completion of concomitant TMZ, and completion of at least one cycle of adjuvant TMZ. The percentage of patients who received any radiotherapy, standard radiotherapy, any chemotherapy, TMZ chemotherapy, or standard treatment was higher when the diagnosis occurred during 2005-2012 than during 1995-2004 (Table
Treatment with surgical resection, radiotherapy, and chemotherapy by time period of glioblastoma diagnosis.
Treatment | Time period of diagnosis | | |
---|---|---|---|
1995-2004 | 2005-2012 | ||
| | ||
| | ||
Surgical resection | 100 (61.3) | 80 (55.6) | 0.30 |
Any radiotherapy | 106 (65.0) | 112 (77.8) | 0.014 |
60 Gray of radiation | 66 (40.5) | 81 (56.3) | 0.0058 |
Any chemotherapy | 63 (38.7) | 113 (78.5) | < 0.0001 |
Temozolomide chemotherapy | 18 (11.0) | 112 (77.8) | < 0.0001 |
Other (non-temozolomide) chemotherapy | 45 (27.6) | 1 (0.7) | < 0.0001 |
Concomitant and adjuvant temozolomide chemotherapy | 2 (1.2) | 60 (41.7) | < 0.0001 |
Standard treatment2 | 1 (0.6) | 52 (36.1) | < 0.0001 |
Radiotherapy without chemotherapy | 50 (30.7) | 5 (3.5) | < 0.0001 |
No radiotherapy and no chemotherapy | 50 (30.7) | 26 (18.1) | 0.011 |
A comparison between patients ≥ 65 years at diagnosis and those < 65 years at diagnosis showed that older patients experienced more comorbid conditions, were less likely to have surgical resection, 60 Gy of radiation, TMZ chemotherapy, or standard treatment, and were more likely to have no radiotherapy and no chemotherapy than younger patients (Table
Glioblastoma patient comorbidities and treatments according to age at diagnosis.
Characteristic | Age at diagnosis | | |
---|---|---|---|
< 65 years | ≥ 65 years | ||
| | ||
| | ||
Charlson comorbidity score | < 0.0001 | ||
0 | 90 (65.7) | 65 (38.2) | |
1 | 8 (5.8) | 21 (12.4) | |
2 | 23 (16.8) | 37 (21.8) | |
≥ 3 | 16 (11.7) | 47 (27.6) | |
Extent of surgery | 0.00065 | ||
Resection | 89 (65.0) | 91 (53.5) | |
Biopsy | 37 (27.0) | 76 (44.7) | |
Unknown | 11 (8.0) | 3 (1.8) | |
Radiation dose | 0.00026 | ||
60 Gy | 84 (61.3) | 63 (37.1) | |
< 60 Gy | 18 (13.1) | 29 (17.0) | |
Unknown dose | 9 (6.6) | 15 (8.8) | |
No radiotherapy | 26 (19.0) | 63 (37.1) | |
Chemotherapy | < 0.0001 | ||
Temozolomide with or without other agents | 70 (51.1) | 60 (35.3) | |
Non-temozolomide agents only | 30 (21.9) | 16 (9.4) | |
No chemotherapy | 37 (27.0) | 94 (55.3) | |
Standard treatment | 38 (27.7) | 15 (8.8) | < 0.0001 |
No radiation and no chemotherapy | 20 (14.6) | 56 (32.9) | 0.00021 |
Sixty patients received bevacizumab treatment and for 10 (16.7%) of these patients, bevacizumab was administered before GBM recurrence. One of the 10 patients was included in a clinical trial that used bevacizumab as first-line treatment. For the other nine patients, subtle increases in tumor size were observed following the start of radiotherapy and chemotherapy, and patients were given bevacizumab because it was uncertain whether these changes were due to tumor progression or the effects of treatment. The other 50 (83.3%) of the 60 patients were treated with bevacizumab after GBM recurrence, determined from brain imaging reports that indicated an increase in tumor size or the appearance of new lesions. Forty-three (86.0%) of the 50 patients received bevacizumab at the first recurrence and seven (14.0%) at the second recurrence. Patients who were treated with bevacizumab also received radiotherapy and TMZ during the course of treatment (Table
Treatments for glioblastoma administered to 60 patients who received bevacizumab therapy.
Bevacizumab treatment sub-groups (number of subjects) | Period when treatment for glioblastoma was received | Treatment received for glioblastoma | ||||
---|---|---|---|---|---|---|
Surgical resection | Any radiotherapy | Temozolomide | Bevacizumab | Other chemotherapy | ||
| | | | | ||
Bevacizumab received before tumor recurrence ( | At diagnosis | 9 (90.0) | 10 (100.0) | 10 (100.0) | 10 (100.0) | 2 (20.0) |
At first recurrence | 2 (20.0) | 0 (0.0) | 0 (0.0) | 2 (20.0) | 3 (30.0) | |
| ||||||
Bevacizumab received at first tumor recurrence ( | At diagnosis | 29 (67.4) | 43 (100.0) | 43 (100.0) | 0 (0.0) | 0 (0.0) |
At first recurrence | 0 (0.0) | 2 (4.7) | 9 (20.9) | 43 (100.0) | 19 (44.2) | |
| ||||||
Bevacizumab received at second tumor recurrence ( | At diagnosis | 7 (100.0) | 6 (85.7) | 5 (71.4) | 0 (0.0) | 2 (28.6) |
At first recurrence | 7 (100.0) | 3 (42.9) | 6 (85.7) | 0 (0.0) | 1 (14.3) | |
At second recurrence | 0 (0.0) | 1 (14.3) | 0 (0.0) | 7 (100.0) | 5 (71.4) |
Three hundred and one (98.0%) of the 307 patients were deceased at last follow-up and the median survival in our patient population was 7.6 (3.2-14.9) months. The percentage of patients that survived one, two, and five years was 32.6%, 11.4%, and 2.3%, respectively. Median survival in the 53 patients who received the standard treatment was 17.0 (13.3-27.1) months compared with 7.0 (4.4-11.5) months in the 29 patients who received 60 Gy of radiation but no chemotherapy (
Overall survival according to treatment for glioblastoma and age at diagnosis.
Treatment received | < 65 years of age at diagnosis | ≥ 65 years of age at diagnosis | | ||
---|---|---|---|---|---|
| Overall survival (months) | | Overall survival (months) | ||
Standard radiotherapy with concomitant and adjuvant temozolomide | 38 | 18.9 (13.7-29.4) | 15 | 16.4 (10.0-19.1) | 0.14 |
Other treatment including temozolomide | 32 | 12.5 (8.1-19.6) | 45 | 6.5 (3.9-13.0) | 0.0036 |
Other non-temozolomide treatment | 55 | 10.2 (5.4-13.8) | 76 | 5.5 (2.1-8.6) | 0.0013 |
No treatment | 12 | 1.9 (1.0-4.1) | 34 | 1.5 (0.6-3.5) | 0.40 |
Because the 43 patients treated with bevacizumab at first GBM recurrence had all received some radiotherapy and TMZ chemotherapy at diagnosis, we compared survival in these patients with survival in the 54 patients who received some radiotherapy and TMZ chemotherapy at diagnosis but no bevacizumab at first GBM recurrence. The groups included in the analysis were the 24 patients who received bevacizumab with other chemotherapy and/or radiotherapy at first GBM recurrence, the 19 patients who received bevacizumab alone at first GBM recurrence, 22 patients who received other (non-bevacizumab) treatment at first GBM recurrence, and 32 patients who received no treatment at first GBM recurrence. The median survival was 17.8 (13.5-29.2) months in patients treated with bevacizumab and other agents, 15.4 (9.2-19.7) months in patients treated with bevacizumab alone, 13.6 (6.1-20.0) months in patients who received other (non-bevacizumab) treatment only, and 5.6 (3.4-9.8) months in patients who received no treatment at first GBM recurrence (Figure
Overall survival according to bevacizumab treatment at first glioblastoma recurrence. Sample sizes were
We considered the possibility that factors other than bevacizumab treatment, such as age, extent of surgery, and dose of radiation at diagnosis, may have contributed to the difference in median overall survival between patients who received bevacizumab and those who received no treatment at first GBM recurrence. The median age at diagnosis was 61.9 (54.7-67.4) years in the 43 patients who received bevacizumab treatment (with or without other agents) at first recurrence versus 70.6 (63.8-79.9) years in the 32 patients with no treatment at first recurrence (
In bivariate analyses, decreased survival was associated with age ≥ 65 years at diagnosis, no surgical resection of the tumor, < 60 Gy of radiation or no radiotherapy, non-TMZ chemotherapy or no chemotherapy, a Charlson comorbidity score > 0, and tumor location in the occipital region or corpus callosum (Table
Factors associated with survival in patients with glioblastoma.
Factor | Log rank test | Hazard ratio | 95% Confidence interval | |
---|---|---|---|---|
Age at diagnosis (years)2 | < 0.0001 | 1.02 | 1.01, 1.03 | 0.00015 |
Extent of surgery (Ref: Biopsy) | < 0.0001 | |||
Resection | 0.52 | 0.40, 0.67 | < 0.0001 | |
Unknown | 0.63 | 0.35, 1.13 | 0.12 | |
Radiation dose (Ref: No radiotherapy) | < 0.0001 | |||
60 Gy | 0.67 | 0.48, 0.93 | 0.015 | |
< 60 Gy | 0.98 | 0.66, 1.46 | 0.93 | |
Unknown | 0.90 | 0.54, 1.48 | 0.67 | |
Chemotherapy (Ref: No chemotherapy) | < 0.0001 | |||
Temozolomide and bevacizumab | 0.32 | 0.22, 0.49 | < 0.0001 | |
Temozolomide without bevacizumab | 0.58 | 0.41, 0.82 | 0.0018 | |
Non-temozolomide agents only | 0.68 | 0.46, 1.01 | 0.054 | |
Charlson comorbidity score2 | 0.049 | 1.06 | 0.99, 1.13 | 0.12 |
Tumor located in occipital region – Yes/No (Ref: No) | 0.0044 | 1.33 | 0.95, 1.86 | 0.10 |
Tumor located in corpus callosum – Yes/No (Ref: No) | 0.00066 | 1.27 | 0.90, 1.79 | 0.17 |
At our institution, the standard treatment became more widely used soon after demonstration of the ability of TMZ chemotherapy to increase survival in a clinical trial, and survival was longer in patients who received the standard treatment, consistent with reports from other population-based studies [
Of the 307 patients in our study, 36.8% received a biopsy, and of the 144 patients diagnosed during the period 2005-2012, 77.8% received radiotherapy, 77.8% received some TMZ, and 41.7% received concomitant and adjuvant TMZ. Similar findings have been reported in previous studies of patterns of care for GBM but estimates varied among studies. In these studies, 4.6-44.4% of patients received a biopsy [
Our findings that a substantial fraction of the study population received a biopsy as maximal safe surgery and as much as 22.2% of patients diagnosed in 2005-2012 were not given TMZ motivate consideration of the factors that influence decisions about GBM treatment at our institution. The available medical record data indicated that the presence of a tumor not amenable to resection, the poor medical condition of the patient, and patient preference were among the factors involved. In a study of GBM patients diagnosed after 2005 in Spain, reasons why patients received no radiotherapy and no chemotherapy after surgery included low performance status, surgical complications, tumor-related symptoms, probable tumor progression, and patient decision [
Bevacizumab at first GBM recurrence was associated with a statistically significant increase in overall survival when compared with no treatment in this study. In a systematic review of 17 other studies, a gain in overall survival with use of bevacizumab compared with use of other treatment for recurrent GBM has been observed [
The limited options currently available for the treatment of recurrent GBM also include tumor-treating fields, electric fields that are delivered by a noninvasive, portable device and that can physically disrupt cell division leading to antimitotic effects on tumor cells [
An advantage of this study was the availability of clinical data for an unselected patient population seen in routine clinical practice in a rural tertiary healthcare center. These patients had less opportunity to participate in research treatment protocols established in many academic centers to treat newly diagnosed or recurrent GBM. Yet, data on this patient population allowed us to assess changes in GBM treatment that occurred once reports demonstrating the efficacy of new treatments became available and to evaluate the effects of the new treatments on survival in patients who were not required to meet any specific criteria such as those used to select patients for enrollment in clinical trials. Disadvantages included the lack of data on several factors known to be associated with prognosis including performance status [
This study captured one rural healthcare institution’s transition to treating GBM with TMZ and bevacizumab once these therapies were introduced. The standard regimen of maximal safe surgery, standard radiotherapy, and concomitant and adjuvant TMZ chemotherapy was more often used to treat patients diagnosed since 2005 than patients diagnosed in previous years, and patients who received this regimen survived longer than patients who received standard radiotherapy without TMZ chemotherapy. Overall survival improved with bevacizumab treatment compared with no treatment at first GBM recurrence but because patients who received bevacizumab at first recurrence had more favorable prognostic factors than patients who received no treatment at first recurrence, the magnitude of the observed increase in survival with bevacizumab treatment may be biased by these prognostic factors. Few studies of GBM in rural populations have been done and ours supports continued use of standard radiotherapy with concomitant and adjuvant TMZ chemotherapy for treatment of GBM in a rural tertiary healthcare setting.
The data used to support the findings of this study are available from the corresponding author upon request.
Benjamin E. Lawler owns stock in Novocure. The other authors declare that they have no conflicts of interest regarding the publication of this paper.
We are grateful to the staff of the Center for Clinical Epidemiology and Population Health and the Histology Laboratory at Marshfield Clinic for assistance with data collection. We also thank Ronald Hamilton for providing valuable comments on the manuscript. This work was supported by philanthropic gifts in support of medical research at Marshfield Clinic and by the National Institutes of Health–National Center for Advancing Translational Sciences [grant number UL1TR000427].