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The Use of Palliative Whole Brain Radiotherapy in the Management of Brain Metastases
Clinical Oncology 24 (2012) e149ee158 Contents lists available at SciVerse ScienceDirect
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Original Article
The Use of Palliative Whole Brain Radiotherapy in the Management of Brain Metastases W. Kong *, C.R. Jarvis *, D.S. Sutton *y, K. Ding z, W.J. Mackillop *y * Division
of Cancer Care and Epidemiology, Queen’s University, Cancer Research Institute, Kingston, Ontario, Canada Department of Community Health and Epidemiology, Queen’s University, Kingston, Ontario, Canada z NCIC Clinical Trials Group, Queen’s University, Kingston, Ontario, Canada y
Received 26 June 2011; received in revised form 25 June 2012; accepted 26 June 2012
Abstract Aims: To describe the use of palliative whole brain radiotherapy (WBRT) in the management of brain metastases in the general cancer population and to identify factors associated with variations in its use. Materials and methods: We conducted a retrospective population-based study of patients who died of cancer in Ontario from 1984 to 2007 and identified those who received WBRT before death. Univariate and multivariate analyses were carried out to identify factors associated with the use of WBRT. Results: Of the 494 709 patients who died of cancer, 5.7% received WBRT. The rate of use of WBRT varied across the province, with county rates ranging from 1.3 to 8.8%. Younger patients and patients living in communities of higher socioeconomic status were more likely to receive WBRT, as were patients diagnosed in a hospital with a radiotherapy facility or living closer to a radiotherapy centre (P < 0.0001). The rate of use of WBRT was stable over the study period. Conclusion: There are inequities in the use of WBRT for the management of brain metastases that are not associated with need. Strategies to increase patient access to WBRT need to be developed and evaluated to ensure optimal outcomes. Ó 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Access; brain metastasis; palliative radiotherapy; population based; whole brain radiotherapy
Introduction The management of brain metastases is an important health care challenge. Most patients with cancer die not from the primary lesion, but from metastases to vital organs or from other complications. Brain metastases are the most common neurological complication of cancer [1]. The exact incidence of brain metastases is unknown and reported rates vary depending on the population studied and the method of assessment [1,2]. Large but now historic autopsy series found brain metastases in 15% of patients who died of cancer [1,3,4], whereas population-based studies reported a lower incidence [5,6]. Brain metastases are one of the most feared complications of cancer, as even small tumours may cause debilitating neurological symptoms and slight Author for correspondence: W.J. Mackillop, Division of Cancer Care and Epidemiology, Queen’s University, Cancer Research Institute, 10 Stuart Street, Level 2, Kingston, ON K7L 3N6, Canada. Tel: þ1-613-533-6895; Fax: þ1-613-533-6794. E-mail address: [email protected] (W.J. Mackillop).
tumour growth can be fatal [3]. Although some patients are asymptomatic, most have presenting symptoms with signs of increased intracranial pressure, such as changes in mental status, headache, nausea and vomiting, or focal signs such as seizures, hemiparesis, aphasia, ataxia and visual field defects [3,7e11]. The brain may increasingly become the first and only site of relapse as it remains a sanctuary for neoplastic cells, sheltered from improved systemic therapy behind the bloodebrain barrier [1,2]. Brain metastases usually occur late in the course of a patient’s cancer when it is widely disseminated. Although many patients die from systemic disease, up to half of the patients die from intracranial progression [12]. The prognosis for patients with brain metastases is poor, with a median survival time of 1e2 months in untreated patients and 3e6 months in patients treated with whole brain radiotherapy (WBRT) [13]. Although there have been no randomised trials showing that WBRT offers a survival advantage over supportive care [12,14], WBRT is the standard recommendation in clinical practice guidelines for the management of brain metastases [13,15]. It has been questioned whether
0936-6555/$36.00 Ó 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2012.08.004
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WBRT is indicated in every case, particularly in the context of non-small cell lung cancer, where the prognosis in patients with multiple brain metastases is very poor [16]. Analyses of prognostic factors have endeavoured to identify which patients would probably benefit from WBRT and which patients would not [17e19]. However, it remains to be validated which patients can be managed safely and palliated without WBRT [19]. Given the limited survival, preservation of cognitive function and quality of life are important considerations in treating patients with brain metastases. The goal of WBRT, in addition to offering a possible survival benefit by controlling intracranial metastases, is to allow for tapering of corticosteroid dose, alleviate neurological symptoms or prevent their progression, prevent neurological deterioration and maintain or enhance quality of life [2,7,20e22]. WBRT is used as adjuvant therapy after surgical resection or radiosurgery in selected patients with a limited number of brain metastases. Clinical studies and trials have shown that palliative WBRT is effective in controlling neurological symptoms with varying response rates [7,12,13,23]. The palliative efficacy of WBRT in terms of neurocognitive function and quality of life has not been a focus of these reports and remains unclear. A review of the literature [22,24] has shown that in some studies general quality of life or certain parameters of quality of life (e.g. fatigue, drowsiness, appetite) tend to deteriorate after WBRT treatment [25e28], particularly in patients with poor prognosis, whereas in other studies quality of life stabilises [21] or improves after WBRT treatment [29e31]. The potential neurocognitive morbidity associated with both brain metastases and their treatment remains a poorly understood concern [32e35]. Neuropsychiatric testing reveals that most patients with brain metastasis have impairment in neurocognitive function before treatment [36]. Although the cognitive decline observed in some studies after WBRT may be the result of the treatment itself [33], it may also be the result of failed tumour control and increased tumour burden [34]. WBRT-induced tumour control has been correlated with better survival and improved neurocognitive function [37], which has been correlated with quality of life [38], suggesting a potential benefit if WBRT itself confers tumour control [32]. WBRT remains an important treatment option. However, patients with brain metastases are a heterogeneous population and treatment is dependent on the individual clinical setting [20]. Optimising cancer outcomes depends on making effective treatments available to all those who might benefit from them. The socialised medical system in Canada is intended to remove barriers to access to treatment. The province of Ontario, like other provinces in Canada, provides palliative radiotherapy through centralised radiotherapy centres. Evidence suggests that access to radiotherapy services is not equitable for all patients requiring radiotherapy across Ontario [39], as well patients specifically requiring palliative radiotherapy for bone metastases [40], and is influenced by factors unrelated to need, such as age, socioeconomic status and proximity to radiotherapy centres [41]. Despite the high morbidity and mortality associated with brain metastases and the known value of WBRT in the management of this condition, the rate of use
of this treatment is not known. The aim of this study was to describe the use of WBRT in the general cancer population and to identify factors associated with variations in its use. The cancer system in the province of Ontario provides an ideal model to study the utilisation of WBRT as all radiotherapy activity in Ontario is provided by a network of regional cancer centres that keep electronic records of treatment activity and these data have been linked to the records of the Ontario Cancer Registry (OCR) to provide a database suitable for studying patterns of care [39e41].
Materials and Methods This was a retrospective, population-based cohort study. The study population consisted of all Ontario residents who died of cancer between the years 1984 and 2007, excluding those with a primary cancer of the brain. Sources of Data Data were obtained from the OCR, a passive, populationbased registry that captures information on >95% of all cancer cases [42] diagnosed in the province from four sources: hospital separation records, pathology reports, death certificates and reports from the provincial cancer centres [43]. Records from these sources are compiled and reconciled by probabilistic linkage. Information on all cases includes: date of birth, gender, date of diagnosis, residence at time of diagnosis, primary site (ICD-9), histology (ICD-O), source of diagnostic information, vital status, date of death and cause of death. Electronic records of all courses of radiotherapy delivered between 1984 and 2007 were made available by the regional cancer centres of Cancer Care Ontario and the Princess Margaret Hospital. The following information was available for each course of treatment: start date of radiotherapy, total dose, number of fractions, intent of treatment and body region irradiated. The resulting radiotherapy database was >95% complete [44]. Few patients are ever referred outside of the province for palliative radiotherapy except for residents of Kenora County, who are often treated in the neighbouring province of Manitoba. Utilisation rates for Kenora are, therefore, not reported here [45]. The Canadian Institute for Health Information provided hospital separation records from all general hospitals in Ontario. These records, which included dates of admission, admitting diagnoses and dates of discharge, were linked to the OCR. Statistics Canada provided information about the median household income at the level of census subdivision and the census enumeration area. This community-level information was linked to each case in the OCR based on the patient’s place of residence at the time of diagnosis, as described previously [46]. Definition of Derived Variables used in the Analysis Courses of WBRT for brain metastases were identified based on the intent of treatment and the body region
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irradiated specified in the prescription. The WBRT utilisation rate for brain metastases was defined as the proportion of patients who received at least one course of WBRT within the last 2 years of life (see Results). We used the term ‘prevailing waiting time’ for radiotherapy as a proxy measure of the relationship between the supply of radiotherapy and the demand for radiotherapy, in a specified location, at a particular point in time [44]. The prevailing waiting time was defined as the median time between the date of diagnosis and the start date of radiotherapy among residents of a community who received adjuvant/curative radiotherapy in the preceding 6 months and was not based on waiting times for WBRT, because the available data provide no means of defining the date when WBRT first became indicated. However, as all types of radiotherapy compete for the same resources, waiting for WBRT may be expected to change in parallel with waiting times for curative/adjuvant radiotherapy. Each patient was attributed a prevailing waiting time for radiotherapy, based on that observed in the community in which he/she resided a year before his/her death. We used records of hospital admissions and the OCR to identify the hospital that was responsible for each patient’s care at the time of diagnosis. We were able to identify a diagnosing hospital in 94.7% of cases. Hospitals were grouped into those with a radiotherapy facility on site or adjacent, and those with no radiotherapy facility. The distance to the nearest cancer centre was defined as the linear distance between a patient’s residence at the time of diagnosis and the cancer centre most frequently visited by patients residing in the same census unit. The median household income was defined as the median household income of the community in which the patient resided at the time of diagnosis. This information was not available for patients diagnosed before 1984. Statistical Methods ArcView was used to create maps and to describe intercounty variations in the use of WBRT. The CochranArmitage test for trend was used to examine temporal trends in the WBRT utilisation rate. Logistic regression was used to identify disease-related, patient-related and health system-related factors that were independently associated with the use of WBRT. The adjusted odds ratio and 95% confidence interval were used to represent the magnitude of observed associations. We carried out secondary analyses, stratified by time period, to determine whether there had been any change in the magnitude of associations between factors of interest and the use of WBRT over the study period. All statistical analyses were carried out using SAS version 9.2.
Results
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Fig 1. Flow chart of cohort definition.
characteristics of the study population are described in Table 1 (first column). The study population consisted of 47% women and 53% men. The median age at death was 72 years and the median survival from diagnosis to death was 10.3 months. The most common primary sites malignancies were: lung cancer (25.7%), breast cancer (8.8%) and colon cancer (8.8%), prostate cancer (6.0%) and pancreatic cancer (5.1%). Use of Whole Brain Radiotherapy for Brain Metastases Of the 494 709 patients in the study population, 28 217 patients, or 5.7% (95% confidence interval 5.6%, 5.8%), underwent at least one course of WBRT before death (Table 1, second column). This WBRT subgroup consisted of 51.8% women and 48.2% men. The most common primary malignancies in this subgroup were: lung cancer (55.7%), breast cancer (16.6%) and melanoma (4.7%). The median age at death was 63 years. The median survival time from the diagnosis of primary tumour to death was 13.8 months and the median survival time from first WBRT to death was 2.8 months. The time between first WBRT and death was: 38.1% at 2 months, 62.0% at 2e36 months and 0 at >36 months. Most WBRT patients received one course of treatment, with a standard fractionation schedule of 20 Gy in five fractions (56%) or 30 Gy in 10 fractions (11%), in accordance with common practice in Canada and clinical practice guidelines [13,15].
Characteristics of the Study Population
Patient-related and Disease-related Factors in Whole Brain Radiotherapy Utilisation Rate
The study population included 494 709 patients who died of cancer in Ontario between 1984 and 2007 (Figure 1). The
To identify patient-related and disease-related factors associated with the use of WBRT, we conducted univariate
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Table 1 Patient-related and disease-related factors associated with the use of whole brain radiotherapy (WBRT) (1984e2007) Number of patients who died of cancer (%)
Number of patients who received WBRT before death (%)
Total 494 709 (100%) 28 217 (100%) Gender Female 232 269 (47.0%) 14 626 (51.8%) Male 262 440 (53.0%) 13 591 (48.2%) Age at death (years) <50 32 677 (6.6%) 4190 (14.8%) 50e59 61 263 (12.4%) 6955 (24.6%) 60e69 119 287 (24.1%) 9601 (34.0%) 70e79 157 360 (31.8%) 6262 (22.2%) 80 124 113 (25.1%) 1209 (4.3%) Socioeconomic status quintile 1 (lowest) 104 435 (21.1%) 5560 (19.7%) 2 100 143 (20.2%) 5648 (20.0%) 3 90 709 (18.3%) 5357 (19.0%) 4 77 358 (15.6%) 4822 (17.1%) 5 (highest) 73 904 (14.9%) 4784 (17.0%) Primary site Bladder 12 360 (2.5%) 179 (0.6%) Breast 43 694 (8.8%) 4689 (16.6%) Colon 43 581 (8.8%) 883 (3.1%) Head and neck 13 556 (2.7%) 199 (0.7%) Gynaecological 23 421 (4.7%) 414 (1.5%) Kidney 9783 (2.0%) 729 (2.6%) Leukaemia 17 170 (3.5%) 107 (0.4%) Lung 127 060 (25.7%) 15 720 (55.7%) Lymphoma 20 373 (4.1%) 685 (2.4%) Melanoma 6511 (1.3%) 1325 (4.7%) Myeloma 9227 (1.9%) 148 (0.5%) Others 86 646 (17.5%) 2229 (7.9%) Pancreas 25 170 (5.1%) 58 (0.2%) Prostate 29 584 (6.0%) 558 (2.0%) Rectum 9890 (2.0%) 206 (0.7%) Stomach 16 683 (3.4%) 88 (0.3%) Time between diagnosis and death (months) 2 112 208 (22.7%) 1808 (6.4%) 2e36 265 307 (53.6%) 19 884 (70.5%) >36 115 527 (23.4%) 6420 (22.8%) * y
Percentage of patients who received WBRT (95% confidence interval)
Odds ratio (95% confidence interval)*
P valuey
1.20 (1.16, 1.24) Reference
<0.0001
(12.5%, 13.2%) (11.1%, 11.6%) (7.9%, 8.2%) (3.9%, 4.1%) (0.92%, 1.03%)
3.3 (3.1, 3.4) 2.7 (2.6, 2.8) 1.92 (1.85, 1.99) Reference 0.30 (0.28, 0.32)
<0.0001
(5.2%, (5.5%, (5.8%, (6.1%, (6.3%,
Reference 1.09 (1.04, 1.10 (1.06, 1.16 (1.12, 1.24 (1.18,
<0.0001
5.7% (5.6%, 5.8%) 6.3% (6.2%, 6.4%) 5.2% (5.1%, 5.3%) 12.8% 11.4% 8.0% 4.0% 0.97% 5.3% 5.6% 5.9% 6.2% 6.5% 1.4% 10.7% 2.0% 1.5% 1.8% 7.5% 0.6% 12.4% 3.4% 20.4% 1.6% 2.6% 0.23% 1.9% 2.1% 0.5%
5.5%) 5.8%) 6.1%) 6.4%) 6.7%)
(1.2%, 1.7%) (10.4%, 11.0%) (1.9%, 2.2%) (1.3%, 1.7%) (1.6%, 1.9%) (6.9%, 8.0%) (0.5%, 0.7%) (12.2%, 12.6%) (3.1%, 3.6%) (19.4%, 21.3%) (1.3%, 1.9%) (2.5%, 2.7%) (0.17%, 0.29%) (1.7%, 2.0%) (1.8%, 2.4%) (0.4%, 0.6%)
1.6% (1.5%, 1.7%) 7.5% (7.4%, 7.6%) 5.6% (5.4%, 5.7%)
1.13) 1.15) 1.22) 1.29)
0.13 (0.11, 0.15) 0.58 (0.56, 0.61) 0.15 (0.14, 0.16) 0.08 (0.07, 0.09) 0.09 (0.08, 0.10) 0.50 (0.46, 0.55) 0.04 (0.03, 0.05) Reference 0.20 (0.19, 0.22) 1.30 (1.21, 1.39) 0.11 (0.09, 0.13) 0.20 (0.19, 0.21) 0.016 (0.012, 0.021) 0.20 (0.18, 0.22) 0.15 (0.13, 0.17) 0.04 (0.03, 0.05)
<0.0001
0.25 (0.24, 0.27) Reference 0.93 (0.90, 0.96)
<0.0001
The odds ratios were derived from a regression that also controlled for health system-related factors. Wald test statistic.
and multivariate analyses (Table 1). Women were slightly more likely than men to receive WBRT (6.3% vs 5.2%). Further analysis stratified by primary cancer site showed that the gender effect was disease specific. The percentage of patients receiving WBRT was lower for women with melanoma compared to men (odds ratio: 0.75, 95% confidence interval: 0.65, 0.86) and higher for women with lung cancer (odds ratio: 1.30, 95% confidence interval: 1.25, 1.35) than men. Younger patients were more likely to receive WBRT (12.8% at < 50 years) than older patients (4.0% at 70e79 years), with WBRT rates decreasing steadily with increasing age and dropping dramatically in patients 80 years (0.97%). Stratified analysis by disease revealed that the age effect occurred across all diseases. Patients living in communities with higher household incomes were more likely to receive WBRT than patients living in communities with lower
household incomes (highest quintile of 6.5% versus lowest quintile of 5.3%). The rate of WBRT use varied with the primary site of the cancer, from only 0.23% in pancreatic cancer to 10.7% in breast cancer, 12.4% in lung cancer and 20.4% in melanoma. Patients who survived for only a short time after the primary diagnosis (1.6% at 2 months) were less likely to receive WBRT compared with those living longer (7.5% at 2e36 months and 5.6% at >36 months). Health System Factors in Whole Brain Radiotherapy Utilisation Rate To identify health system-related factors that may affect the use of WBRT, we conducted univariate and multivariate analyses (Table 2). Most of the study population (66.3%) and the WBRT population (60.8%) had their cancer diagnosed in
W. Kong et al. / Clinical Oncology 24 (2012) e149ee158
a hospital that did not have a radiotherapy facility. About 30% of the study population and the WBRT population lived >50 km away from the nearest radiotherapy centre at the time of diagnosis. Wait times were evenly distributed across quintiles in both groups. Multivariate analyses show that patients diagnosed in a hospital with a radiotherapy facility were more likely (odds ratio: 1.33, 95% confidence interval: 1.29, 1.37) to receive WBRT than patients diagnosed in a hospital without a radiotherapy facility; patients who lived further away from the nearest radiotherapy centre (>50 km) were less likely (odds ratio: 0.93, 95% confidence interval: 0.90, 0.97) to receive WBRT than those living closer (10e50 km); the prevailing waiting time for WBRT at the nearest radiotherapy centre was not significantly associated with the use of WBRT. Geographical Variations in Whole Brain Radiotherapy Utilisation Rate
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the highest quintile. The median WBRT rate in counties with cancer centres was 7.0%, compared with 5.7% in counties without cancer centres. Temporal Changes in the Rate of Use of Whole Brain Radiotherapy for Brain Metastases The overall rate of use of WBRT increased significantly over the study period from 1984 to 2007 (Table 2). Trends in the use of WBRT varied according to primary cancer site. There was a slight increase in WBRT associated with melanoma, lung, breast, colon and kidney cancer (Figure 3). Multivariate analyses stratified by time period revealed that the associations between the patient-related and health system-related factors and the use of WBRT shown in Tables 1 and 2 did not change significantly over the entire study period, from 1984e2007 (data not presented).
Discussion To determine whether there were geographical variations in the rate of use of WBRT among patients who died of cancer in Ontario from 1984 to 2007, we examined the rates of WBRT utilisation within the various counties across northern and southern Ontario (Figure 2). The overall provincial rate for the use of WBRT during this time period was 5.9%. Rates varied widely with an inter-county range between 1.3% and 8.8%. Significant differences (a < 0.05) from the provincial rate are denoted by a triangle (:higher, ;lower). Half the counties (4/8) with radiotherapy centres had WBRT utilisation rates in
Our results show that 5.7% of patients who died of cancer in Ontario between 1984 and 2007 received WBRT. We cannot comment on whether this is an appropriate rate of use of WBRT, as the incidence of brain metastases in Ontario is unknown, as is the proportion of those who might benefit from WBRT. In accordance with previous reports and prognostic indexes [9,17,18,20], the median age at death was 63 years and the median survival times from the diagnosis of primary tumour to death and from first WBRT to death
Table 2 Health system-related factors associated with the use of whole brain radiotherapy (WBRT) (1984e2007) Number of patients who died of cancer (%)
Number of patients who received WBRT before death (%)
Total 494 709 (100%) 28 217 (100%) Availability of radiotherapy services at the diagnosing hospital Not diagnosed in hospital 32 435 (6.6%) 1006 (3.6%) No radiotherapy facility 327 985 (66.3%) 17 167 (60.8%) Radiotherapy facility 134 289 (27.1%) 10 044 (35.6%) Distance to nearest radiotherapy centrez <10 km 149 027 (30.1%) 9102 (32.3%) 10e50 km 151 168 (30.6%) 9293 (32.9%) >50 km 146 863 (29.7%) 7797 (27.6%) Prevailing waiting time (quintiles)z 1 (lowest) 95 954 (19.4%) 5245 (18.6%) 2 95 141 (19.2%) 5310 (18.8%) 3 94 388 (19.1%) 5394 (19.1%) 4 93 346 (18.9%) 5581 (19.8%) 5 (highest) 93 302 (18.9%) 5791 (20.5%) Year of death 1984e1988 84 631 (17.1%) 4585 (16.2%) 1989e1993 95 167 (19.2%) 5042 (17.9%) 1994e1998 104 750 (21.2%) 5835 (20.7%) 1999e2002 90 657 (18.3%) 5596 (19.8%) 2003e2007 119 504 (24.2%) 7159 (25.4%) * y z
Percentage of patients who received WBRT (95% confidence interval)
Odds ratio (95% confidence interval)*
P valuey
5.7% (5.6%, 5.8%) 3.1% (2.9%, 3.3%) 5.2% (5.2%, 5.3%) 7.5% (7.3%, 7.6%)
0.88 (0.82, 0.95) Reference 1.33 (1.29, 1.37)
6.1% (6.0%, 6.2%) 6.1% (6.0%, 6.3%) 5.3% (5.2%, 5.4%)
1.06 (1.02, 1.09) Reference 0.93 (0.90, 0.97)
5.5% 5.6% 5.7% 6.0% 6.2%
(5.3%, (5.4%, (5.6%, (5.8%, (6.1%,
5.6%) 5.7%) 5.9%) 6.1%) 6.4%)
Reference 1.03 (0.97, 1.01 (0.95, 0.99 (0.93, 1.05 (0.98,
5.4% 5.3% 5.6% 6.2% 6.0%
(5.3%, (5.2%, (5.4%, (6.0%, (5.9%,
5.6%) 5.4%) 5.7%) 6.3%) 6.1%)
0.74 (0.69, 0.74 (0.71, 0.84 (0.80, 0.99 (0.96, Reference
<.00001
<0.0001
0.1202 1.09) 1.08) 1.07) 1.13) 0.80) 0.79) 0.88) 1.03)
The odds ratios were derived from a regression that also controlled for patient-related and disease-related factors. Wald test statistic. Place of residence was not available in about 10% of cases.
<0.0001
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Fig 2. Intercounty variation in the use of WBRT in Ontario (1984–2007). The map shows geographic variation in the rate of use of WBRT in Ontario. Cancer centres are named and their location shown on the map as a white dot. The gray scale shows the rate of WBRT utilization in each county. Counties in which the utilization rate differs significantly from the provincial average (P < 0.05) are denoted by a triangle (6 higher; 7 lower).
were 14 months and 3 months, respectively. Our findings identify several individual patient-related factors that were associated with patterns of WBRT use: gender, women were more likely to receive WBRT than men; age, younger patients were more likely to receive WBRT than older patients; socioeconomic status, patients living in richer communities were more likely to receive WBRT than patients living in poorer communities; primary site of cancer, patients with melanoma, lung, breast and renal cancers were more likely to receive WBRT than those with other primary cancers; time between diagnosis and death, patients with a short life span were less likely to receive WBRT compared with those with a longer life span.
Although some of these variations may be appropriate and related to a patient’s need, others may not. The gender effect on WBRT rates was dependent on the primary cancer, with higher WBRT rates observed in men with melanoma and women with lung cancer. This effect, although unexplained, is consistent with the gender differences in the incidence proportion for brain metastases reported in these primary cancers albeit in a different population [6]. Gender differences in palliative radiotherapy utilisation rates were not observed in our previous studies [40]. The rate of use of WBRT decreased with increasing age, with notable differences observed between the younger
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Fig 3. Temporal trends in the use of WBRT over the period of study for all cases combined (C), lung cancer (6), breast cancer (B), melanoma (-), kidney (,), and colon (:).
(<60 years) and older age groups (>70 years). Similar decreases in palliative radiotherapy utilisation rates in the elderly have been described for its general use in Nova Scotia [47] and Ontario [41,48e50], and for its specific use in bone metastases in Ontario [40], bone metastases and breast cancer in Alberta [51,52] and lung metastases in the USA [53]. The observed association between age and WBRT in the present study is consistent with reported peak incidence of brain metastases in patients under 60 years of age at the time of primary cancer diagnosis [6]. These lower incidence rates and lower utilisation rates in the elderly could reflect an age-related difference in tumour biology or a diagnostic bias, whereby the diagnostic work-up to detect brain metastases in older patients may be less extensive [5,54]. However, the much steeper decline in WBRT utilisation rates in the elderly, compared with the reported decline in the incidence of brain metastases suggests bias against the use of WBRT in older patients. Although advanced age alone is not an absolute contraindication to radiotherapy [55e57], it may influence treatment decisions in the management of brain metastases, as it is consistently associated with poorer prognosis [18]. Although a declining performance status and the presence of co-morbidities may make radiotherapy treatment less feasible in the elderly, it does not fully explain the relatively steep decline in radiotherapy in the elderly [50,58,59]. It is possible that older patients may prefer less active treatment for brain metastases, but we are unaware of any evidence to support this. These low WBRT rates may be driven by a lack of awareness of the benefit of WBRT in elderly patients [60]. Ensuring that elderly cancer patients receive appropriate diagnostic work-ups, and that health professionals, patients and their caregivers receive education on the potential benefits of WBRT in the elderly, may help ensure that the elderly receive appropriate treatment. Despite universal healthcare, our findings indicate that residents of richer communities are more likely to receive
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WBRT than residents of poorer communities and this is consistent with previous studies on palliative radiotherapy in the general cancer population [41,47], as well as those focusing on palliative radiotherapy rates in breast cancer [51], bone metastases [40] and non-small cell lung cancer populations [53]. Although there are no explicit financial barriers to radiotherapy access, there may be implicit financial barriers, such as securing transportation, time off work and childcare. There may be higher effectiveness in advocating for specialist treatment among patients and caregivers of higher socioeconomic status [40]. Some of the patient-related variations in WBRT use are consistent with appropriate case selection. Observed WBRT utilisation rates are highest in the primary cancers that are most frequently associated with brain metastases, such as lung, breast and melanoma [5,6,9,10]. WBRT is used less frequently in patients who would survive for only a short time, as reported in other contexts [40]. Estimating the duration of survival is difficult in this heterogeneous population and is often inaccurate [61], as it is with other cancer populations [62], and the further development of prognostic indexes will help identify which patient groups would potentially benefit from WBRT and which groups could be safely managed without WBRT [19]. Our findings have identified health system-related factors that are associated with increased WBRT utilisation rates: patients diagnosed in a hospital with a radiotherapy facility were more likely to receive WBRT than patients diagnosed in a hospital without a radiotherapy facility; patients who lived close to a radiotherapy centre were more likely to receive WBRT than those who lived further away. The prevailing waiting time for radiotherapy at the nearest radiotherapy centre was not significantly associated with the rate of WBRT use. Our data show that there were geographical variations in the rate of use of WBRT within counties across northern and southern Ontario. Many of the counties where radiotherapy centres were located had WBRT utilisation rates in the highest quintile. Together these results are similar to our previous findings for the use of palliative radiotherapy for bone metastases [40] and are consistent with other studies on accessibility [47,48,51,52,63,64]. Conversely, in other health care systems having no financial barriers to treatment, palliative radiotherapy utilisation rates have not been found to vary with proximity to treatment facility [65]. In the present study, increased travel times associated with living further away from radiotherapy centres may have deterred WBRT as a treatment decision by the patient’s health professional or as accepted treatment by the patient [40]. However, distance itself may not be a critical factor, but may reflect differing levels of awareness of the potential benefit of WBRT among local physicians. Disparities in the health system-related factors associated with WBRT use are modifiable and might be avoided by increasing the level of awareness among health care professionals that treat cancer patients and by improving patient access to consultation with radiation oncologists through establishment of outreach clinics or by the provision of additional radiotherapy centres.
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In the present study period, from 1984 to 2007, the overall rate of use of WBRT increased only slightly. Moreover, the associations between patient-related and health systemrelated factors remained constant over two decades. The disparities associated with identified patient-related and health system-related factors will probably continue to affect the use of WBRT unless active interventions are adopted to remove barriers to access. The total WBRT workload increased steadily over the study period due to the steady increase in cancer death, suggesting that providing WBRT use may become an increasing challenge for the health care system. A Swedish population-based study reported a doubling of admissions for brain metastases between 1987 and 2006 [66], while a population-based study in the Netherlands found no increase in the incidence of brain metastasis in patients with breast or lung cancer [5]. In the present study, the slight increase in WBRT use for brain metastases associated with primary lung cancer and breast cancer could be due to improved systemic treatment, leading to prolonged survival and an increased opportunity for the development of brain metastases. Improved imaging techniques with early detection of smaller tumours could lead to an apparent increase in the incidence of brain metastases [2,8] and could also contribute to the slight increase in WBRT use over time. This study examined the use of WBRT in one Canadian province, but it seems likely that the use of WBRT for brain metastases will prove to be affected by similar factors elsewhere in the world, particularly in other health systems that operate relatively centralised radiotherapy programmes. As our database is a large population-based cancer registry, our results should be generalised to other geographical areas with similar demographics. This will only be clear once similar population-based studies have been conducted in other health care systems. WBRT will continue to play an important role in the management of patients with brain metastases. Interventions designed to improve access to WBRT are needed, as well as ways to evaluate their effectiveness. Centralised radiotherapy centres should not only provide access to treatment, but should also act as a hub for the improvement of cancer management, quality control, training and advocacy. As the incidence of the indication for WBRT is generally unknown, we cannot comment on the magnitude of the unmet need for treatment. As we strive to deliver optimum care, we will also need to establish what the appropriate level of care is.
Acknowledgements This study was supported by grants from the Canadian Institutes of Health Research and Cancer Care Ontario. The authors thank Cancer Care Ontario, the Ontario Cancer Registry and the Ontario radiotherapy centres for access to their records.
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Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
The Use of Palliative Whole Brain Radiotherapy in the Management of Brain Metastases W. Kong *, C.R. Jarvis *, D.S. Sutton *y, K. Ding z, W.J. Mackillop *y * Division
of Cancer Care and Epidemiology, Queen’s University, Cancer Research Institute, Kingston, Ontario, Canada Department of Community Health and Epidemiology, Queen’s University, Kingston, Ontario, Canada z NCIC Clinical Trials Group, Queen’s University, Kingston, Ontario, Canada y
Received 26 June 2011; received in revised form 25 June 2012; accepted 26 June 2012
Abstract Aims: To describe the use of palliative whole brain radiotherapy (WBRT) in the management of brain metastases in the general cancer population and to identify factors associated with variations in its use. Materials and methods: We conducted a retrospective population-based study of patients who died of cancer in Ontario from 1984 to 2007 and identified those who received WBRT before death. Univariate and multivariate analyses were carried out to identify factors associated with the use of WBRT. Results: Of the 494 709 patients who died of cancer, 5.7% received WBRT. The rate of use of WBRT varied across the province, with county rates ranging from 1.3 to 8.8%. Younger patients and patients living in communities of higher socioeconomic status were more likely to receive WBRT, as were patients diagnosed in a hospital with a radiotherapy facility or living closer to a radiotherapy centre (P < 0.0001). The rate of use of WBRT was stable over the study period. Conclusion: There are inequities in the use of WBRT for the management of brain metastases that are not associated with need. Strategies to increase patient access to WBRT need to be developed and evaluated to ensure optimal outcomes. Ó 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Access; brain metastasis; palliative radiotherapy; population based; whole brain radiotherapy
Introduction The management of brain metastases is an important health care challenge. Most patients with cancer die not from the primary lesion, but from metastases to vital organs or from other complications. Brain metastases are the most common neurological complication of cancer [1]. The exact incidence of brain metastases is unknown and reported rates vary depending on the population studied and the method of assessment [1,2]. Large but now historic autopsy series found brain metastases in 15% of patients who died of cancer [1,3,4], whereas population-based studies reported a lower incidence [5,6]. Brain metastases are one of the most feared complications of cancer, as even small tumours may cause debilitating neurological symptoms and slight Author for correspondence: W.J. Mackillop, Division of Cancer Care and Epidemiology, Queen’s University, Cancer Research Institute, 10 Stuart Street, Level 2, Kingston, ON K7L 3N6, Canada. Tel: þ1-613-533-6895; Fax: þ1-613-533-6794. E-mail address: [email protected] (W.J. Mackillop).
tumour growth can be fatal [3]. Although some patients are asymptomatic, most have presenting symptoms with signs of increased intracranial pressure, such as changes in mental status, headache, nausea and vomiting, or focal signs such as seizures, hemiparesis, aphasia, ataxia and visual field defects [3,7e11]. The brain may increasingly become the first and only site of relapse as it remains a sanctuary for neoplastic cells, sheltered from improved systemic therapy behind the bloodebrain barrier [1,2]. Brain metastases usually occur late in the course of a patient’s cancer when it is widely disseminated. Although many patients die from systemic disease, up to half of the patients die from intracranial progression [12]. The prognosis for patients with brain metastases is poor, with a median survival time of 1e2 months in untreated patients and 3e6 months in patients treated with whole brain radiotherapy (WBRT) [13]. Although there have been no randomised trials showing that WBRT offers a survival advantage over supportive care [12,14], WBRT is the standard recommendation in clinical practice guidelines for the management of brain metastases [13,15]. It has been questioned whether
0936-6555/$36.00 Ó 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2012.08.004
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WBRT is indicated in every case, particularly in the context of non-small cell lung cancer, where the prognosis in patients with multiple brain metastases is very poor [16]. Analyses of prognostic factors have endeavoured to identify which patients would probably benefit from WBRT and which patients would not [17e19]. However, it remains to be validated which patients can be managed safely and palliated without WBRT [19]. Given the limited survival, preservation of cognitive function and quality of life are important considerations in treating patients with brain metastases. The goal of WBRT, in addition to offering a possible survival benefit by controlling intracranial metastases, is to allow for tapering of corticosteroid dose, alleviate neurological symptoms or prevent their progression, prevent neurological deterioration and maintain or enhance quality of life [2,7,20e22]. WBRT is used as adjuvant therapy after surgical resection or radiosurgery in selected patients with a limited number of brain metastases. Clinical studies and trials have shown that palliative WBRT is effective in controlling neurological symptoms with varying response rates [7,12,13,23]. The palliative efficacy of WBRT in terms of neurocognitive function and quality of life has not been a focus of these reports and remains unclear. A review of the literature [22,24] has shown that in some studies general quality of life or certain parameters of quality of life (e.g. fatigue, drowsiness, appetite) tend to deteriorate after WBRT treatment [25e28], particularly in patients with poor prognosis, whereas in other studies quality of life stabilises [21] or improves after WBRT treatment [29e31]. The potential neurocognitive morbidity associated with both brain metastases and their treatment remains a poorly understood concern [32e35]. Neuropsychiatric testing reveals that most patients with brain metastasis have impairment in neurocognitive function before treatment [36]. Although the cognitive decline observed in some studies after WBRT may be the result of the treatment itself [33], it may also be the result of failed tumour control and increased tumour burden [34]. WBRT-induced tumour control has been correlated with better survival and improved neurocognitive function [37], which has been correlated with quality of life [38], suggesting a potential benefit if WBRT itself confers tumour control [32]. WBRT remains an important treatment option. However, patients with brain metastases are a heterogeneous population and treatment is dependent on the individual clinical setting [20]. Optimising cancer outcomes depends on making effective treatments available to all those who might benefit from them. The socialised medical system in Canada is intended to remove barriers to access to treatment. The province of Ontario, like other provinces in Canada, provides palliative radiotherapy through centralised radiotherapy centres. Evidence suggests that access to radiotherapy services is not equitable for all patients requiring radiotherapy across Ontario [39], as well patients specifically requiring palliative radiotherapy for bone metastases [40], and is influenced by factors unrelated to need, such as age, socioeconomic status and proximity to radiotherapy centres [41]. Despite the high morbidity and mortality associated with brain metastases and the known value of WBRT in the management of this condition, the rate of use
of this treatment is not known. The aim of this study was to describe the use of WBRT in the general cancer population and to identify factors associated with variations in its use. The cancer system in the province of Ontario provides an ideal model to study the utilisation of WBRT as all radiotherapy activity in Ontario is provided by a network of regional cancer centres that keep electronic records of treatment activity and these data have been linked to the records of the Ontario Cancer Registry (OCR) to provide a database suitable for studying patterns of care [39e41].
Materials and Methods This was a retrospective, population-based cohort study. The study population consisted of all Ontario residents who died of cancer between the years 1984 and 2007, excluding those with a primary cancer of the brain. Sources of Data Data were obtained from the OCR, a passive, populationbased registry that captures information on >95% of all cancer cases [42] diagnosed in the province from four sources: hospital separation records, pathology reports, death certificates and reports from the provincial cancer centres [43]. Records from these sources are compiled and reconciled by probabilistic linkage. Information on all cases includes: date of birth, gender, date of diagnosis, residence at time of diagnosis, primary site (ICD-9), histology (ICD-O), source of diagnostic information, vital status, date of death and cause of death. Electronic records of all courses of radiotherapy delivered between 1984 and 2007 were made available by the regional cancer centres of Cancer Care Ontario and the Princess Margaret Hospital. The following information was available for each course of treatment: start date of radiotherapy, total dose, number of fractions, intent of treatment and body region irradiated. The resulting radiotherapy database was >95% complete [44]. Few patients are ever referred outside of the province for palliative radiotherapy except for residents of Kenora County, who are often treated in the neighbouring province of Manitoba. Utilisation rates for Kenora are, therefore, not reported here [45]. The Canadian Institute for Health Information provided hospital separation records from all general hospitals in Ontario. These records, which included dates of admission, admitting diagnoses and dates of discharge, were linked to the OCR. Statistics Canada provided information about the median household income at the level of census subdivision and the census enumeration area. This community-level information was linked to each case in the OCR based on the patient’s place of residence at the time of diagnosis, as described previously [46]. Definition of Derived Variables used in the Analysis Courses of WBRT for brain metastases were identified based on the intent of treatment and the body region
W. Kong et al. / Clinical Oncology 24 (2012) e149ee158
irradiated specified in the prescription. The WBRT utilisation rate for brain metastases was defined as the proportion of patients who received at least one course of WBRT within the last 2 years of life (see Results). We used the term ‘prevailing waiting time’ for radiotherapy as a proxy measure of the relationship between the supply of radiotherapy and the demand for radiotherapy, in a specified location, at a particular point in time [44]. The prevailing waiting time was defined as the median time between the date of diagnosis and the start date of radiotherapy among residents of a community who received adjuvant/curative radiotherapy in the preceding 6 months and was not based on waiting times for WBRT, because the available data provide no means of defining the date when WBRT first became indicated. However, as all types of radiotherapy compete for the same resources, waiting for WBRT may be expected to change in parallel with waiting times for curative/adjuvant radiotherapy. Each patient was attributed a prevailing waiting time for radiotherapy, based on that observed in the community in which he/she resided a year before his/her death. We used records of hospital admissions and the OCR to identify the hospital that was responsible for each patient’s care at the time of diagnosis. We were able to identify a diagnosing hospital in 94.7% of cases. Hospitals were grouped into those with a radiotherapy facility on site or adjacent, and those with no radiotherapy facility. The distance to the nearest cancer centre was defined as the linear distance between a patient’s residence at the time of diagnosis and the cancer centre most frequently visited by patients residing in the same census unit. The median household income was defined as the median household income of the community in which the patient resided at the time of diagnosis. This information was not available for patients diagnosed before 1984. Statistical Methods ArcView was used to create maps and to describe intercounty variations in the use of WBRT. The CochranArmitage test for trend was used to examine temporal trends in the WBRT utilisation rate. Logistic regression was used to identify disease-related, patient-related and health system-related factors that were independently associated with the use of WBRT. The adjusted odds ratio and 95% confidence interval were used to represent the magnitude of observed associations. We carried out secondary analyses, stratified by time period, to determine whether there had been any change in the magnitude of associations between factors of interest and the use of WBRT over the study period. All statistical analyses were carried out using SAS version 9.2.
Results
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Fig 1. Flow chart of cohort definition.
characteristics of the study population are described in Table 1 (first column). The study population consisted of 47% women and 53% men. The median age at death was 72 years and the median survival from diagnosis to death was 10.3 months. The most common primary sites malignancies were: lung cancer (25.7%), breast cancer (8.8%) and colon cancer (8.8%), prostate cancer (6.0%) and pancreatic cancer (5.1%). Use of Whole Brain Radiotherapy for Brain Metastases Of the 494 709 patients in the study population, 28 217 patients, or 5.7% (95% confidence interval 5.6%, 5.8%), underwent at least one course of WBRT before death (Table 1, second column). This WBRT subgroup consisted of 51.8% women and 48.2% men. The most common primary malignancies in this subgroup were: lung cancer (55.7%), breast cancer (16.6%) and melanoma (4.7%). The median age at death was 63 years. The median survival time from the diagnosis of primary tumour to death was 13.8 months and the median survival time from first WBRT to death was 2.8 months. The time between first WBRT and death was: 38.1% at 2 months, 62.0% at 2e36 months and 0 at >36 months. Most WBRT patients received one course of treatment, with a standard fractionation schedule of 20 Gy in five fractions (56%) or 30 Gy in 10 fractions (11%), in accordance with common practice in Canada and clinical practice guidelines [13,15].
Characteristics of the Study Population
Patient-related and Disease-related Factors in Whole Brain Radiotherapy Utilisation Rate
The study population included 494 709 patients who died of cancer in Ontario between 1984 and 2007 (Figure 1). The
To identify patient-related and disease-related factors associated with the use of WBRT, we conducted univariate
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Table 1 Patient-related and disease-related factors associated with the use of whole brain radiotherapy (WBRT) (1984e2007) Number of patients who died of cancer (%)
Number of patients who received WBRT before death (%)
Total 494 709 (100%) 28 217 (100%) Gender Female 232 269 (47.0%) 14 626 (51.8%) Male 262 440 (53.0%) 13 591 (48.2%) Age at death (years) <50 32 677 (6.6%) 4190 (14.8%) 50e59 61 263 (12.4%) 6955 (24.6%) 60e69 119 287 (24.1%) 9601 (34.0%) 70e79 157 360 (31.8%) 6262 (22.2%) 80 124 113 (25.1%) 1209 (4.3%) Socioeconomic status quintile 1 (lowest) 104 435 (21.1%) 5560 (19.7%) 2 100 143 (20.2%) 5648 (20.0%) 3 90 709 (18.3%) 5357 (19.0%) 4 77 358 (15.6%) 4822 (17.1%) 5 (highest) 73 904 (14.9%) 4784 (17.0%) Primary site Bladder 12 360 (2.5%) 179 (0.6%) Breast 43 694 (8.8%) 4689 (16.6%) Colon 43 581 (8.8%) 883 (3.1%) Head and neck 13 556 (2.7%) 199 (0.7%) Gynaecological 23 421 (4.7%) 414 (1.5%) Kidney 9783 (2.0%) 729 (2.6%) Leukaemia 17 170 (3.5%) 107 (0.4%) Lung 127 060 (25.7%) 15 720 (55.7%) Lymphoma 20 373 (4.1%) 685 (2.4%) Melanoma 6511 (1.3%) 1325 (4.7%) Myeloma 9227 (1.9%) 148 (0.5%) Others 86 646 (17.5%) 2229 (7.9%) Pancreas 25 170 (5.1%) 58 (0.2%) Prostate 29 584 (6.0%) 558 (2.0%) Rectum 9890 (2.0%) 206 (0.7%) Stomach 16 683 (3.4%) 88 (0.3%) Time between diagnosis and death (months) 2 112 208 (22.7%) 1808 (6.4%) 2e36 265 307 (53.6%) 19 884 (70.5%) >36 115 527 (23.4%) 6420 (22.8%) * y
Percentage of patients who received WBRT (95% confidence interval)
Odds ratio (95% confidence interval)*
P valuey
1.20 (1.16, 1.24) Reference
<0.0001
(12.5%, 13.2%) (11.1%, 11.6%) (7.9%, 8.2%) (3.9%, 4.1%) (0.92%, 1.03%)
3.3 (3.1, 3.4) 2.7 (2.6, 2.8) 1.92 (1.85, 1.99) Reference 0.30 (0.28, 0.32)
<0.0001
(5.2%, (5.5%, (5.8%, (6.1%, (6.3%,
Reference 1.09 (1.04, 1.10 (1.06, 1.16 (1.12, 1.24 (1.18,
<0.0001
5.7% (5.6%, 5.8%) 6.3% (6.2%, 6.4%) 5.2% (5.1%, 5.3%) 12.8% 11.4% 8.0% 4.0% 0.97% 5.3% 5.6% 5.9% 6.2% 6.5% 1.4% 10.7% 2.0% 1.5% 1.8% 7.5% 0.6% 12.4% 3.4% 20.4% 1.6% 2.6% 0.23% 1.9% 2.1% 0.5%
5.5%) 5.8%) 6.1%) 6.4%) 6.7%)
(1.2%, 1.7%) (10.4%, 11.0%) (1.9%, 2.2%) (1.3%, 1.7%) (1.6%, 1.9%) (6.9%, 8.0%) (0.5%, 0.7%) (12.2%, 12.6%) (3.1%, 3.6%) (19.4%, 21.3%) (1.3%, 1.9%) (2.5%, 2.7%) (0.17%, 0.29%) (1.7%, 2.0%) (1.8%, 2.4%) (0.4%, 0.6%)
1.6% (1.5%, 1.7%) 7.5% (7.4%, 7.6%) 5.6% (5.4%, 5.7%)
1.13) 1.15) 1.22) 1.29)
0.13 (0.11, 0.15) 0.58 (0.56, 0.61) 0.15 (0.14, 0.16) 0.08 (0.07, 0.09) 0.09 (0.08, 0.10) 0.50 (0.46, 0.55) 0.04 (0.03, 0.05) Reference 0.20 (0.19, 0.22) 1.30 (1.21, 1.39) 0.11 (0.09, 0.13) 0.20 (0.19, 0.21) 0.016 (0.012, 0.021) 0.20 (0.18, 0.22) 0.15 (0.13, 0.17) 0.04 (0.03, 0.05)
<0.0001
0.25 (0.24, 0.27) Reference 0.93 (0.90, 0.96)
<0.0001
The odds ratios were derived from a regression that also controlled for health system-related factors. Wald test statistic.
and multivariate analyses (Table 1). Women were slightly more likely than men to receive WBRT (6.3% vs 5.2%). Further analysis stratified by primary cancer site showed that the gender effect was disease specific. The percentage of patients receiving WBRT was lower for women with melanoma compared to men (odds ratio: 0.75, 95% confidence interval: 0.65, 0.86) and higher for women with lung cancer (odds ratio: 1.30, 95% confidence interval: 1.25, 1.35) than men. Younger patients were more likely to receive WBRT (12.8% at < 50 years) than older patients (4.0% at 70e79 years), with WBRT rates decreasing steadily with increasing age and dropping dramatically in patients 80 years (0.97%). Stratified analysis by disease revealed that the age effect occurred across all diseases. Patients living in communities with higher household incomes were more likely to receive WBRT than patients living in communities with lower
household incomes (highest quintile of 6.5% versus lowest quintile of 5.3%). The rate of WBRT use varied with the primary site of the cancer, from only 0.23% in pancreatic cancer to 10.7% in breast cancer, 12.4% in lung cancer and 20.4% in melanoma. Patients who survived for only a short time after the primary diagnosis (1.6% at 2 months) were less likely to receive WBRT compared with those living longer (7.5% at 2e36 months and 5.6% at >36 months). Health System Factors in Whole Brain Radiotherapy Utilisation Rate To identify health system-related factors that may affect the use of WBRT, we conducted univariate and multivariate analyses (Table 2). Most of the study population (66.3%) and the WBRT population (60.8%) had their cancer diagnosed in
W. Kong et al. / Clinical Oncology 24 (2012) e149ee158
a hospital that did not have a radiotherapy facility. About 30% of the study population and the WBRT population lived >50 km away from the nearest radiotherapy centre at the time of diagnosis. Wait times were evenly distributed across quintiles in both groups. Multivariate analyses show that patients diagnosed in a hospital with a radiotherapy facility were more likely (odds ratio: 1.33, 95% confidence interval: 1.29, 1.37) to receive WBRT than patients diagnosed in a hospital without a radiotherapy facility; patients who lived further away from the nearest radiotherapy centre (>50 km) were less likely (odds ratio: 0.93, 95% confidence interval: 0.90, 0.97) to receive WBRT than those living closer (10e50 km); the prevailing waiting time for WBRT at the nearest radiotherapy centre was not significantly associated with the use of WBRT. Geographical Variations in Whole Brain Radiotherapy Utilisation Rate
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the highest quintile. The median WBRT rate in counties with cancer centres was 7.0%, compared with 5.7% in counties without cancer centres. Temporal Changes in the Rate of Use of Whole Brain Radiotherapy for Brain Metastases The overall rate of use of WBRT increased significantly over the study period from 1984 to 2007 (Table 2). Trends in the use of WBRT varied according to primary cancer site. There was a slight increase in WBRT associated with melanoma, lung, breast, colon and kidney cancer (Figure 3). Multivariate analyses stratified by time period revealed that the associations between the patient-related and health system-related factors and the use of WBRT shown in Tables 1 and 2 did not change significantly over the entire study period, from 1984e2007 (data not presented).
Discussion To determine whether there were geographical variations in the rate of use of WBRT among patients who died of cancer in Ontario from 1984 to 2007, we examined the rates of WBRT utilisation within the various counties across northern and southern Ontario (Figure 2). The overall provincial rate for the use of WBRT during this time period was 5.9%. Rates varied widely with an inter-county range between 1.3% and 8.8%. Significant differences (a < 0.05) from the provincial rate are denoted by a triangle (:higher, ;lower). Half the counties (4/8) with radiotherapy centres had WBRT utilisation rates in
Our results show that 5.7% of patients who died of cancer in Ontario between 1984 and 2007 received WBRT. We cannot comment on whether this is an appropriate rate of use of WBRT, as the incidence of brain metastases in Ontario is unknown, as is the proportion of those who might benefit from WBRT. In accordance with previous reports and prognostic indexes [9,17,18,20], the median age at death was 63 years and the median survival times from the diagnosis of primary tumour to death and from first WBRT to death
Table 2 Health system-related factors associated with the use of whole brain radiotherapy (WBRT) (1984e2007) Number of patients who died of cancer (%)
Number of patients who received WBRT before death (%)
Total 494 709 (100%) 28 217 (100%) Availability of radiotherapy services at the diagnosing hospital Not diagnosed in hospital 32 435 (6.6%) 1006 (3.6%) No radiotherapy facility 327 985 (66.3%) 17 167 (60.8%) Radiotherapy facility 134 289 (27.1%) 10 044 (35.6%) Distance to nearest radiotherapy centrez <10 km 149 027 (30.1%) 9102 (32.3%) 10e50 km 151 168 (30.6%) 9293 (32.9%) >50 km 146 863 (29.7%) 7797 (27.6%) Prevailing waiting time (quintiles)z 1 (lowest) 95 954 (19.4%) 5245 (18.6%) 2 95 141 (19.2%) 5310 (18.8%) 3 94 388 (19.1%) 5394 (19.1%) 4 93 346 (18.9%) 5581 (19.8%) 5 (highest) 93 302 (18.9%) 5791 (20.5%) Year of death 1984e1988 84 631 (17.1%) 4585 (16.2%) 1989e1993 95 167 (19.2%) 5042 (17.9%) 1994e1998 104 750 (21.2%) 5835 (20.7%) 1999e2002 90 657 (18.3%) 5596 (19.8%) 2003e2007 119 504 (24.2%) 7159 (25.4%) * y z
Percentage of patients who received WBRT (95% confidence interval)
Odds ratio (95% confidence interval)*
P valuey
5.7% (5.6%, 5.8%) 3.1% (2.9%, 3.3%) 5.2% (5.2%, 5.3%) 7.5% (7.3%, 7.6%)
0.88 (0.82, 0.95) Reference 1.33 (1.29, 1.37)
6.1% (6.0%, 6.2%) 6.1% (6.0%, 6.3%) 5.3% (5.2%, 5.4%)
1.06 (1.02, 1.09) Reference 0.93 (0.90, 0.97)
5.5% 5.6% 5.7% 6.0% 6.2%
(5.3%, (5.4%, (5.6%, (5.8%, (6.1%,
5.6%) 5.7%) 5.9%) 6.1%) 6.4%)
Reference 1.03 (0.97, 1.01 (0.95, 0.99 (0.93, 1.05 (0.98,
5.4% 5.3% 5.6% 6.2% 6.0%
(5.3%, (5.2%, (5.4%, (6.0%, (5.9%,
5.6%) 5.4%) 5.7%) 6.3%) 6.1%)
0.74 (0.69, 0.74 (0.71, 0.84 (0.80, 0.99 (0.96, Reference
<.00001
<0.0001
0.1202 1.09) 1.08) 1.07) 1.13) 0.80) 0.79) 0.88) 1.03)
The odds ratios were derived from a regression that also controlled for patient-related and disease-related factors. Wald test statistic. Place of residence was not available in about 10% of cases.
<0.0001
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W. Kong et al. / Clinical Oncology 24 (2012) e149ee158
Fig 2. Intercounty variation in the use of WBRT in Ontario (1984–2007). The map shows geographic variation in the rate of use of WBRT in Ontario. Cancer centres are named and their location shown on the map as a white dot. The gray scale shows the rate of WBRT utilization in each county. Counties in which the utilization rate differs significantly from the provincial average (P < 0.05) are denoted by a triangle (6 higher; 7 lower).
were 14 months and 3 months, respectively. Our findings identify several individual patient-related factors that were associated with patterns of WBRT use: gender, women were more likely to receive WBRT than men; age, younger patients were more likely to receive WBRT than older patients; socioeconomic status, patients living in richer communities were more likely to receive WBRT than patients living in poorer communities; primary site of cancer, patients with melanoma, lung, breast and renal cancers were more likely to receive WBRT than those with other primary cancers; time between diagnosis and death, patients with a short life span were less likely to receive WBRT compared with those with a longer life span.
Although some of these variations may be appropriate and related to a patient’s need, others may not. The gender effect on WBRT rates was dependent on the primary cancer, with higher WBRT rates observed in men with melanoma and women with lung cancer. This effect, although unexplained, is consistent with the gender differences in the incidence proportion for brain metastases reported in these primary cancers albeit in a different population [6]. Gender differences in palliative radiotherapy utilisation rates were not observed in our previous studies [40]. The rate of use of WBRT decreased with increasing age, with notable differences observed between the younger
W. Kong et al. / Clinical Oncology 24 (2012) e149ee158
Fig 3. Temporal trends in the use of WBRT over the period of study for all cases combined (C), lung cancer (6), breast cancer (B), melanoma (-), kidney (,), and colon (:).
(<60 years) and older age groups (>70 years). Similar decreases in palliative radiotherapy utilisation rates in the elderly have been described for its general use in Nova Scotia [47] and Ontario [41,48e50], and for its specific use in bone metastases in Ontario [40], bone metastases and breast cancer in Alberta [51,52] and lung metastases in the USA [53]. The observed association between age and WBRT in the present study is consistent with reported peak incidence of brain metastases in patients under 60 years of age at the time of primary cancer diagnosis [6]. These lower incidence rates and lower utilisation rates in the elderly could reflect an age-related difference in tumour biology or a diagnostic bias, whereby the diagnostic work-up to detect brain metastases in older patients may be less extensive [5,54]. However, the much steeper decline in WBRT utilisation rates in the elderly, compared with the reported decline in the incidence of brain metastases suggests bias against the use of WBRT in older patients. Although advanced age alone is not an absolute contraindication to radiotherapy [55e57], it may influence treatment decisions in the management of brain metastases, as it is consistently associated with poorer prognosis [18]. Although a declining performance status and the presence of co-morbidities may make radiotherapy treatment less feasible in the elderly, it does not fully explain the relatively steep decline in radiotherapy in the elderly [50,58,59]. It is possible that older patients may prefer less active treatment for brain metastases, but we are unaware of any evidence to support this. These low WBRT rates may be driven by a lack of awareness of the benefit of WBRT in elderly patients [60]. Ensuring that elderly cancer patients receive appropriate diagnostic work-ups, and that health professionals, patients and their caregivers receive education on the potential benefits of WBRT in the elderly, may help ensure that the elderly receive appropriate treatment. Despite universal healthcare, our findings indicate that residents of richer communities are more likely to receive
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WBRT than residents of poorer communities and this is consistent with previous studies on palliative radiotherapy in the general cancer population [41,47], as well as those focusing on palliative radiotherapy rates in breast cancer [51], bone metastases [40] and non-small cell lung cancer populations [53]. Although there are no explicit financial barriers to radiotherapy access, there may be implicit financial barriers, such as securing transportation, time off work and childcare. There may be higher effectiveness in advocating for specialist treatment among patients and caregivers of higher socioeconomic status [40]. Some of the patient-related variations in WBRT use are consistent with appropriate case selection. Observed WBRT utilisation rates are highest in the primary cancers that are most frequently associated with brain metastases, such as lung, breast and melanoma [5,6,9,10]. WBRT is used less frequently in patients who would survive for only a short time, as reported in other contexts [40]. Estimating the duration of survival is difficult in this heterogeneous population and is often inaccurate [61], as it is with other cancer populations [62], and the further development of prognostic indexes will help identify which patient groups would potentially benefit from WBRT and which groups could be safely managed without WBRT [19]. Our findings have identified health system-related factors that are associated with increased WBRT utilisation rates: patients diagnosed in a hospital with a radiotherapy facility were more likely to receive WBRT than patients diagnosed in a hospital without a radiotherapy facility; patients who lived close to a radiotherapy centre were more likely to receive WBRT than those who lived further away. The prevailing waiting time for radiotherapy at the nearest radiotherapy centre was not significantly associated with the rate of WBRT use. Our data show that there were geographical variations in the rate of use of WBRT within counties across northern and southern Ontario. Many of the counties where radiotherapy centres were located had WBRT utilisation rates in the highest quintile. Together these results are similar to our previous findings for the use of palliative radiotherapy for bone metastases [40] and are consistent with other studies on accessibility [47,48,51,52,63,64]. Conversely, in other health care systems having no financial barriers to treatment, palliative radiotherapy utilisation rates have not been found to vary with proximity to treatment facility [65]. In the present study, increased travel times associated with living further away from radiotherapy centres may have deterred WBRT as a treatment decision by the patient’s health professional or as accepted treatment by the patient [40]. However, distance itself may not be a critical factor, but may reflect differing levels of awareness of the potential benefit of WBRT among local physicians. Disparities in the health system-related factors associated with WBRT use are modifiable and might be avoided by increasing the level of awareness among health care professionals that treat cancer patients and by improving patient access to consultation with radiation oncologists through establishment of outreach clinics or by the provision of additional radiotherapy centres.
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In the present study period, from 1984 to 2007, the overall rate of use of WBRT increased only slightly. Moreover, the associations between patient-related and health systemrelated factors remained constant over two decades. The disparities associated with identified patient-related and health system-related factors will probably continue to affect the use of WBRT unless active interventions are adopted to remove barriers to access. The total WBRT workload increased steadily over the study period due to the steady increase in cancer death, suggesting that providing WBRT use may become an increasing challenge for the health care system. A Swedish population-based study reported a doubling of admissions for brain metastases between 1987 and 2006 [66], while a population-based study in the Netherlands found no increase in the incidence of brain metastasis in patients with breast or lung cancer [5]. In the present study, the slight increase in WBRT use for brain metastases associated with primary lung cancer and breast cancer could be due to improved systemic treatment, leading to prolonged survival and an increased opportunity for the development of brain metastases. Improved imaging techniques with early detection of smaller tumours could lead to an apparent increase in the incidence of brain metastases [2,8] and could also contribute to the slight increase in WBRT use over time. This study examined the use of WBRT in one Canadian province, but it seems likely that the use of WBRT for brain metastases will prove to be affected by similar factors elsewhere in the world, particularly in other health systems that operate relatively centralised radiotherapy programmes. As our database is a large population-based cancer registry, our results should be generalised to other geographical areas with similar demographics. This will only be clear once similar population-based studies have been conducted in other health care systems. WBRT will continue to play an important role in the management of patients with brain metastases. Interventions designed to improve access to WBRT are needed, as well as ways to evaluate their effectiveness. Centralised radiotherapy centres should not only provide access to treatment, but should also act as a hub for the improvement of cancer management, quality control, training and advocacy. As the incidence of the indication for WBRT is generally unknown, we cannot comment on the magnitude of the unmet need for treatment. As we strive to deliver optimum care, we will also need to establish what the appropriate level of care is.
Acknowledgements This study was supported by grants from the Canadian Institutes of Health Research and Cancer Care Ontario. The authors thank Cancer Care Ontario, the Ontario Cancer Registry and the Ontario radiotherapy centres for access to their records.
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