A systematic review of geographical variation in access to chemotherapy

Background Rising cancer incidence, the cost of cancer pharmaceuticals and the introduction of the Cancer Drugs Fund in England, but not other United Kingdom(UK) countries means evidence of ‘postcode prescribing’ in cancer is important. There have been no systematic reviews considering access to cancer drugs by geographical characteristics in the UK. Methods Studies describing receipt of cancer drugs, according to healthcare boundaries (e.g. cancer network [UK]) were identified through a systematic search of electronic databases and grey literature. Due to study heterogeneity a meta-analysis was not possible and a narrative synthesis was performed. Results 8,780 unique studies were identified and twenty-six included following a systematic search last updated in 2015. The majority of papers demonstrated substantial variability in the likelihood of receiving chemotherapy between hospitals, health authorities, cancer networks and UK countries (England and Wales). After case-mix adjustment, there was up to a 4–5 fold difference in chemotherapy utilisation between the highest and lowest prescribing cancer networks. There was no strong evidence that rurality or distance travelled were associated with the likelihood of receiving chemotherapy and conflicting evidence for an effect of travel time. Conclusions Considerable variation in chemotherapy prescribing between healthcare boundaries has been identified. The absence of associations with natural geographical characteristics (e.g. rurality) and receipt of chemotherapy suggests that local treatment habits, capacity and policy are more influential. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-2026-y) contains supplementary material, which is available to authorized users.


Background
Cancer is the leading cause of mortality in the United Kingdom (UK) [1]. Cancer incidence is rising and so too is the proliferation of high-cost, life-extending cancer drugs. There are potential restrictions on access to cancer drugs in the UK National Health Service (NHS) at a number of levels: national policy; regional and local commissioner and provider activity; clinician prescribing preferences, and individual patient care seeking behaviour [2][3][4]. The UK was ranked 12th of 14 European countries for the prescribing of cancer pharmaceuticals launched in the last 5 years [5]. Within the UK, there has been considerable attention on regional variation in prescribing [6,7] and this was a major factor in the establishment of the National Institute for Health and Care Excellence (NICE) in 1999; an attempt to ameliorate the so called, 'postcode lottery of prescribing'. The recent restructuring of the NHS, with a move to Strategic Clinical Networks, (SCNs) instead of Cancer Networks; the continued trend for centralisation of cancer services to drive quality and efficiency improvements, and divergent cancer drugs funding policy, with the establishment of the Cancer Drugs Fund in England, but not in Wales, Scotland or Northern Ireland, are all important changes that may impact on equity of cancer pharmaceutical prescribing by geographical region.
' Access' to cancer drugs, encompasses the quality, equitability, acceptability and availability of chemotherapy for those in need [8]. The term chemotherapy is frequently used in the literature to represent anti-cancer drugs, although chemotherapy can represent any-drug therapy or specific anti-cancer therapies that exclude hormonal treatments or radiopharmaceuticals for instance. For the purpose of this paper chemotherapy is used interchangeably with anti-cancer drug therapy to capture all relevant papers. It is challenging to measure access and therefore rates of utilisation alone are frequently used as a proxy. Utilisation may appear appropriate for the size of population under study, but instead represent health demand, rather than clinically assessed 'health need' and in some circumstances, mask inequitable use of services [9]. Furthermore, variation may result from explicit resource allocation decisions, such as the decision by Wales not to have a Cancer Drugs Fund, prioritising spend earlier in the cancer pathway. However, poor uptake of cancer drugs has been associated with reduced life expectancy in correlational studies [10] and therefore, variation in use or access to these drugs where it is unwarranted according to clinical need may represent a threat to health. Variation may be considered inequitable and contrary to the NHS constitution [11] if it is the result of opaque healthcare boundary differences in provision or 'natural' geographical barriers (e.g. distance).
Three systematic [12][13][14] and seven literature reviews [3,4,[15][16][17][18][19] have considered diffusion of pharmaceuticals and innovations in developed and developing nations alongside distribution and uptake of other cancer treatment modalities. However, none of these reviews are systematic accounts of barriers to access to cancer pharmaceuticals. The international literature includes surveys of patient perceptions of the role of rurality or distance to treatment in their chemotherapy decisionmaking and both found evidence that the distance to treatment has an influence on uptake or compliance with treatment options for their cancer [20,21]. Widely cited, grey literature publications in the UK, comparing chemotherapy utilisation by healthcare geographical area: England vs Wales vs Scotland; Strategic Health Authority (SHA) or Primary Care Trust level, have found large variation [22,23]. Exploring and quantifying this variation and the reasons for variation in chemotherapy prescribing by geographical area is therefore important for quality, equitable care for NHS patients.
We aimed to systematically identify published studies considering geographical barriers to use of cancer pharmaceuticals in the UK NHS.

Search Strategy
The review methodology was performed in accordance with the Centre for Reviews and Dissemination (National Institute for Health Research [NIHR]) guidance on systematic reviews [24,25] and reported according to the PRISMA statement, checklist (Additional file 1) and flowdiagram [26]. A systematic literature search was carried out using electronic databases, electronic citation tracking (ISI Web of Knowledge citation indexes), hand-searching of references identified in eligible studies, and greyliterature searching. The search strategy was tailored to each electronic database to account for differing wildcards and system features. Search terms included key words, synonyms and MeSH terms for cancer drugs OR access OR inequality. The search strategy was written by the first author and refined by a medical librarian (CB) and an experienced systematic reviewer (MB). Scoping took place between September and December 2012, with a formal search run by the experienced systematic reviewer (MB) in March 2013. An update of the electronic database search was conducted in July 2015 by the first author (CC). A list of the nine interrogated electronic databases, including MEDLINE and EMBASE is available in the Additional file 2 along with the search strategy. Informal approaches are also described in the Additional file 2 and included Google and specific health and health policy websites (last updated in July 2013).
The search strategy was kept deliberately broad to include all potential barriers to chemotherapy utilisation, including policy and system barriers; environmental context obstacles (including geographical barriers), and challenges resulting from variation in individual patient characteristics (such as age or gender) affecting professional prescribing and appropriateness of services.

Study Eligibility
Papers were classified according to three themes: 'policy/ systems' , 'geographical' and 'individual patient characteristics' , and where eligible for more than one theme, were included in all suitable themes. Eligible studies which did not have geographical exposure variables were excluded from this report, for future study under other theme headings. The primary outcome measure was receipt of chemotherapy, defined by prescribing data.The exposure was geographical healthcare boundary (e.g. cancer network, strategic health authority, acute hospital trust), or other measured geographical characteristic, such as population density (rurality), distance to treatment centre, or travel-time to treatment centre. Inclusion criteria includeddescription of cancer pharmaceutical prescribing in adults (>18 years) in the UK NHS. All cancer drug prescribing, including reports of sub-optimal or delayed prescribing were included. Geographical chracteristics of natural geographical boundaries (testing the influence of rurality, time or distance to treatment) or healthcare geographical boundaries (including healthcare designated areas arranged by policy or organisation, such as acute trust or cancer network) and their influence on chemotherapy receipt were all eligible for inclusion. There were no time or language limitations to the eligibility criteria. Exclusion criteria included papers which focused on all pharmaceuticals and not primarily cancer pharmaceuticals, conference proceedings, quantitative papers with <30 participants or commentary pieces. Study quality was considered, but studies were not excluded on grounds of quality alone.

Study Selection
Title and abstract screening was performed by CC using EndNote software, with independent double-screening (JB) of a sample of abstracts to assess reliability (5 % of CC excluded abstracts and all CC included abstracts). In the event of uncertainty, studies were included for fulltext review. Disagreements were to be resolved with discussion and consensus between JB, CC and WH.

Data Extraction
Pre-defined data items, as per the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist headings (e.g. study design, outcome and exposure variables, methods, analysis approach and results amongst others) and study description (author, year, title, journal), whether the manuscript was peerreviewed, and whether it met the eligibility criteria and if not, why not (reason for exclusion) were extracted from each full-text study in Microsoft Access (CC). Principle summary measures included Odds Ratios (odds of receipt of chemotherapy by the geographical exposure) as well as descriptive statistics with proportions and percentages and appropriate statistical tests (e.g. t-test).

Analysis
Reporting clarity was evaluated with the STROBE observational checklist and methodological quality with the NICE adapted Graphical Appraisal Tool for Epidemiological studies (GATE) [27]. Narrative synthesis was performed by the first reviewer (CC) and verified by the senior author (WH). The objectives of the systematic review were peer-reviewed as part of the NIHR Doctoral Fellowship award. A protocol was not publicly listed.

Results
5,987 unique titles and abstracts (5,961 identified from electronic bibliographic databases and 80 from other sources) were screened, after removal of duplicates (54) in March 2013. An additional 2,894 studies were identified from a repeat of the systematic search strategy of the included electronic databases (July 2015, 2,793 after removal of duplicates [101]). Of 344 double-screened included and excluded abstracts, one initially excluded paper was included in the final analysis. Initial exclusion referred the paper to a different theme and was an error based on mistaking the use of geographical exposure variables, as well as individual characteristics, as part of the study design. Twenty six papers, following the update, were included in the analysis: 16 peer-reviewed and 10 from the grey literature (Fig. 1). Nine grey literature studies were annual National Lung Cancer Audit (NLCA) reports [28]. For simplicity, only one NLCA report is presented in the tables and referenced in the report. All earlier reports follow the same template and are available online. Six included studies referred to multiple cancer types [6,[29][30][31][32][33] 15 to lung cancer only [34][35][36][37][38][39] four to colorectal cancer [40][41][42][43], and one in prostate cancer [44]. Table 1 presents study characteristics and Tables 2-7 present the key findings. Additional file 3: Table S1 describes the reporting quality and Additional file 4: Table  S2-S8 the methodological quality of the included studies.

Characteristics of included studies
Twenty-four cohort studies [28-32, 34-43, 45], one correlational study [6] and two before and after studies [30,33] were included in the review. Identified geographical exposure variables included: travel time or distance to a cancer treatment centre; rurality; and geographical area, defined by healthcare boundaries (e.g. acute hospital trust, cancer network or SHA). The majority of included studies relied on analysis of cancer registry data, with or without linkage to hospital records for co-morbidities [29, 31, 35-38, 40-42, 44]. Remaining data sources were IMS Health hospital prescribing data [6,30,33], local hospital data [32] and nationally collected audit data [34,39,46].
Four different tools measuring deprivation were used in the included studies: Index of Multiple Deprivation (IMD) [28,36,38,40,42] Carstairs [29,41], DepCat [43], Townsend [37,39] or none [6,32,33,45]. Rurality was defined and measured in different ways. Campbell et al. [29] defined rurality by the 'distance to the nearest cancer centre in Aberdeen or Inverness, which, based on previous research implied low settlement size and rurality'. Laing described rural areas according to a "pre-existing classification" of an area as "accessible rural or remote-rural" (Highland and Western Isles) and compared it with Lothian, a "large urban or other urban" area. [45] Where these definitions of the rurality of the population are derived from is not included, though it is implied this may use the rural urban classification used by the UK Government [47]. McLeod [41] and Pitchforth et al. [43] defined 'rurality' using population density (persons per hectare) based on census data, which presumably coincides with Urban-rural classification, but has not been assessed.

Reporting Clarity and Quality Assessment
The poorest reported areas were inclusion of a participant flow-chart; reporting of study design in the title or abstract; description of study result generalizability and missing data fields. Many papers did not report on efforts to limit bias. Additional file 3: Table S1.    'NICE GATE adapted quality appraisals' are presented in Additional file 4: Table S2-S8. Areas of potential selection bias, such as moving residence between cancer registration and treatment (cross-border flows) or the use of the 'nearest' geographical treatment centre to calculate distance, which may not be the treating hospital, was poorly considered in the majority of studies. Other potential selection biases included variability in the criteria for chemotherapy or poorly defining the population eligible for treatment in different geographical areas, inappropriately inflating or deflating some trusts/networks/SHA patient denominators. Finally, the exclusion of missing data may also introduce bias.

Narrative Synthesis
Since meta-analysis was not possible due to the heterogeneity of included studies, a narrative synthesis relying more heavily on those studies with strong reporting and methodological quality follows.

Distance travelled/travel time
Four studies examined distance or travel time and chemotherapy receipt (lung and colorectal cancer). No evidence of an association was demonstrated for distance to treatment centre and receipt of chemotherapy in a study based on low numbers (only 77 lung cancer patients and 114 colorectal cancer patients received chemotherapy). (15) Of three studies examining travel time to centre and receipt of chemotherapy, one study found no evidence of an association for colorectal cancer chemotherapy [40], but the remaining two studies had limited single quartile associations, which conflicted in the direction of their association [31,36]. The largest study considered multiple cancer types [31]

Rurality
There was no good evidence of an effect of 'rurality' on receipt of chemotherapy for colorectal cancer with three studies (two of which overlapped for two years of registry data) showing statistically non-significant trends of a positive association of increasing rurality with receipt of chemotherapy [41,43]. Although one study appreared to show later cancer stage at presentation and poorer survival for rural popuations of men with prostate cancer, the disease stage was not adequately adjusted for and the "percentage of patients undergoing chemotherapy or watchful waiting" was the same same between the rural and urban populations (p = 0.12) [45]. However, the study did show a marginal difference in receipt of hormonal therapy between the rural Highlands and the Western Isles and the more urban Lothian (No adjustment by disease stage). The Highlands and Western Isles received less hormonal therapy, 16 % v 19 % respectively, P = 0.042 [45].

Healthcare boundaries Country
Only one study considered inter-country variation in cancer prescribing the UK. (Chamberlain et al.) [30] Prescribing of some high-cost cancer drugs was found to be up to seven times higher in England than in Wales. Only three of the fifteen drugs reviewed showed higher prescribing in Wales, compared with England-all three were drugs released around the time of the introduction of the Cancer Drugs Fund in England and were later found to be cost effective [30]. Results were not case-mix adjusted, but compared per 100,000 head of population only.
Not adjusted 0.12 Jack et al. [37] was the only included study which fully adjusted for case-mix (age at diagnosis, stage, histological sub-type, deprivation quartile and gender) and found rates of chemotherapy varied between 26 SHAs from 4 to 17 %. No test for statistical significance was performed for receipt of treatment by SHA.

Cancer Network
Cancer network level variation in chemotherapy prescribing was found in all studies in which it was examined [6,28,34,38]. Only two studies quantified the inter-network variation with summary statistics, rather than a range. A chisquared test for heterogeneity between cancer networks was performed (χ2 = 927.5, P < 0.001) in one study (8)where there was a more than four-fold difference between the lowest adjusted proportion receiving chemotherapy (6.1 %) and the highest (27.7 %). Variation was also expressed as a ratio of the 90th percentile to the 10th percentile of volumes prescribed in another: the findings suggested a range for inter-network variation from 2.6 fold variation (Rituximab) to an 11.6 fold variation (Temozolamide) [6]. Adjusted ORs for the most recent NLCA data, resulted in no evidence of a statistically significant different odds of receiving any chemotherapy in patients with Small Cell Lung Cancer (SCLC) in any cancer network, with the exception of one network (OR 1.9, 95 % CI 1.2 to 3.0). However, a much greater number of networks were statistically significantly different from the whole lung cancer audit population in the odds of receiving chemotherapy for Non-Small Cell Lung Cancer (NSCLC) (Stage IIIb/IV PS 0 or 1). Nine (of 30) cancer networks had statistical evidence to reject the null, with a range of 0.4 (0.3 to 0.6) to 1.9 (1.3 to 2.8) indicating nearly five times (4.7) greater prescribing in the highest, compared with the lowest prescribing cancer network [46].

Acute hospital trust
All four studies considering geographical variation at the Trust level also found evidence of variability in chemotherapy prescribing. There were, however, no summary values for the degree of heterogeneity or variation between the trusts in any of the reviewed studies. Two cohort studies [39,41] assessed variability in access to chemotherapy for colorectal and lung cancer and found persistent variability, with the percentage of patients receiving chemotherapy per trust ranging from 0 to 68 %, with a median of 3 % in McLeod [41], compared with a range of 14 to 86 % (median of 62 %) in Rich et al. [39]

Main findings
There is clear evidence of variation in chemotherapy use by geographical area, implying that even in the post NICE era, a postcode lottery in prescribing is still present. The cause of the geographical variation appears to be associated with healthcare boundaries, i.e. cancer network, and SHA level, associated with policy makers, commissioners and providers, rather than 'natural geographic factors' such as time or distance to chemotherapy centres, or rurality of the patient population. The best quality, case-mix adjusted studies demonstrate a 4-5 fold difference in chemotherapy receipt by network [38,46].

Strengths and Limitations (study and synthesis level)
Strengths of this review include the use of a systematic methodology to identify all relevant articles, including peer-reviewed, grey-literature and citation searching. There are no other systematic reviews pertaining to cancer drugs access in the NHS, despite the importance of this area for quality and equitable care in the NHS. Strengths at the study-level are the number of studies published in peer-reviewed sources which have attempted to adjust for differential case-mix. The major limitation of this review was the challenge of designing a sufficiently inclusive search strategy in an area that has no pre-existing search filters. We were also unable to conduct a meta-analysis due to the heterogeneous study designs, which lack a unifying measure of geographical variation and variably adjusted for case-mix or stratified for deprivation. Arguably, by making the search strategy as inclusive as possible to capture all barriers to chemotherapy access, the search specific to geographical barriers did not use specific geographic key words and therefore may have missed some papers.

Confounding
The most significant limitation of the included studies is the absence of case-mix adjustment, particularly stage and performance status. Those studies with no case-mix adjustment risk introduced bias where apparent differences (or lack of differences) between healthcare areas may refect differing health need in the study population. This bias may under-or over-estimate the relationship between geography and receipt of chemotherapy. Many studies adjusted for deprivation [29,31,37,38,40]; however, it is uncertain whether adjusting for this potential confounder may in fact artificially reduce and mask the association with geography and likelihood of receipt of chemotherapy.Stratifying by deprivation [36,40] may have been a more appropriate way to accommodate the potentially modifying variable. In addition, studies used different deprivation indices (Carstairs, DepCat, IMD (or Scottish IMD) for adjustment. While these scales are similar, they have differing underlying assumptions, which may marginally contribute to differing findings. Finally, studies which are not based on population-based denominators, such as acute trusts, where the denominator reflects differential referral patterns, may result in non-equivalent populations which are challenging to compare. The review has therefore focused on cancer networks and health authority level data which have more comparable populations. The minor variations in study populations (e.g. uncertain use of DCO cases, restriction of included centres by size) do not clealy map to differences in outcome results. The differences clearly may contribute to a risk of bias and therefore studies are combined narratively, rather than statistically. Finally, although there are observed differences in chemotherapy utilisation, these differences cannot be translated into clinically 'good' or 'bad' outcomes. Outliers with high or low chemotherapy usage may both reflect poor clinical care [5,6].

Comparison with previous literature
Despite the number of papers describing variation nationally and internationally there have been no systematic reviews establishing the obstacles and facilitators to access to cancer drugs in the NHS or in any other publiclyfunded health systems. One recent Canadian literature review [19] described 32 studies pertaining to inequitable access to cancer care (not solely pharmaceuticals) associated with geography including: variability between geographical regions affecting access to cancer treatments, rural vs urban barriers and distance/time travelled. Regional access to chemotherapy by healthcare boundaries for lung cancer was shown to vary between studies, supporting our review findings [19]. This review also described an association between greater distance to a cancer centre and reduced access to chemotherapy and palliative radiotherapy. Neither of the two papers referenced in the article provide evidence of an association between increasing distance and decreasing chemotherapy access, although there is an association with radiotherapy [48,49]. The international literature also finds evidence of variability in chemotherapy access by healthcare boundaries, with less papers considering 'natural' factors of time or distance to treatment centre specifically [50].
The most comparable UK literature includes a recent review [2] which covers variability in access to NICE recommended pharmacotherapy, (not solely those specific to cancer). The literature review summarises some of the potential causes for the 'gap' between recommended and actual cancer prescribing in the UK, such as gaps in molecular testing by healthcare region (e.g. tests for the Epidermal Growth Factor Receptor [EGFR] mutation which is required before the prescription of some newer anti-cancer drug prescribing). Widely cited, grey literature UK publications prior to this review, which have been excluded due to inadequate outcome measures [51,52], may have been misleading, having no case-mix adjustment and comparing geographical areas across different time periods, rendering the apparent three-fold (Scotland) and five-fold (Wales) reduction in access to chemotherapy compared with England hard to interpret. However, a peer-reviewed study, released in 2014 supported evidence of growing inter-country variation in chemotherapy prescribing between England and Wales following the introduction of the Cancer Drugs Fund (in England, not Wales) with an up to seven-fold difference in prescribing of chemotherapy [30].

Implications for research and practice
International data have shown the UK to have a lower than average adoption of cancer drugs released in the last five years, when compared with other high-income countries [5]. In 2010 the UK government established the Cancer Drugs Fund to address this seeming 'drugs shortfall' in England. However, the devolved UK countries of Northern Ireland, Scotland and Wales did not introduce equivalent Cancer Drugs Funds. These different policy directions will logically increase the geographical variation between UK countries. The results of this review lend weight to the evidence that variation in chemotherapy prescribing is occurring at different healthcare boundaries, such as the variation in prescribing between England and Wales [30] and these may be more important policy areas to intervene for equitable prescribing than adjusting for time and distance travelled to cancer treatment centres. Distinguishing between explicit policy decisions which lead to differential prescribing and implicit conventions, such as local individual prescriber variation is important to ensure equity of access to chemotherapy. There are limited longitudinal analyses of variability in access to cancer drugs over time, which could improve understanding of the effects of various health reforms on utilisation of cancer drugs. The study of geographical variation would benefit from a standardised methodology and outcome measures for the conduct of studies, so that future studies may synthesise summary estimates of variation.
System process factors, including multi-disciplinary meetings, the role of assigned specialists, and cancer nurse specialists should be explored [53][54][55][56] as potential sources for variation in prescribing by geographical region. Finally, once variation in chemotherapy prescribing has been identified by geographical region, as in this review, the clinical significance of that variation, where both under-or over-use may be problematic, needs to be considered in the context of overall survival.