In 2000, colorectal cancer accounted for approximately 579,000 deaths (equivalent to 1% of all deaths and 8% of deaths due to malignant neoplasms) worldwide. In burden-of-disease terms, colorectal cancer accounts for 0.38% of all DALYs and 7.2% of DALYs due to malignant neoplasms 1. Geographical disparities in the burden of colorectal cancer are pronounced. For example, colorectal cancer incidence rates are 5-10 times higher in the most developed regions of the world than in developing regions (personal communication, K.Shibuya, World Health Organization).

Cost effectiveness analyses of the many interventions (primary prevention, screening or treatment) for reducing the burden of colorectal cancer have usually been restricted to developed country settings and with often considerable variation in the analytical methods used. This limits the value of the existing literature to inform colorectal cancer control policies in low to middle-income country settings. Assessment of costs and effects of different strategies can help guide decisions on the allocation of resources across interventions, as well as between interventions for colorectal cancer and interventions for other conditions or risk factors.

This research presents estimates on the costs and effects of various combinations of available intervention strategies for colorectal cancer across regions using standardised methods, data sources and tools 2345678910 that have been developed by the WHO-CHOICE (CHOosing Interventions that are Cost Effective) program. The results should help answer policy questions such as whether and what type of screening programmes should be added in populations with a high level of access to treatment, or, in developing countries, whether to put scarce resources into screening or into expanding levels of treatment coverage. In addition, the study will facilitate the prioritisation process by allowing comparisons to be made, using similar methodologies, with interventions (whether, primary prevention, screening or treatment) for cardiovascular 11 and other diseases 12.

We present the results for three representative regions (Table 2]: AmrA, characterised according to the WHO rubrick 1 by high income ($I 31,477 GNP per head) and low child and adult mortality, EurC, characterised by low income ($I 6,916 GNP per head), low child and high adult mortality and AfrE, characterised by very low income ($I 1,576 GNP per head), high child and very high adult mortality.

AmrA (Canada, United States Of America, Cuba)Two main groups of interventions emerge in the AmrA region (Fig. 2) which are based on the results presented in Table 2.

The first consists of the screening interventions (with surgical removal of polyps) in an environment where treatment (in the form of surgery, radiotherapy and chemotherapy) was not provided. Campaigns to increase fruit and vegetable consumption are close to the expansion path (indicating the lowest costs per DALY for that level of resource usage) despite the omission of benefits from decreases in diseases besides colorectal cancer. However such an intervention only accounted for a small absolute reduction in DALYs. One-off colonoscopy at age 50 falls on the expansion path. However, because of the variability inherent in both the effectiveness (i.e: increase in DALYS saved) and cost estimates, it is unlikely that there are any significant differences in the cost per DALY generated by any of the screening methods, implying no one single method can be thought of as dominant. Interventions in this group are all very cost effective (including the use of the DRE) shown by their falling to the right of the broken-arrow line indicating the points where the cost per DALY are exactly equal to the GDP per capita.

The second group consists of screening interventions with treatment. Interventions in this group cost more and yield more DALYs than interventions in the first (no-treatment) group, although they are still very cost effective. In this treatment scenario, annual FOBT combined with sigmoidoscopy every five years is now indicated by being on the expansion path (Fig. 3), having an incremental cost effectiveness ratio (ICER) well below the GNP per head threshold. Once again due to variations in the estimates, no single intervention combined with treatment can be thought of as being superior to the others.

EurC (Belarus, Estonia, Hungary, Kazakhstan, Latvia, Lithuania, Republic of Moldova, Russian Federation, Ukraine)

Again two main distinct groupings emerge (Fig. 4) which are based on the results presented in Table 2. However the no-treatment group is less homogeneous than in AmrA. The one off screening interventions at age 50 (colonoscopy, sigmoidoscopy with and without FOBT) were very cost-effective as was sigmoidoscopy every five years and colonoscopy every ten years. The other screening interventions (including the DRE) were just cost-effective, falling between the dotted and dashed lines representing the three and one times the GNP per head thresholds respectively.

All the screening interventions with treatment are very cost effective falling to the right of the dashed line. As more resources become available the expansion path shifts interventions in the current scenario (characterised by medium levels of treatment coverage) to universal treatment, then to sigmoidoscopy at age 50, colonoscopy at age 50, to colonoscopy screening every 10 years, gaining the most DALYS when a combined FOBT and sigmoidoscopy programme is complemented by full treatment (Fig. 5).

The ICER of moving along the expansion path showed that all the interventions up to supplying colonoscopies every 10 years to be very cost-effective. However expansion to a combined FOBT and sigmoidoscopy intervention might be considered as just cost effective as its ICER is between one and three times the per capita GNP. Once again, no single intervention combined with treatment dominates.

AfrE (Botswana, Burundi, Central African Republic, Congo, Côte d'Ivoire, Democratic Republic Of The Congo, Eritrea, Ethiopia, Kenya, Lesotho, Malawi, Mozambique, Namibia, Rwanda, South Africa, Swaziland, Uganda, United Republic of Tanzania, Zambia, Zimbabwe)

As a result of cost differentials associated with programme implementation, there is a wide range of costs between screening programmes without treatment (Fig. 6) which are based on the results presented in Table 2. All of the screening interventions (in the no treatment scenario) were found to be not cost effective (ie: they fall to the left of the dotted arrowed line) due primarily to the lower incidence of the disease in the region.

Universal treatment, (ie: 100% treatment scenario), colonoscopy at age 50 (with polyp removal), colonoscopy every 10 years and sigmoidoscopy every five years combined with annual FOBT with treatment appear on the expansion path, only the first three being cost-effective (ie: falling between the dotted and dashed lines) (Fig. 7). However, using the yardstick that any intervention whose ICER is in excess of three times the per capita GNP is not cost effective, then adding any of the screening programmes to treatment will not be considered as being cost effective. Screening persons aged under 50 years old yielded less favourable cost-effectiveness ratios than commencing screening at age 50 years.

Cost-effectiveness estimates for developed countries (mainly USA and countries in Europe) have reported a wide range of incremental costs per life year for the colorectal cancer interventions examined in this, over and above that of treatment alone. Baseline costs per life year (in USD at 2000 price levels) relative to a no screening strategy for both the one-off and repetitive screening vary considerably. Seven studies reported costs per life year of $20,000 or more 49585960697071, eight reported in the range $10,000 - $19,999 4748565758596270, three between $5,000 - $9,999 555758 and three between $0-$4999 566488. Some models even indicated incremental cost-savings (alongside effectiveness gains), both for one-off 72 and repeated screening interventions 5672.

Such wide ranges in the cost-utility ratio and the subsequent lack of dominance of any one screening mode (reflected by different rankings between the screening methods) are a consequence of the heterogeneous nature of the model specifications (on the effectiveness side), variations in the duration of operation of screening programmes and wide variations in the estimates of the interventions unit costs. These ranged considerably, with sigmoidoscopy costing between six 69 to 27 times 70 that of FOBT, colonoscopy costing between 10 72 to 100 times that of FOBT 5766. Our estimates showed sigmoidoscopy and colonoscopy costs to be between 18 and 48 times that of the basic FOBT test. Additional research is clearly needed on estimating screening programme costs as these considerably affect the cost per DALY outcomes, especially in developing countries.

Our epidemiological model was simpler than most of published models and lacked refinements such as taking into account the distribution of multiple polyps and biphasic polyp dwelling times 68. In addition, our model did not include provision for more frequent screening of persons identified as having a polyp or with a familial history of CRC.

While our model was based on regional specific age and gender distributions, information on age-specific polyp incidence distribution was based only on available USA data. If a developing country's relative distribution of polyp incidence is skewed to a younger age than the USA, then this would mean that the screening programme would have a lower efficacy (unless screening ages were adjusted) and so our cost-effectiveness ratios are likely to be upwardly biased. On the other hand, our somewhat optimistic compliancy assumption that all persons screened positive on FOBT or Sigmoidoscopy would receive a subsequent colonoscopy served to downwardly bias the presented cost per DAYS, as some cases are likely to be lost to follow-up in practice.

Our estimated cost-effectiveness ratios for the incremental addition of various screening programmes to treatment (for comparability with the literature, discounted at 3% but not age-weighted; see Additional file 2) in AmrA of $800-$2,200 per DALY (for screening from age 50 to 80) and $2,400-$3,500 (for one-off interventions) fell towards the lower end of the wide spectrum of results presented in the opening paragraph of this discussion. This could be attributed to a variety of causes, such as the use of economic costs as opposed to charges or prices for procedures and the longer duration (relative to much of the literature) of the time-horizon used to evaluate our interventions. Inclusion of morbidity gains in our denominator reduced still further our ratios, although this was somewhat counterbalanced by our use of healthy life years in the denominator (as opposed to life years as reported in most of the literature).

In general the following policy recommendations could be inferred from our results. In subregions characterised by high income, low mortality and high existing treatment coverage (eg: AmrA subregion), both the incremental (ie: the additional cost per DALY of adding a screening programme to the existing treatment provision) and general (ie: compared to the null) cost-effectiveness results point to the very cost-effective nature of the screening intervention, although no particular specific intervention is indicated as being dominant.

In subregions characterised by low income, low mortality with existing treatment coverage around 50% (eg: EurC subregion), expanding treatment with or without combining it with screening programmes appears to be cost-effective or very cost-effective. Abandoning treatment in favour of funding screening programmes that would operate in a no treatment scenario would not be a cost-effective measure.

In subregions which have low income, low mortality and low treatment levels (eg; AfrE subregion), the best strategy is to provide resources to treat persons with colorectal cancer as opposed to providing a screening programme.

Use of the DRE alone was very cost-effective in the AmrA subregion and cost-effective in EurC. However it has low efficacy and provides a low level of absolute DALY gains. Despite its low technological approach, DRE is not cost-effective in the low incidence AfrE subregion. However, the low cost simple DRE (both with and without follow-up diagnostic colonoscopy), suffers from a lack of direct evidence that the exam reduces mortality from colorectal cancer, our modelled efficacy being based on a single no-significant result (OR = 0.96, 95% CI 0.56-1.70) from a case control study from northern California 18. Sensitivity is low, as fewer than 10% of colorectal cancer causing polyps are within reach of the examining finger. There is therefore no solid basis for recommending this method as a stand alone screening intervention for colorectal cancer. Moreover, a comprehensive assessment of this intervention should include its effect on reducing mortality from prostate cancer.

Like the digital rectal examination, the introduction of a fruit and vegetable campaign gains fewer DALYS then any of the screening interventions. Such a campaign was however found to be very cost effective in AmrA even without the inclusion of additional benefits resulting from decreases in other diseases. The fruit and vegetable campaign was marginally cost-effective in EurC, but was not cost-effective at all in AfrE. However, the external validity of applying the effectiveness results from one health promotion campaign in Australia 55 to other regions of the world can be questioned.

The 20% price subsidy will actually be less effective than health promotion in increasing fruit and vegetable consumption, and hence in reducing colorectal cancer. Estimating the economic cost of such an intervention is beyond the scope of this paper. Moreover, an evaluation of such an intervention requires the effectiveness benefits of reductions in heart disease, stroke and other cancers to be included. The cost per DALY, however, might be underestimated since the income freed up by the food subsidy might result in increased consumption of red meat, which could well be a risk factor for colorectal cancer 2627.

Our use of a single measure of relative risk reduction for each age and gender specific intervention simplifies the reality, where the risk reduction and subsequent cost-effectiveness ratio can differ depending on the socio-economic context of the screening subgroups 88. One could also argue that present models on colorectal cancer screening are inadequate for aiding public health decision-making because the efficacy evidence is too preliminary for any screening modality other than FOBT 89. Lack of such randomized controlled trial evidence precluded an evaluation of immunological FOBT testing, which is likely to yield lower costs per QALY than guaiac-based tests 61, due to the higher sensitivity of immunological FOBT to detect colorectal neoplasms 909192 outweighing increased unit costs. Our analysis also did not consider the options of targeting screening to high-risk populations which despite reducing the overall DALY gains may well increase the cost-effectiveness of the interventions 51.

The CEAs presented represent first order point estimates of various interventions. When allowance is made for variations of the estimates by sensitivity analysis then it appears there is no clear discernable difference in terms of cost-effectiveness between the major screening options. Perhaps another key factor in deciding what option or mix of options to adopt, would be those interventions which have the highest expected attainable coverage rates. Adoption of screening policies between the ages of 50 and 80 will only eradicate a small portion (between 14%-24%) of the existing colorectal cancer burden, since the application of the compliancy rate to the intervention efficacy, even in the case of colonoscopy every 10 years will only result in a 24.1% reduction in incidence. One-off screening policies will reduce an even lower percentage of the total disease burden.

The cost-effectiveness ratios are insensitive to changes in compliancy, particularly in scenarios that include access to treatment and where programme operational overheads are low. Basically, the increases or decreases in programme efficacy resulting from changes in compliancy are somewhat counterbalanced (except for the programme cost overheads) by decreases or increases in costs.

The cost-effectiveness ratios are also biased upwards (or downwards) to the extent that transport costs and costs of work lost due to treatment exceed (or are exceeded by) the transport costs and costs of work lost due to screening 9394.

Decisions to adopt interventions are usually made by health services and governments at the country level. Although the model used in this analysis is based on regions, the parameters defining the model can be adjusted to country level.

CEA: Cost Effectiveness Analysis; CFR: Case Fatality Rate; CHOICE: Choosing Interventions that are Cost-Effective; DALY: Disability Adjusted Life Year; DRE: Digital Rectal Exams; EIP: Evidence and Information in policy; FOBT: Fecal Occult Blood Test; GBD: Global Burden of Disease; GCEA: Generalized Cost Effectiveness Analysis; GNP: Gross National Product; HSV: Health Status Valuation; ICER: Incremental Cost Effectiveness Ratio; Ln: Natural Logarithm; POPMOD: A state transitional population model; PPP: Purchasing Power Parity; HO: World Health Organization.

This study was undertaken by persons who were on the salaried staff of the WHO at the time of the study. None of the authors have any competing interests.

GG collected data, designed, calculated and wrote up the study. SL provided technical assistance with the modelling and commented on earlier drafts. JL provided technical assistance with the modelling and wrote up the study. BJ provided assistance on the costings. CS provided assistance related to the medical and epidemiological aspects.

All authors have read and approved the final manuscript.