Shift to earlier stage at diagnosis as a consequence of the National Bowel Cancer Screening Program

Stage at diagnosis is critical in determining the probability of survival with colorectal cancer (CRC). In randomised controlled trials, population screening using faecal occult blood tests (FOBT) results in earlier stage at diagnosis for screen-detected cancers,1 and reduced mortality from colorectal malignancy compared with controls.2-4 Evaluations of cancer prevention programs with mortality as an end point take many years to complete. However, we know that early stage at diagnosis is linked to better prognosis and reduced mortality from CRC, so stage at diagnosis can serve as a surrogate marker for population mortality, and provides an early signal of program benefit.

After a pilot study in 2003, a faecal immunochemical test (FIT)-based National Bowel Cancer Screening Program (NBCSP) has been progressively rolled out across Australia. Participants in the program receive a free two-sample FIT kit by mail from a central register, collect samples and return them for testing. Results are mailed to participants and their nominated primary care practitioner (PCP). The PCP arranges follow-up of people with positive FIT results.

There is mandatory reporting of CRC in Australia, and the South Australian Cancer Registry (SACR) holds up-to-date records of CRC diagnoses in South Australia, including tumour stage. Thus the data held by the SACR and the NBCSP register records provide an opportunity to evaluate the effect of the NBCSP, as implemented in SA, on CRC stage at diagnosis.

Our primary aim was to determine whether CRCs diagnosed in people who had been invited to the NBCSP were diagnosed at an earlier stage than CRCs diagnosed in people not invited to the program. Our secondary aim was to determine whether downstaging was evident in the subpopulations that participated or that had positive test results in the screening program.

Patients were eligible for inclusion if they had CRC that had been reported to the SACR with a date of diagnosis between 1 January 2003 and 31 December 2008, and if they were aged 55–75 years at the date of diagnosis. This date and age range ensured inclusion of individuals invited to have a screening test in the NBCSP pilot program in SA (February 2003 to June 2004, with eligible participants aged 55–74 years on 1 January 2003) or in the NBCSP Phase I (22 January 2007 to 30 June 2008, with participants eligible if they turned 55 or 65 years of age in that period).

We compared the stage profiles of eligible patients invited to the NBCSP (invited), those who took up the offer to have a screening test (participant) and those who had positive results in the screening test (positive), relative to the stage profile of the study population excluding the group of interest (all other patients), on an intention-to-screen basis. Patients were allocated to the invited, participant and positive cohorts if their date of diagnosis was between 15 and 365 days from the date of invitation to participate in the NBCSP pilot program or Phase I trial. Finally, to gain some insight into the value of an invitation alone, we compared the stage profiles of patients who were invited to the NBCSP but did not participate in testing with those of patients who were not invited.

CRC stage was defined according to the Australian Clinico-Pathological Staging System (ACPS), with stages graded from A to D in order of increasing disease spread.5 Experienced SACR staff extracted ACPS stage from clinical reports. Where stage data were incomplete, additional information was sought from three public hospital-based cancer registries.

A list of invitees to both the NBCSP pilot program and Phase I trial was obtained from the NBCSP register. The Australian Institute of Health and Welfare carried out data-matching and provided a merged and de-identified dataset with, for each individual, CRC stage at diagnosis, NBCSP invitation status, NBCSP participation status, FIT result, age, sex, socioeconomic status (SES) and remoteness index data. Cohort stage profiles were compared by χ2 analyses. Multinomial logistic regression was performed using Stata version 12 (StataCorp) to control for possible differences between cohorts in age, sex, SES and geographical remoteness.

Ethics approval was obtained from the SA Health Human Research Ethics Committee and the Department of Health and Ageing Departmental Ethics Committee. Additional approvals were obtained from the Epidemiology Branch, SA Health, for access to the SACR; from the Royal Adelaide Hospital, Queen Elizabeth Hospital and Flinders Medical Centre for access to hospital-based registries; and from Medicare Australia for extracting data from the NBCSP register.

We identified 3481 eligible patients with CRC reported to the SACR. Of these, 221 were allocated to the invited cohort. Staging data were available for 87.0% of patients: no data were available for 6.6%, and a further 6.4% had insufficient data to determine ACPS stage. The invited cohort differed significantly from all other patients in age, SES and remoteness (Box 1).

In this intention-to-screen analysis-based evaluation of the NBCSP, we found that CRCs diagnosed in people within 1 year of receiving an invitation to participate in the screening program were on average at an earlier stage than CRCs diagnosed in people who did not receive an invitation. There was a large and highly significant increase in stage A lesions and a corresponding decrease in stage D CRC in those invited to the program relative to the rest of the study population, and the shift towards earlier stage progressively increased in participants in the screening test and in those who were recorded as having positive results in the FIT. Thus CRC downstaging was associated with an invitation to the NBCSP, and the strength of the effect increased in groups that excluded non-participants or people who had negative results in the FIT.

Downstaging was evident regardless of the inclusion or exclusion of patients with missing or insufficient data to determine staging. In addition, in a multivariate model, the relationship between early stage and screening through the NBCSP persisted when possible confounders — age, SES and remoteness — were taken into account.

Earlier detection of CRC has a major impact on survival. United Kingdom data show 5-year relative survival rates of > 90% for Dukes’ stage A cancer and < 7% for Dukes’ stage D (Dukes’ cancer stages are graded A–D in order of increasing spread and metastases).6 As randomised controlled trials have shown that CRCs detected through screening are diagnosed at an earlier stage, and screened populations had reduced mortality relative to control populations,1-4 it is valid to use downstaging as a surrogate for effect on mortality. The significantly earlier stage profile in patients who participated in the NBCSP should lead to reduced mortality rates in this population. Although at the moment, only a relatively small proportion of the eligible Australian population is offered screening each year, the proposed gradual expansion of the NBCSP should result in greater reductions in CRC mortality over time, assuming that participation rates remain stable or increase.

Our findings are consistent with an earlier report using a hospital-based database of CRC patients, which showed an earlier stage distribution in people self-reporting that they were diagnosed through the NBCSP, compared with stage in symptomatic patients (ACPS stage I, 40% in those diagnosed through the NBCSP versus 14% in non-participants; and stage IV, 3% in those diagnosed through the NBCSP versus 15% in non-participants).7 However, that study did not assess all CRCs diagnosed in the entire population. Further, the study was subject to recall bias and did not analyse results on an intention-to-screen basis. Our study included all cases of CRC reported to the SACR over the periods of implementation of the NBCSP pilot program and Phase I trial, and was based on an intention-to-screen analysis, which has allowed us to avoid sampling, temporal and follow-up quality bias.

Our results are also consistent with overseas evaluations of national CRC screening programs, although the methods used vary depending on the health system. The National Bowel Cancer Screening Programme in England reported a shift towards earlier stage disease in participants compared with patients with cancer diagnosed before the screening program.8 However, it is difficult to determine whether that downstaging represents improvement in practice over time or whether it was a direct result of the program. A decrease in the proportion of more advanced stage tumours for both men and women (but significant only in men) was also seen in the early stages of the English bowel cancer screening program, in a comparison of those who took up the offer of screening with those who did not,9 but the effect was not compared with stage distribution in patients diagnosed outside of the program. The Scottish CRC screening demonstration pilot study found a high proportion of cancers at Dukes’ stage A (almost 50%) when screening with guaiac faecal occult blood testing (gFOBT).10 A similar high proportion of stage A cancers was observed in the French pilot study.11 Unlike the overseas programs, Australia’s NBCSP uses the FIT, and this is the first report of downstaging in a mass screening program using this testing method.

It was important to analyse the program in the first instance on an intention-to-screen basis as an impact at such a level demonstrates the value of the public health program and justifies its implementation.

This study has several strengths. Data were obtained from independently held and well managed databases, and individuals were matched across databases, and then de-identified by an independent third party, before analysis by the investigators. Selection bias was minimised, if not removed altogether, as it is unlikely that there was a difference between the proportions of CRCs reported to the SACR among NBCSP participants and the proportion reported among patients diagnosed outside of the program. All CRC diagnoses in the study population resulted from usual follow-up of patients after testing through the existing public and private primary care systems, and thus there were no systematic biases in the type of follow-up received by each cohort or in the time from referral to diagnosis. Additionally, stage data were extracted and interpreted by experienced SACR staff from histopathology reports. The cohorts examined had similar low proportions of patients with unknown CRC stage because of missing or insufficient data. Finally, this was a whole-of-population study that compared CRC stage at diagnosis of populations differing only in screening invitation status.

Although this is an observational study and it could be argued that other factors might have influenced stage, it was possible to adjust for a number of potential confounders. A second concern was that it was impossible to directly attribute an invitation to the NBCSP to a specific diagnosis of CRC. However, allocating patients to the invited cohort on the basis of a diagnosis between 14 and 366 days from the date of invitation is reasonable, considering the time taken for the clinical steps to final diagnosis after a positive test result; 14 days would appear to be the shortest time to a diagnosis. This timeline from the date of referral for colonoscopy to a diagnosis of CRC is consistent with results of studies across different health systems.12

In the context of a national CRC screening program with normal follow-up care for patients after testing, CRCs were diagnosed at a significantly earlier stage in people who had been invited to the program compared with people not invited to the program. Benefits were even greater in screening participants and those with positive results in the FIT. These results show that CRC screening works in practice and is likely to reduce CRC mortality in Australia.

2 Distribution of colorectal cancer stage in patients (where stage was known; n = 3026) according to whether they were invited to participate in the National Bowel Cancer Screening Program (NBCSP)*

ACPS = Australian Clinico-Pathological Staging System. * Only patients with known colorectal cancer stage are included in sample shown; patients with missing or insufficient stage data are excluded.