NIHR DC Discover

NIHR Signal Blood tests alone are not sufficient for detecting recurrent bowel cancer

Published on 1 March 2016

doi: 10.3310/signal-000207

The carcinoembryonic antigen (CEA) blood test – part of the usual approach for monitoring for bowel cancer– is not sensitive or specific enough to depend on alone for detecting recurrence. This new Cochrane review added more detail to existing evidence about the low sensitivity and specificity of CEA, a test which has been available in the UK for many years. The review clarifies that no threshold level for CEA testing gives sufficient sensitivity and specificity to allow it to be used alone to detect recurrence. Instead, it is more reliable to consider the results of blood and imaging tests together for detecting recurrence of bowel cancer.

The findings confirm NICE guidance from 2011, to include regular CT scans of chest, abdomen and pelvis, and colonoscopy, as well as CEA testing, when monitoring people who have had cancer removed from the colon or rectum.

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Why was this study needed?

Bowel cancer is the fourth most common cancer in the UK, and costs the UK £1.6bn per year in terms of premature death, lost employment, health costs and informal care. However, survival has doubled in the last 40 years, to 57% at ten years after initial diagnosis.

After surgery to remove bowel cancer, people who then have no detectable cancer are monitored for cancer recurrence. This monitoring includes a CEA blood test every three to six months, for up to five years, and less frequent imaging tests – including CT scans and colonoscopy.

The CEA blood test has been used as a tumour marker – a sign of cancer presence – for many years. The problem is it isn’t very specific. The levels are raised in most cases of bowel cancer, but they can also be raised by smoking, or by other conditions such as liver disease, lung cancer or pancreatic cancer. More information was needed on whether altering the cut off level for the test could reliably improve the detection of true bowel cancer recurrence, and minimise false alarms and missed cases, when used in a staged approach to investigation.

What did this study do?

This Cochrane review included 52 diagnostic test accuracy studies, trials and cohort studies published between 1974 and 2014 that compared CEA test results to a reference test, for people who had undergone surgery to remove colorectal cancer. The reference test against which CEA was compared varied between studies, but nearly three quarters of studies used combinations of imaging, subsequent recurrence of cancer and biopsy, and ongoing medical history.

The researchers looked at what impact different threshold levels of CEA had. In theory, having a low threshold for detection should identify more people who have cancer, but may also falsely identify people who don’t have cancer. Having a high threshold would reduce the number of ‘false positives’, but risks missing people who do have cancer.

Over half of the included studies had a high risk of bias in at least one aspect of study design, mostly from inappropriate exclusions, such as for advanced age, that may have influenced the results more than if the sample had been consecutive or random. In addition, reporting quality and study design varied widely. Although the review was well conducted, these aspects reduce our confidence in the findings.

What did it find?

  • Seven studies used a CEA test threshold for cancer recurrence of 2.5μg per litre. Their pooled results gave sensitivity of 82% (95% confidence interval [CI] 78% to 86%) and specificity of 80% (95% CI 59% to 92%).
  • 23 studies used a threshold of 5μg per litre. Their pooled results gave sensitivity of 71% (95% CI 64% to 76%) and a specificity of 88% (95% CI 84% to 92%).
  • Seven studies used a threshold of 10μg per litre. Their pooled results gave sensitivity of 68% (95% CI 53% to 79%) and specificity of 97% (95% CI 90% to 99%).
  • Based on an estimated 2% of patients having recurrence in any single testing period, for every 1000 patients tested:
    • a threshold of 2.5μg per litre would correctly identify 16 people with cancer, 196 ‘false positives’ (receiving unnecessary referral for cancer investigation) and miss four people with cancer.
    • a threshold of 5μg per litre would correctly identify 14 people with cancer, 118 ‘false positives’ and miss six people with cancer.
    • increasing the threshold to 10μg per litre would correctly identify 14 cases and reduce the number of ‘false positives’ to 29 but still miss six people with cancer.

What does current guidance say on this issue?

2011 NICE guidance on colorectal cancer recommends that people should have regular follow up after they have had colorectal cancer surgically removed. This follow up should include CEA blood tests at least every six months in the first three years, along with at least two CT scans of the chest, abdomen and pelvis in the first three years. A year after the first treatment, the guidance recommends that a visual check for cancer recurrence should also be carried out using colonscopy.

In February 2016, NICE decided that this guideline should be updated, including the follow-up recommendations, though a publication date is yet to be decided.

What are the implications?

The findings are in agreement with existing guidance, to carry out CT scans and colonscopy in addition to CEA testing, to check for colorectal cancer recurrence.

The review adds more detail to existing knowledge that CEA is not a highly specific or sensitive test for colon cancer recurrence. It confirms that CEA should not be used as the sole test for recurrence. Even if a low level of CEA is used to flag recurrence, many people who do not have cancer may be subjected to unnecessary and worrying investigations, while up to a fifth of people with cancer recurrence remain undetected. Other strategies for the use of CEA in monitoring for recurrence could be the subject of future research.

Citation and Funding

Nicholson BD, Shinkins B, Pathiraja I, et al. Blood CEA levels for detecting recurrent colorectal cancer. Cochrane Database Syst Rev. 2015;(12):CD011134.

This work is partly funded by the National Institute of Health Research (NIHR) Health Technology Appraisal Programme project grant “What CEA level should trigger further investigation during follow up after curative treatment for colorectal cancer?” (project number 11/136/81).
The Nuffield Department of Primary Care Health Sciences receives funding from the NIHR.

Bibliography

NHS Choices. Carcinoembryonic antigen test (CEA). Leeds: NHS Choices; 2015.

NICE. Colorectal cancer: diagnosis and management. CG131. London: National Institute for Health and Care Excellence; 2011.

Patient. Carcinoembryonic antigen (CEA). Leeds: EMIS; 2015.

Why was this study needed?

Bowel cancer is the fourth most common cancer in the UK, and costs the UK £1.6bn per year in terms of premature death, lost employment, health costs and informal care. However, survival has doubled in the last 40 years, to 57% at ten years after initial diagnosis.

After surgery to remove bowel cancer, people who then have no detectable cancer are monitored for cancer recurrence. This monitoring includes a CEA blood test every three to six months, for up to five years, and less frequent imaging tests – including CT scans and colonoscopy.

The CEA blood test has been used as a tumour marker – a sign of cancer presence – for many years. The problem is it isn’t very specific. The levels are raised in most cases of bowel cancer, but they can also be raised by smoking, or by other conditions such as liver disease, lung cancer or pancreatic cancer. More information was needed on whether altering the cut off level for the test could reliably improve the detection of true bowel cancer recurrence, and minimise false alarms and missed cases, when used in a staged approach to investigation.

What did this study do?

This Cochrane review included 52 diagnostic test accuracy studies, trials and cohort studies published between 1974 and 2014 that compared CEA test results to a reference test, for people who had undergone surgery to remove colorectal cancer. The reference test against which CEA was compared varied between studies, but nearly three quarters of studies used combinations of imaging, subsequent recurrence of cancer and biopsy, and ongoing medical history.

The researchers looked at what impact different threshold levels of CEA had. In theory, having a low threshold for detection should identify more people who have cancer, but may also falsely identify people who don’t have cancer. Having a high threshold would reduce the number of ‘false positives’, but risks missing people who do have cancer.

Over half of the included studies had a high risk of bias in at least one aspect of study design, mostly from inappropriate exclusions, such as for advanced age, that may have influenced the results more than if the sample had been consecutive or random. In addition, reporting quality and study design varied widely. Although the review was well conducted, these aspects reduce our confidence in the findings.

What did it find?

  • Seven studies used a CEA test threshold for cancer recurrence of 2.5μg per litre. Their pooled results gave sensitivity of 82% (95% confidence interval [CI] 78% to 86%) and specificity of 80% (95% CI 59% to 92%).
  • 23 studies used a threshold of 5μg per litre. Their pooled results gave sensitivity of 71% (95% CI 64% to 76%) and a specificity of 88% (95% CI 84% to 92%).
  • Seven studies used a threshold of 10μg per litre. Their pooled results gave sensitivity of 68% (95% CI 53% to 79%) and specificity of 97% (95% CI 90% to 99%).
  • Based on an estimated 2% of patients having recurrence in any single testing period, for every 1000 patients tested:
    • a threshold of 2.5μg per litre would correctly identify 16 people with cancer, 196 ‘false positives’ (receiving unnecessary referral for cancer investigation) and miss four people with cancer.
    • a threshold of 5μg per litre would correctly identify 14 people with cancer, 118 ‘false positives’ and miss six people with cancer.
    • increasing the threshold to 10μg per litre would correctly identify 14 cases and reduce the number of ‘false positives’ to 29 but still miss six people with cancer.

What does current guidance say on this issue?

2011 NICE guidance on colorectal cancer recommends that people should have regular follow up after they have had colorectal cancer surgically removed. This follow up should include CEA blood tests at least every six months in the first three years, along with at least two CT scans of the chest, abdomen and pelvis in the first three years. A year after the first treatment, the guidance recommends that a visual check for cancer recurrence should also be carried out using colonscopy.

In February 2016, NICE decided that this guideline should be updated, including the follow-up recommendations, though a publication date is yet to be decided.

What are the implications?

The findings are in agreement with existing guidance, to carry out CT scans and colonscopy in addition to CEA testing, to check for colorectal cancer recurrence.

The review adds more detail to existing knowledge that CEA is not a highly specific or sensitive test for colon cancer recurrence. It confirms that CEA should not be used as the sole test for recurrence. Even if a low level of CEA is used to flag recurrence, many people who do not have cancer may be subjected to unnecessary and worrying investigations, while up to a fifth of people with cancer recurrence remain undetected. Other strategies for the use of CEA in monitoring for recurrence could be the subject of future research.

Citation and Funding

Nicholson BD, Shinkins B, Pathiraja I, et al. Blood CEA levels for detecting recurrent colorectal cancer. Cochrane Database Syst Rev. 2015;(12):CD011134.

This work is partly funded by the National Institute of Health Research (NIHR) Health Technology Appraisal Programme project grant “What CEA level should trigger further investigation during follow up after curative treatment for colorectal cancer?” (project number 11/136/81).
The Nuffield Department of Primary Care Health Sciences receives funding from the NIHR.

Bibliography

NHS Choices. Carcinoembryonic antigen test (CEA). Leeds: NHS Choices; 2015.

NICE. Colorectal cancer: diagnosis and management. CG131. London: National Institute for Health and Care Excellence; 2011.

Patient. Carcinoembryonic antigen (CEA). Leeds: EMIS; 2015.

Blood CEA levels for detecting recurrent colorectal cancer

Published on 15 December 2015

Nicholson, B. D.,Shinkins, B.,Pathiraja, I.,Roberts, N. W.,James, T. J.,Mallett, S.,Perera, R.,Primrose, J. N.,Mant, D.

Cochrane Database Syst Rev Volume 12 , 2015

BACKGROUND: Testing for carcino-embryonic antigen (CEA) in the blood is a recommended part of follow-up to detect recurrence of colorectal cancer following primary curative treatment. There is substantial clinical variation in the cut-off level applied to trigger further investigation. OBJECTIVES: To determine the diagnostic performance of different blood CEA levels in identifying people with colorectal cancer recurrence in order to inform clinical practice. SEARCH METHODS: We conducted all searches to January 29 2014. We applied no language limits to the searches, and translated non-English manuscripts. We searched for relevant reviews in the MEDLINE, EMBASE, MEDION and DARE databases. We searched for primary studies (including conference abstracts) in the Cochrane Central Register of Controlled Trials (CENTRAL), in MEDLINE, EMBASE, and the Science Citation Index & Conference Proceedings Citation Index - Science. We identified ongoing studies by searching WHO ICTRP and the ASCO meeting library. SELECTION CRITERIA: We included cross-sectional diagnostic test accuracy studies, cohort studies, and randomised controlled trials (RCTs) of post-resection colorectal cancer follow-up that compared CEA to a reference standard. We included studies only if we could extract 2 x 2 accuracy data. We excluded case-control studies, as the ratio of cases to controls is determined by the study design, making the data unsuitable for assessing test accuracy. DATA COLLECTION AND ANALYSIS: Two review authors (BDN, IP) assessed the quality of all articles independently, discussing any disagreements. Where we could not reach consensus, a third author (BS) acted as moderator. We assessed methodological quality against QUADAS-2 criteria. We extracted binary diagnostic accuracy data from all included studies as 2 x 2 tables. We conducted a bivariate meta-analysis. We used the xtmelogit command in Stata to produce the pooled estimates of sensitivity and specificity and we also produced hierarchical summary ROC plots. MAIN RESULTS: In the 52 included studies, sensitivity ranged from 41% to 97% and specificity from 52% to 100%. In the seven studies reporting the impact of applying a threshold of 2.5 microg/L, pooled sensitivity was 82% (95% confidence interval (CI) 78% to 86%) and pooled specificity 80% (95% CI 59% to 92%). In the 23 studies reporting the impact of applying a threshold of 5 microg/L, pooled sensitivity was 71% (95% CI 64% to 76%) and pooled specificity 88% (95% CI 84% to 92%). In the seven studies reporting the impact of applying a threshold of 10 microg/L, pooled sensitivity was 68% (95% CI 53% to 79%) and pooled specificity 97% (95% CI 90% to 99%). AUTHORS' CONCLUSIONS: CEA is insufficiently sensitive to be used alone, even with a low threshold. It is therefore essential to augment CEA monitoring with another diagnostic modality in order to avoid missed cases. Trying to improve sensitivity by adopting a low threshold is a poor strategy because of the high numbers of false alarms generated. We therefore recommend monitoring for colorectal cancer recurrence with more than one diagnostic modality but applying the highest CEA cut-off assessed (10 microg/L).

CEA stands for carcino embryonic antigen – proteins that are normally produced by cells in an embryo’s gut tissue, but are not normally present after birth. Some cancer cells revert to the characteristics of embryonic cells, and shed proteins such as CEA into the blood. This can make the cancer cells detectable using tests for these embryonic proteins, so the test can pick up some cancers that originated in the gut such as colon cancer. Other common conditions can also have raised CEA levels, such as liver disease, inflammatory bowel disease, or other cancers. So the test is not very specific for colon cancer recurrence.

Normal ranges for levels of CEA in the blood vary by exact test and laboratory, but are generally are less than 2.5 to 5μg per litre. The pattern of changing levels over time is useful for identifying potential risk of recurrence, for example a significant rise over two readings.

Expert commentary

This Cochrane review is a reasonable summary of current knowledge on CEA which concludes that it is not an ideal marker. It has long been recognised by pathologists that tumour markers lack sensitivity or specificity. Although some clinicians try to use them as general tests for cancer, it is not recommended. A multi-modal approach to recurrence detection is therefore wisest.

Other strategies for improving sensitivity are possible. For example, CEA could be assessed before treatment so that it’s known to be a marker for that patient's tumour, before monitoring is started. The conclusion in the report that a single use of the marker is suboptimal and that trend analysis over time is essential, are both sensible. Indeed a rising trend is more important than a threshold measurement. So if a low/unmeasurable CEA is shown after initial treatment but there is a progressive rise, it would be a foolish physician who failed to act on the trend data even before a threshold had been reached.

Professor Tim Reynolds, Consultant Chemical Pathologist / Divisional Medical Director (CH&CSS) / R&D Lead, Burton Hospitals NHS Foundation Trust