Current noninvasive tests for colorectal cancer screening: An overview of colorectal cancer screening tests

Colorectal cancer (CRC) has become the third most common cancer in the world. Screening has been shown to be an effective way to identify early CRC and precancerous lesions, and to reduce its morbidity and mortality. Several types of noninvasive tests have been developed for CRC screening, including the fecal occult blood test (FOBT), the fecal immunochemical test (FIT), the fecal-based DNA test and the blood-based DNA test (the SEPT9 assay). FIT has replaced FOBT and become the major screening test due to high sensitivity, specificity and low costs. The fecal DNA test exhibited higher sensitivity than FIT but its current cost is high for a screening assay. The SEPT9 assay showed good compliance while its performance in screening needs further improvements. These tests exhibited distinct sensitivity and specificity in screening for CRC and adenoma. This article will focus on the performance of the current noninvasive in vitro diagnostic tests that have been used for CRC screening. The merits and drawbacks for these screening methods will also be compared regarding the techniques, usage and costs. We hope this review can provide suggestions for both the public and clinicians in choosing the appropriate method for CRC screening.     

Screening for colorectal cancer

This review will comprise a general overview of colorectal cancer (CRC) screening. We will cover the impact of CRC, CRC risk factors, screening modalities, and guideline recommendations for screening in average-risk and high-risk individuals. Based on this data, we will summarize our approach to CRC screening.     

Screening for colorectal cancer

Colorectal cancer (CRC) is the most common cancer in the Nordic countries after breast and prostate cancer. About 15 000 new cancers are diagnosed and more than 7 000 patients will die from CRC in 2005. CRC fulfils most of the criteria for applying screening; the natural history is well known compared with many other cancers. CRC may be cured by detection at an early stage and even prevented by removal of possible precursors like adenomas. Faecal occult blood test is the only CRC screening modality that has been subjected to adequately sized randomised controlled trials (RCT) with long-term follow-up results, using Hemoccult-II. Sensitivity for strictly asymptomatic CRC is less than 30% for a single screening round, but programme sensitivity has been estimated to be more. Biennial screening with un-rehydrated Hemoccult-II slides has shown a CRC mortality reduction of 15-18% after approximately 10 years of follow-up in those targeted for screening. For those attending, the mortality reduction has been estimated at 23%. Denmark has decided to do feasibility studies to try to evaluate whether a population-based screening run by the community will have the same effect as has been demonstrated in the randomised trials. In Norway the government has accepted no formal population-based screening. In Finland, the Ministry of Social Affairs and Health made a recommendation in 2003 to the municipalities to run a randomised feasibility study with FOBT screening for colorectal cancer as a public health policy that is repeated every second year. In 2004 the first municipalities started. It has been claimed that today Sweden cannot afford CRC screening despite the potential mortality benefit. There is sufficient evidence for the efficacy of screening for colorectal cancer with fecal occult blood test every second year. There is, however, only little evidence on the effectiveness of screening when run as a public health service and there is insufficient knowledge of harmful effects and costs, even in RCTs.     

Metastatic colorectal cancer: Therapeutic options

Opinion statement For the past several decades, the therapy for metastatic colorectal cancer had modest benefits because of the limited therapeutic options. Bolus 5-fluorouracil (5FU) and leucovorin (LV) were the standard of care in the United States until 2002, with a response rate of 25% and a median survival of 10 to 12 months. However, with the advent of new agents, namely oxaliplatin and irinotecan, there has been a dramatic change in the way we treat metastatic colorectal cancer. Based on many well-conducted large randomized trials, we have evidence that combination chemotherapy incorporating oxaliplatin or irinotecan with infusional 5FU/LV is superior to 5FU/LV, with doubling of overall survival (OS) to approximately 20 months. There remains some uncertainty as to the best first-line regimen. This might be irrelevant because studies have shown that OS is dependent on exposure to all the active agents, regardless of the time period of exposure. Bevacizumab, which uses anti-angiogenic strategies, has improved diseasefree survival (DFS) and OS when combined with standard chemotherapy and is a vital component of metastatic colorectal cancer therapy. However, there are no data supporting its use past progression. Cetuximab, an epithelial growth factor receptor inhibitor, is mainly used in irinotecan-refractory patients. In spite of all these advances, 5-year OS rates continue to be limited. Patients with curative resection of metastatic disease seem to have longer DFS and better 5-year OS rates. This should be a potential goal for responding patients with upfront unresectable, organ-limited disease.     

Molecular tests for colorectal cancer screening

Detecting and removing high-risk adenomas and early colorectal cancer (CRC) can reduce mortality of this disease. The noninvasive fecal occult blood test (FOBT; guaiac-based or immunochemical) is widely used in screening programs and although effective, it leaves room for improvement in terms of test accuracy. Molecular tests are expected to be more sensitive, specific and informative than current detection tests, and are promising future tools for CRC screening. This review provides an overview of the performances of DNA, RNA, and protein markers for CRC detection in stool and blood. Most emphasis currently is on DNA and protein markers. Among DNA markers there is trend to move away from mutation markers in favor of methylation markers. The recent boost in proteomics research leads to many new candidate protein markers. Usually in small series, some markers show better performance than the present FOBT. Evaluation in large well-controlled randomized trials is the next step needed to take molecular markers for CRC screening to the next level and warrant implementation in a screening setting.     

Screening of colorectal cancer

Cost-effectiveness analyses have shown that the cost per year of life saved by screening with any of the tests recommended is reasonable by US standards. Although the specific results vary among analyses, in general the marginal cost-effectiveness of this screening is less than $25,000 per year of life saved. Screening for CRC was among the highest ranked services in an analysis of the value of preventive services based on the burden of disease prevented and cost-effectiveness. Although the up-front costs vary by screening modality, the long-term cost-effectiveness is similar across screening tests, so that decisions about which options to include--in the long run and from the perspective of society--do not need to be affected heavily by costs. Costs increase out of proportion to benefits with shorter intervals between screening examinations. Screening has provided great opportunities. Screening can prevent CRC by polypectomy and find early-stage cancers for treatment with less morbidity. Screening can reduce the burden of treating advanced cancers and can identify families at increased risk. Screening also has provided a better understanding of the biology of CRC. Screening for CRC should be part of a complete prevention program that includes a healthy lifestyle and familial risk assessment. Individuals with increased familial risk require special screening approaches, whereas individuals with average risk can have more standard screening. The average-risk individuals can be stratified further into persons who require intensive follow-up and persons who require less intensive or no follow-up at all. We are beginning to learn how to apply screening and surveillance approaches based on risk stratification for a more cost-effective approach to conserve resources and reduce complications and costs. Chemoprevention can be added to the program when substantial benefit of agents has been demonstrated. We have a better understanding of the biology of CRC and the technology to intervene in that biology to make a difference in the lives of many people. We have the concepts and technology to reduce substantially the mortality for CRC and even prevent it entirely. Newer screening tests or others yet to be developed may, with time, replace the modern options. Screening should take place with the tests currently available and not wait until something better comes along. In this way, needless suffering and loss of life can be avoided for this leading cause of cancer death. Screening may become even more successful if the promise of new technologies is confirmed and they enter clinical practice. In the last analysis, the best test is the one that gets done and gets done immediately.     

Hereditary colorectal cancer: Screening and management

Opinion statement Colorectal cancer (CRC) affects approximately 6% of the US population, with equal distribution between men and women. It is hereditary in a high proportion of cases and is one of the most preventable cancers. Detection and removal of its precursor lesions, the adenomatous polyps, is the foundation of preventive strategies. However, once CRC is diagnosed, surgical resection is the only cure. The likelihood of cure is higher when CRC is diagnosed at an early stage. Dietary and lifestyle modifications have little, if any, impact on CRC. Endoscopy with polypectomy prevents cancer deaths. The most important issues are screening and surveillance by any of the recommended modalities. Remaining concerns include the choice of screening tests, optimal testing intervals, and cost effectiveness. Patients may be stratified by personal and family risk and by the specific strategies used. Newer developments in genetic testing and imaging, including virtual colonoscopy, hold promise for future prevention. Chemoprevention with nonsteroidal anti-inflammatory drugs may have a role in highrisk populations. Colonoscopy is the most effective method of CRC prevention.     

Screening and surveillance for colorectal cancer.

Colorectal cancer is the second most common cause of cancer death among American men and woman. Currently available screening and surveillance techniques are effective in detecting early-stage colorectal cancer and its premalignant precursor lesion, the adenomatous polyp (adenoma). Removal of adenomas by colonoscopic polypectomy significantly reduces the incidence of colorectal cancer. Appropriate screening and surveillance recommendations should be based on the individual's colorectal cancer risk stratification. High-risk groups, such as patients with hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), should be offered genetic counseling and specialized screening recommendations for colorectal and associated extracolonic malignancies.     

A short-term colorectal cancer sphere culture as a relevant tool for human cancer biology investigation

Background:

Ex vivo colospheres have been previously characterised as a colorectal cancer (CRC) well-rounded multicellular model, exclusively formed by carcinoma cells, and derived from fresh CRC tissue after mechanical dissociation. The ability to form colospheres was correlated with tumour aggressiveness. Their three-dimensional conformation prompted us to further investigate their potential interest as a preclinical cancer tool.

Methods:

Patient-derived CRC xenografts were used to produce numerous colospheres. Mechanism of formation was elucidated by confocal microscopy. Expression analysis of a panel of 64 selected cancer-related genes by real-time qRT–PCR and hierarchical clustering allowed comparison of colospheres with parent xenografts. In vitro and in vivo assays were performed for migration and chemosensitivity studies.

Results:

Colospheres, formed by tissue remodelling and compaction, remained viable several weeks in floating conditions, escaping anoikis through their strong cell–cell interactions. Colospheres matched the gene expression profile of the parent xenograft tissue. Colosphere-forming cells migrated in collagen I matrix and metastasised when subrenally implanted in nude mice. Besides, the colosphere responses to 5-fluorouracil and irinotecan, two standard drugs in CRC, reproduced those of the in vivo original xenografts.

Conclusion:

Colospheres closely mimic biological characteristics of in vivo CRC tumours. Consequently, they would be relevant ex vivo CRC models.