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PubMed1996

Screening of average-risk individuals for colorectal cancer and postoperative evaluation of patients with colorectal cancer.

Screening of the average-risk individual for disease creates a different relationship between practitioner and subject than the normal doctor-patient relationship. Screened individuals are asymptomatic, have a whole range of motivations from denial to neurosis, and, for the most part, derive no benefit from the screen, as they are destined never to contract the disease. Rewards to the few must clearly outweigh the risks to the many. The screening strategy must be economical when applied to a large population, safe, and effective in achieving the ultimate goal, which, in the case of colorectal cancer, is reduction in the mortality rate. Prediagnostic screening of asymptomatic adults over the age of 45 years for primary disease has been shown to fulfill all of these criteria. Postoperative screening of asymptomatic individuals after curative resection of colorectal cancer for recurrence has been shown to fulfill none of them.

Adult↗
PubMed1992

Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project.

PURPOSE: A meta-analysis was performed on nine randomized clinical trials that compared fluorouracil (5-FU) with 5-FU plus intravenous (IV) leucovorin (LV) for the treatment of advanced colorectal cancer. DESIGN: The analysis was based on the most recently updated individual patient data from all trials. The end points of interest were tumor response and overall survival. RESULTS: Therapy with 5-FU plus LV administered either as weekly or monthly regimens showed a highly significant benefit over single-agent 5-FU in terms of tumor response rate (23% v 11%; response odds ratio (OR), 0.45; P less than 10(-7)). This increase in response did not result in a discernable improvement of overall survival (survival OR, 0.97; P = .57). The large number of patients who did not respond to treatment in both groups, and cross-overs from 5-FU alone to 5-FU plus LV are discussed as plausible explanations for the lack of a survival difference. CONCLUSION: These results confirm the advantage of 5-FU plus leucovorin over 5-FU alone in terms of objective tumor response. They also suggest that in planning future trials, tumor response should not be considered a valid surrogate end point for survival in patients with advanced colorectal cancer.

Colorectal Neoplasms↗
PubMed2003

Endoscopic light-induced autofluorescence spectroscopy for the diagnosis of colorectal cancer and adenoma.

To evaluate the new, bio-optical method of light-induced autofluorescence spectroscopy for the endoscopic in-vivo diagnosis of (pre)-cancerous lesions of the colorectum, 311 endogenous fluorescence spectra were obtained from normal, adenomatous and cancerous colorectal tissue in 11 patients with cancer, six patients with familial adenomatous polyposis, and six patients with multiple adenomatous polyps. A light source delivered either white or violet-blue light for excitation of tissue autofluorescence via a flexible endoscope. Endogenous fluorescence spectra emitted by the tissue were picked up with a fiberoptic probe and analysed with a spectrograph. Biopsies were taken for definitive classification of the spectra. Rectal cancer (n=11) as well as adenomas with severe dysplasia (n=19) showed specific differences between the emitted fluorescence spectra as compared with normal mucosa and hyperplastic polyps. Having applied a mathematical algorithm to the spectra, a sensitivity of 96% and a specificity of 93% were obtained for the diagnosis of rectal cancer. The equivalent values for the diagnosis of dysplastic ademomas were 98 and 89%, respectively. Light-induced autofluorescence spectroscopy is a new and promising bio-optical procedure for the endoscopic in-vivo diagnosis of colorectal cancer and dysplasia.

Adenoma↗
PubMed1999

Colorectal cancer screening.

Colorectal cancer is an important problem in the United States, with over 130,000 new cases and 55,000 deaths each year. There is now strong evidence that screening for colorectal cancer with fecal occult blood testing can decrease mortality, and additional evidence that removing benign adenomas can decrease cancer incidence. Evidence-based screening guidelines depend on colorectal cancer risk. Individuals at higher risk because of a personal or family history deserve more intensive screening than asymptomatic individuals over age 50.

Adenomatous Polyposis Coli↗
PubMed1994

[Diagnosis and staging of colorectal cancers].

Early colorectal cancer produces no symptom, thus justifying efforts at detection in screening programs. Symptoms are usually secondary to obstruction, local invasion, perforation or bleeding. Any fecal bleeding must be investigated to rule out a colorectal cancer. The initial imaging study to identify a colorectal cancer is often colonoscopy, which is frequently supplemented with a double contrast barium enema. Once the presence of cancer is histologically proven, the preoperative evaluation includes detection of hepatic and extrahepatic spread, especially with ultrasound and CT scan. Endorectal ultrasonography has been shown to be a significant advance for staging rectal cancer. It provides the best staging in selecting patients for preservation of sphincter function and for adjuvant therapies. The most useful prognostic factors in tumors without distant metastases are the depth of tumor extension, the number of positive lymph nodes and the histologic grade. Preoperative CEA level, vascular invasion and ploidy are also important prognostic factors.

Colorectal Neoplasms↗
PubMed1995

Familial aggregation of tumors and detection of hereditary non-polyposis colorectal cancer in 3-year experience of 2 population-based colorectal-cancer registries.

The clinical data of 2 population-based registries, located in areas with different incidence rates of colorectal cancer, were used in order to assess the role of familial factors in the pathogenesis of these tumors. The occurrence of tumors in family members was investigated in 389 subjects with colorectal cancer registered in Modena (Northern Italy, an area characterized by a high incidence of colorectal malignancies) between 1984 and 1986; similar information was obtained in 213 patients with tumors of the large bowel registered in Ragusa (Sicily, Southern Italy, an area of similar magnitude and with low incidence rates for these tumors) in the 3-year period 1988 to 1990. In both series, colorectal cancer occurred significantly more often among relatives of patients. Controls were patients of the same sex and age (+/- 5 years) hospitalized during the study periods, but not for gastrointestinal or neoplastic diseases. There were 89 cancer cases (3.1%) among 2,851 relatives of patients in Modena, vs. 17 cases among 1,744 relatives (1.0%) in Ragusa (p < 0.01). Apart from colorectal cancer, there was no excess of other types of tumors in patients' families (in both series). During the 3 years of registration, 17 cases of hereditary non-polyposis colorectal cancer (HNPCC, or Lynch syndrome) were diagnosed in Modena; in contrast, this syndrome was more rare in Ragusa (one case only during 3 years of observation). Similarly, many more families with clinical suspicion of HNPCC were recorded in Northern regions (44 vs. 10). Although incidence rates of colorectal cancer are appreciably higher in Northern than in Southern Italian regions, the excess of this cancer type among close relatives is similar. However, full-blown HNPCC or suspected Lynch syndrome were significantly more frequent in Northern Italy.

Aged↗
PubMed1999

Microsatellite instability-a useful diagnostic tool to select patients at high risk for hereditary non-polyposis colorectal cancer: a study in different groups of patients with colorectal cancer.

BACKGROUND: Clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is based on a typical family history. As molecular genetic testing is predominantly restricted to these families, gene carriers not meeting the clinical criteria may be missed. AIMS: To examine the value of microsatellite instability (MSI) as a tool to increase the likelihood for uncovering a mismatch repair germline mutation in patients with colorectal cancer and to identify a genotype-phenotype relation in families with verified mutations. METHODS: Systematic search for germline mutations (hMSH2 and hMLH1 genes) was performed in 96 patients: 57 fulfilled the Amsterdam criteria (group 1) and 12 the looser HNPCC criteria (group 2). Seventeen patients showed familial clustering of cancers (group 3) and 10 patients under 50 years had sporadic cancer (group 4), the latter of whom all exhibited MSI+ tumours. RESULTS: A similar proportion of germline mutations was found in patients who fulfilled the clinical criteria of HNPCC and had MSI+ tumours (groups 1 and 2; 15/39) compared with patients who did not meet these clinical criteria but who had MSI+ tumours (groups 3 and 4; 8/27 patients). Affected relatives of patients with hMLH1 mutations showed a significantly higher frequency of colorectal cancer but a lower frequency of endometrium cancer than those with hMSH2 mutations. CONCLUSIONS: MSI in tumour tissue is a useful criterion for selecting patients who should be tested for germline mutations in the mismatch repair genes hMSH2 and hMLH1 irrespective of their family history. Among carriers of hMSH2 mutations the tumour spectrum was broader than among carriers of hMLH1 mutations.

Adult↗
PubMed2005

Colorectal screening is associated with reduced colorectal cancer risk: a case-control study within the population-based Ontario Familial Colorectal Cancer Registry.

OBJECTIVE: This is the first study to evaluate the association between colonic screening and colorectal cancer risk among Canadians. METHODS: A case-control study was conducted. Cases were diagnosed with cancer of the colorectum, between 1997 and 2000, aged 20 to 74 years, identified through the population-based Ontario Cancer Registry and recruited by the Ontario Familial Colorectal Cancer Registry. Controls were a sex- and age-matched random sample of the population of Ontario. 971 cases and 1944 controls completed questionnaires (including colorectal screening history and many risk factors). Multivariate logistic regression analysis was used to obtain adjusted odds ratios (OR) estimates. RESULTS: Having had a fecal occult blood screen was associated with reduced colorectal cancer risk (OR=0.76; 95% confidence interval (CI): 0.59, 0.97). Having had a screening sigmoidoscopy was associated with a halving of colorectal cancer risk (OR = 0.52; 95% CI: 0.34, 0.80). Having had a screening colonoscopy did not significantly reduce colorectal cancer risk (OR = 0.69; 95% CI: 0.44, 1.07); however, having had either screening endoscopy was associated with a significant reduction in colorectal cancer risk (OR = 0.62; 95% CI: 0.44, 0.87). Findings differed slightly by anatomic sub-site (proximal and distal colorectum). CONCLUSIONS: We report a reduction in colorectal cancer risk among persons who underwent colorectal cancer screening; in particular, sigmoidoscopy. Findings are of great importance for the prevention of colorectal cancer.

Adult↗
PubMed2001

Differential expression of a novel colorectal cancer differentiation-related gene in colorectal cancer.

AIM: To investigate SBA2 expression in CRC cell lines and surgical specimens of CRC and autologous healthy mucosa. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used for relative quantification of SBA2 mRNA levels in 4 human CRC cell lines with different grades of differentiation and 30 clinical samples. Normalization of the results was achieved by simultaneous amplification of beta-actin as an internal control. RESULTS: In the exponential range of amplification, fairly good linearity demonstrated identical amplification efficiency for SBA2 and beta-actin (82%). Markedly lower levels of SBA2 mRNA were detectable in tumors, as compared with the coupled normal counterparts P<0.01). SBA2 expression was significantly (0.01>P < 0.05) correlated with the grade of differentiation in CRC, with relatively higher levels in well-differentiated samples and lower in poorly-differentiated cases. Of the 9 cases with lymph nodes affected, 78% (7/9) had reduced SBA2 mRNA expression in contrast to 24% (5/21) in non-metastasis samples 0.01>P<0.05). CONCLUSION: SBA2 gene might be a promising novel biomarker of cell differentiation in colorectal cancer and its biological features need further studies.

Biomarkers, Tumor↗
PubMed1990

Risk and surveillance of individuals with colorectal polyps. Who Collaborating Centre for the Prevention of Colorectal Cancer.

Since colorectal adenomas are very probably the precursors of colorectal cancer, their detection and removal should result in a decrease in the incidence and mortality from colorectal cancer. Individuals who harbour an adenoma have a 30-50% probability of having additional adenomas at that time, and a 30% probability of having additional adenomas later. Adenomas are prevalent in countries where colorectal cancer is prevalent, about two-thirds of them being tubular and the rest tubulovillous or villous. The initial management of patients with an adenoma consists in searching by colonoscopy the entire colon and removing all additional polyps. Surgical resection is required wherever there is invasive cancer with adverse histological factors. Follow-up in most patients can be after 2-4 years, earlier follow-up being reserved for patients with numerous polyps or with a polyp that had been removed piecemeal. The results of ongoing trials should provide firm guidelines for follow-up and could also be used in mathematical modelling to examine alternative strategies and to help understand the evolving patterns of appearance of new polyps. Finally, a deeper understanding of the biology and inherited and acquired genetics will help identify individuals at risk for adenomas initially and at follow-up. Nutritional factors may also provide a basis for prevention of adenomas in high-risk countries. Many of these issues are being addressed in current research.

Adenoma↗
PubMed2004

What is the best way to assess microsatellite instability status in colorectal cancer? Study on a population base of 462 colorectal cancers.

The assessment of the microsatellite instability (MSI) status in colorectal cancers is presently warranted for three reasons: 1) as a screening tool for hereditary nonpolyposis colorectal cancer, 2) as a prognostic marker, and 3) as a potential predictive factor of chemotherapy response. The aim of this study was to evaluate, on a large scale with tissue samples coming from a number of different sources, the difficulties met with routine use of immunohistochemistry (IHC) and to determine if it really does offer an accurate alternative to PCR genotyping. Colorectal carcinomas from 462 consecutive patients resected in public or private hospitals were assessed for MSI status by two methods: MSI testing (with BAT-26 microsatellite) and IHC detection of hMLH1, hMSH2, and hMSH6 proteins. Of the 398 cancers tested, immunohistochemistry was noncontributory in 42 (10.5%), focal in 9 (2.3%), and discordant with the PCR results in 36 (9%). For these 87 cases, complementary analyses were performed to explain discrepancy. After additional IHC assay with modified processing protocols, 8 cases remained noncontributory, 2 focal, and 28 discordant: 18 microsatellite stability IHC/MSI PCR and 10 MSI IHC/microsatellite stability PCR. For these discordant cases, we performed a multiplex PCR assay on DNA extracted from the frozen sample and BAT-26 was amplified from DNA extracted from the paraffin blocks used for IHC. Four discordant cases were reclassified after PCR multiplex assay (3 as MSI and 1 as microsatellite stability). Five other cases displayed intratumoral heterogeneity and 19 remained discordant. The discrepancy could be partly explained by variable technical protocols of fixation in the different laboratories, leading to variations in staining quality and difficulties in IHC interpretation. This population-based study is the first one to show that IHC is not sensitive and specific enough to be used routinely. Immunohistochemistry analysis of MMR proteins must be performed in standardized conditions and interpreted by confirmed pathologists. It cannot replace PCR as long as protocols are not optimized and harmonized.

Aged↗
PubMed2000

Prognostic significance of extensive microsatellite instability in sporadic clinicopathological stage C colorectal cancer.

BACKGROUND: Colorectal cancers exhibiting microsatellite instability (MSI) appear to have unique biological behaviour. This study analyses the association between extensive MSI (MSI-H), clinicopathological features and survival in an unselected group of patients with sporadic Australian Clinico-Pathological Stage (ACPS) C (tumour node metastasis stage III) colorectal cancer. METHODS: Some 255 patients who underwent resection for sporadic ACPS C colorectal cancer between 1986 and 1992 were studied. No patient had received chemotherapy. Minimum follow-up for all patients was 5 years. Archival normal and tumour DNA was extracted and amplified by polymerase chain reaction using a radioactive labelling technique. MSI-H was defined as instability in 40 per cent or more of seven markers. RESULTS: Twenty-one patients showed MSI-H. No association was found between MSI and age or sex. Tumours exhibiting MSI-H were more commonly right sided (P<0.00001), larger (P = 0.002) and more likely to be high grade (P = 0.049). After adjustment for age, sex and other pathological variables, patients whose cancers exhibited MSI-H had improved survival (P = 0.015). CONCLUSION: Recognition of MSI-H in sporadic ACPS C tumours identifies a subset of cancers with improved prognosis. Such stratification should be considered in trials of adjuvant therapy and may be relevant to therapeutic decision making.

Adult↗
PubMed2000

Potential roles of genetic biomarkers in colorectal cancer chemoprevention.

Colorectal cancer is a significant cause of morbidity and mortality in industrialized societies and the second most frequent cause of cancer death in the United States. Surrogate endpoint biomarkers are gaining wide acceptance in early diagnosis and short-term cancer chemoprevention trials in place of cancer endpoints. Molecular genetic biomarkers can be useful tools in identifying subjects at risk of developing cancer and screening for early cancers amenable to complete cure. They may be useful both in predicting and assessing response to a given therapy and in determining prognosis after an initial diagnosis has been made. Ideally, biomarkers should fulfill some, if not all, of the following criteria: variability of expression between phases of carcinogenesis, association with cancer risk, ability to undergo modification in response to a chemopreventive agent, and finally, permit ease of measurement. In consideration of colorectal cancer chemoprevention, several genetic biomarkers seem to meet many of these criteria, as they do exhibit distinct variability of expression at different phases of carcinogenesis, are often strongly associated with increased cancer risk (especially the hereditary/familial syndromes), are generally able to be measured relatively easily through peripheral blood sampling (germline mutations) or by colonic mucosal sampling by endoscopic techniques (somatic mutations). In some cases, genetic biomarkers have also been demonstrated to undergo modification in response to a chemopreventive agent. With further understanding of the genetic and molecular changes involved in sporadic and familial colorectal carcinogenesis, genetic biomarkers appear to hold great potential for the identification of subjects at high risk of developing colorectal cancer, as well as the development of novel chemopreventive approaches and form a promising area for further research.

Anticarcinogenic Agents↗
PubMed2005

[Chemotherapy for liver metastasis of colorectal cancer].

In colorectal cancer, liver metastasis is the most common and most important prognostic factor. Although surgical resection is the first choice of treatment for liver metastasis of colorectal cancer, there are many cases we cannot choose the surgical treatment. The chemotherapy is very important in such cases. We examined 18 cases of unresectable liver metastases from colorectal cancer which were adapted a hepatic arterial infusion of 5-FU (HAI) with a weekly high-dose infusion method (WHF) as the first-line treatment, and then systemic chemotherapy of CPT-11 in combination with 5-FU as the second-line treatment. The response rate of this treatment is 72% (13/18) and the 1-, 2-, 3-year survival rates were 100% (16/16), 83% (10/12), and 50% (5/10), respectively. The combination chemotherapy of HAI with systemic chemotherapy using CPT-11 seemed to be an effective treatment method.

Aged↗
PubMed1994

Allelic loss of chromosome 18q and prognosis in colorectal cancer.

BACKGROUND: Colorectal cancer occurs in approximately 150,000 people each year in the United States. Prognostic assessment influences the treatment of patients with colorectal cancer, including decisions about adjuvant therapy. We evaluated chromosome 18q allelic loss, a genetic event associated with tumor progression, as a prognostic marker for this disease. METHODS: We developed procedures to examine the status of chromosome 18q with microsatellite markers and DNA from formalin-fixed, paraffin-embedded tumors. Allelic loss of chromosome 18q was assessed in 145 consecutively resected stage II or III colorectal carcinomas. RESULTS: Among patients with stage II disease, the five-year survival rate was 93 percent in those whose tumor had no evidence of allelic loss of chromosome 18q and 54 percent in those with allelic loss; among patients with stage III disease, survival was 52 and 38 percent, respectively. The overall estimated hazard ratio for death in patients whose tumor had chromosome 18q allelic loss was 2.83 (P = 0.008) according to univariate analysis. Furthermore, chromosome 18q allelic loss remained a strong predictive factor (hazard ratio for death, 2.46; 95 percent confidence interval, 1.06 to 5.71; P = 0.036) after adjustment for all other evaluated factors, including tumor differentiation, vein invasion, and TNM stage. CONCLUSIONS: The status of chromosome 18q has strong prognostic value in patients with stage II colorectal cancer. The prognosis in patients with stage II cancer and chromosome 18q allelic loss is similar to that in patients with stage III cancer, who are thought to benefit from adjuvant therapy. In contrast, patients with stage II disease who do not have chromosome 18q allelic loss in their tumor have a survival rate similar to that of patients with stage I disease and may not require additional therapy.

Aged↗
PubMed2005

New chemotherapeutic strategies in colorectal cancer.

Since colorectal cancer is the second most prevalent cancer worldwide, its treatment remains a major challenge for researchers, gastroenterologists and oncologists. Despite curative resections, half of all patients diagnosed with colorectal cancer die because of their underlying disease. Integral chemotherapeutic components of standard regimens are 5-fluorouracil (5-FU), its modulation by folinic acid and irinotecan or oxaliplatin. All these drugs sequentially given have results in terms of median overall survival of more than 20 months in the palliative treatment of advanced colorectal cancer. Oral fluoropyrimidines, currently under clinical investigation, are likely to substitute continuous 5-FU. Inhibitors of growth factor receptors or their signaling may further prolong disease-free and overall survival rates. Preliminary evidence exists that improved adjuvant and neoadjuvant chemotherapy strategies may further improve the prognosis, mainly because more patients are able to go for primary or secondary surgery with curative intent.

Administration, Oral↗
PubMed2004

[Colorectal cancer management].

Colorectal cancer is a frequent disease with an increasing incidence. Its prognosis improved recently because of progress in diagnostic and therapeutic procedures. Rationale and guidelines for colorectal cancer screening using the faecal occult blood test in the average risk population and screening recommendations for high risk groups are presented, as well as diagnostic and therapeutic principles. Because of the efficacy of the new chemotherapy regimens, the availability of biotherapies and the fact that surgery can potentially cure more and more patients, colorectal cancer management needs to be multidisciplinary.

Adenocarcinoma↗