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PubMed2001

[Significance of liver resection for multiple hepatic metastases from colorectal cancer].

In colorectal cancer, liver metastasis is the most common and most important prognostic factor. To elucidate the significance of liver resection, we examined 72 cases (H2: 29 cases, H3: 43 cases). The 3-year survival rate for H2 and H3 patients was 71.5% and 4.5%, respectively. The liver resection rate in H2 and H3 patients was 58.6% (17/29) and 16.3% (7/43), respectively. In H2 patients the 3-year survival rate of those with liver resection and non-resection was 71.3% and 9.2%, respectively (p < 0.001). However, in H3 patients the 3-year survival rate in liver resection and non-resection patients was 80.0% and 43.9%, respectively (not significant). Many therapies, such as liver resection, hepatic arterial infusion, and systemic chemotherapy, were attempted for patients with hepatic metastases. Our data show that liver resection can prolong the survival of H2 patients only. On the other hand, hepatic arterial infusion therapy prolongs the survival of H3 patients only. Systemic chemotherapy does not prolong the survival of either H2 or H3 patients.

Adult↗

PubMedDate not supplied

Colorectal cancer screening.

Colorectal cancer (CRC) is the third most common cancer in the world, and mortality has remained the same for the past 50 years, despite advances in diagnosis and treatment. Because significant numbers of patients present with advanced or incurable stages, patients with pre-malignant lesions (adenomatous polyps) that occur as result of genetic inheritance or age should be screened, and patients with long-standing inflammatory bowel disease should undergo surveillance. There are different risk groups for CRC, as well as different screening strategies. It remains to be determined which screening protocol is the most cost-effective for each risk catagory. The objective of screening is to reduce morbidity and mortality in a target population. The purpose of this review is to analyze the results of the published CRC screening studies, with regard to the measured reduction of morbidity and mortality, due to CRC in the studied populations, following various screening procedures. The main screening techniques, used in combination or alone, include fecal occult blood tests, flexible sigmoidoscopy, and colonoscopy. Evidence from the published literature on screening methods for specific risk groups is scanty and frequently does not arise from controlled studies. Nevertheless, data from these studies, combined with recent advances in molecular genetics, certainly lead the way to greater efficacy and lower cost of CRC screening.

Colonoscopy↗

PubMed2001

The clinical application of positron emission tomography to colorectal cancer management.

Colorectal cancer (CRC) is the second commonest cancer in the Western World. Successful treatment relies significantly on accurate detection and staging of primary disease as well as the early identification of the presence and extent of recurrence. Morphological imaging techniques, particularly computed tomography (CT), are well established and widely available to carry out these tasks in addition to predicting and monitoring response to therapy. This review analyses the current inadequacies for imaging CRC and critically assesses the potential role of functional imaging with positron emission tomography (PET). We review the current literature, use our experience from the first 1000 PET studies carried out at our Institution and the perspective of surgical colleagues. We find little evidence for the use of 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET for screening asymptomatic individuals and current modalities appear better suited for detection of symptomatic primary CRC. There is evidence of increased accuracy for FDG-PET in staging primary disease, but this area remains controversial and larger studies are necessary. The situation is quite the reverse with respect to imaging suspected recurrent disease with FDG-PET being more sensitive and specific than conventional techniques. This benefit manifests itself through alteration in patient management and results in cost savings. PET also appears to have a specific place in the evaluation of patients undergoing radiotherapy and chemotherapy, a role that will expand. The evidence suggests that PET will ultimately become routinely incorporated into CRC patient management algorithms. Technological advances coupled with novel tracer research will facilitate this.

Colorectal Neoplasms↗

PubMed2006

[Cost-effectiveness of colorectal cancer screening].

Colorectal cancer (CRC) screening in France is based on a faecal occult blood test every two years in average risk subjects 50-74 years of age while other endoscopic or non-endoscopic screening methods are used in Europe and in the USA. Beside the reduced incidence of and mortality from CRC found in available studies, cost-effectiveness data need to be taken into account. Because of the delay between randomized controlled trials and clinical results, transitional probabilistic models of screening programs are useful for public health policy makers. The aim of the present review was to promote the implementation of cost-effectiveness studies, to provide a guide to analyze cost-effectiveness studies on CRC screening and, to propose a French cost effectiveness study comparing CRC screening strategies. Most of these trials were performed by US or UK authors and demonstrate that the incremental cost-effectiveness ratio varies between 5 000 and 15 000 US dollars/one year life gained, with wide variations: these results were highly dependent on the unit costs of the different devices as well as the predictive values of the screening tests. Although CRC screening programs have been implemented in several administrative districts of France since 2002, and the results of these randomized controlled trials using fecal occult blood have been updated, cost-effectiveness criteria need to be integrated; especially since the results of screening campaigns based on other tools such as flexible sigmoidoscopy should be available in 2007.

Aged↗

PubMed2004

Genetic polymorphisms in UDP-glucuronosyltransferases and glutathione S-transferases and colorectal cancer risk.

Colorectal cancer (CRC) is one of the most common malignancies in the Western world showing an increasing incidence, and has been associated with genetic and lifestyle factors. Individual susceptibility to CRC may be due partly to variations in detoxification capacity in the gastrointestinal tract. Genetic polymorphisms in detoxification enzymes may result in variations in detoxification activities, which subsequently might influence the levels of toxic/carcinogenic compounds, and this may influence the risk for CRC. To determine whether genetic polymorphisms in detoxification enzymes predispose to the development of CRC, 371 patients with sporadic CRC and 415 healthy controls were genotyped for polymorphisms in the important detoxification enzymes UDP-glucuronosyltransferase UGT1A1, UGT1A6, UGT1A7 and UGT1A8, and glutathione S-transferase GSTA1, GSTM1, GSTP1 and GSTT1. Patients and controls were all of Caucasian origin. DNA was isolated from either blood or tissue and tested by polymerase chain reaction followed by restriction fragment length polymorphism analyses. Logistic regression analyses showed significant age- and gender-adjusted risks for CRC associated with variant genotypes of UGT1A6 [OR 1.5, 95% (confidence interval) CI 1.03-2.3] and UGT1A7 (OR 2.4, 95% CI 1.3-4.6), whereas no associations were found between CRC and the other polymorphic genes as mentioned above. In conclusion, the data suggest that the presence of variant UGT1A6 and UGT1A7 genotypes with expected reduced enzyme activities, might enhance susceptibility to CRC.

Adult↗

PubMedDate not supplied

Tolerability of Raltitrexed ('Tomudex') in elderly patients with colorectal cancer.

PURPOSE: Colorectal cancer (CRC) is one of the major health problems of the Western world and the proportion of elderly patients with CRC is growing. Raltitrexed ('Tomudex'), a specific thymidylate synthase inhibitor, has shown efficacy and manageable toxicity in elderly CRC patients. In this retrospective study, the tolerability of raltitrexed in patients with CRC was examined in relation to age. PATIENTS AND METHODS: Toxicity parameters, graded according to World Health Organization criteria, were assessed in two patient groups: < 70 and > or = 70 years old. In total, 56% (50 out of 90) of patients treated with raltitrexed (3 mg/m2 as a 15-minute intravenous infusion every 3 weeks) were aged > 70 years (M:F 28:22; Eastern Cooperative Oncology Group performance status 0-1:2 38:12). RESULTS: Overall, 437 cycles of chemotherapy were administered and grade 3-4 toxicity was reported in < 10% of patients. There were no clinically significant differences between the two age groups, apart from grade 3-4 asthenia, which was reported by 6% and 0% of patients aged > or = 70 and < 70 years, respectively. This was in spite of a significantly lower calculated mean creatinine clearance in patients aged > or = 70 years compared with those patients < 70 years of age. CONCLUSION: The raltitrexed toxicity profile does not appear to be significantly influenced by age; however caution is recommended in the management of elderly patients, particularly in the presence of impaired renal function.

Adenocarcinoma↗

PubMed2003

Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer.

Sporadic colorectal cancer (CRC) is characterized by genetic and epigenetic changes such as regional DNA hypermethylation and global DNA hypomethylation. Epidemiological and animal studies suggest that aberrant DNA methylation is associated with low dietary folate intake, which is aggravated by high alcohol intake. The relationship between promoter methylation of genes involved in CRC carcinogenesis and folate and alcohol intake was investigated. Methylation of the APC-1A, p14(ARF), p16(INK4A), hMLH1, O(6)-MGMT, and RASSF1A promoters was studied using methylation-specific PCR in 122 sporadic CRCs, derived from patients with folate and alcohol intake at either the lower or the higher quintiles of the distribution. Overall, promoter hypermethylation frequencies observed were: 39% for APC; 33% for p14(ARF); 31% for p16(INK4A); 29% for hMLH1; 41% for O(6)-MGMT; and 20% for RASSF1A. For each of the tested genes, the prevalence of promoter hypermethylation was higher in CRCs derived from patients with low folate/high alcohol intake (n = 61) when compared with CRCs from patients with high folate/low alcohol intake (n = 61), but the differences were not statistically significant. The number of CRCs with at least one gene methylated was higher (84%) in the low folate intake/high alcohol intake group when compared with the high folate intake/low alcohol intake group (70%; P = 0.085). Despite the size limitations of this study, these data suggest that folate and alcohol intake may be associated with changes in promoter hypermethylation in CRC.

Aged↗

PubMed2006

BRAF mutation, CpG island methylator phenotype and microsatellite instability occur more frequently and concordantly in mucinous than non-mucinous colorectal cancer.

Mucinous colorectal cancer (CRC) has been reported to have distinct clinicopathological and genetic characteristics. However, the incidence and the relationship among microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and BRAF and KRAS mutations in mucinous and non-mucinous CRC are not known. Activating mutations of BRAF and KRAS and their relationship with MSI and CIMP were examined in 83 sporadic CRC specimens (26 mucinous and 57 non-mucinous CRC). MSI, CIMP, BRAF and KRAS mutation were observed in 17, 24, 25 and 36% of the tumors, respectively. BRAF mutation was highly correlated with MSI (p < 0.001) and CIMP (p < 0.001). A higher incidence of MSI (27% vs. 12%), CIMP (38% vs. 18%, p < 0.05) and BRAF mutation (46% vs. 16%, p < 0.01) was observed in mucinous CRC. KRAS mutation (27% vs. 40%) was observed more frequently in non-mucinous CRC. Significantly higher percentages of mucinous CRC (54%, p < 0.05) had MSI or CIMP or BRAF mutations. Concordant occurrence of 2 or more of these alterations was observed in 39% of mucinous CRC and only 11% of non-mucinous CRC (p < 0.01). The more frequent occurrence and closer association among MSI, CIMP and BRAF mutation in mucinous CRC observed in our study further supports the idea that its pathogenesis may involve distinct genetic and epigenetic changes.

Adenocarcinoma, Mucinous↗

PubMed1986

Current issues in the treatment of colorectal cancer.

For colorectal cancers that are confined to the bowel wall with uninvolved nodes, surgery alone is curative in most patients, and adjuvant treatment is usually not indicated. A combined modality approach for the initial treatment of many rectal and selected colonic carcinomas is based on data that "radical" operations do not necessarily prevent either local regrowth or distant failures and acceptance of a significant palliative but infrequent curative role for irradiation and chemotherapy when such failures occur. Published data for rectal cancer indicates that local recurrence can be markedly reduced by moderate to high dose pre- and post-operative irradiation +/- chemotherapy. For colon cancer, data from pilot trials suggest that post-operative irradiation may reduce local recurrence by stage when compared with surgery alone analyses, but randomized trials are needed. With locally advanced disease, aggressive treatment combinations appear to increase both local control and survival, but much interaction is required between involved physicians.

Adenocarcinoma↗

PubMed1987

Reporting colorectal cancer.

Reporting colorectal cancer comprises two phases: the careful collection of pathological data; and the division of patients into groups with differing prognoses. Dukes' classification of rectal cancer was the outcome of this dual approach. It evolved over many years, and full details of its final form were not published until 1958, towards the end of his career. Others modified the classification during its evolution, and numerous rival pathological and clinicopathological systems now exist. The resulting confusion that surrounds the Dukes classification may make it impossible to compare pathological findings and the results of treatment between different centres. The importance of meticulous dissection and examination of surgical specimens is emphasised and a simple set of recommendations made. It is shown how modern statistical methods may identify pathological variables that have independent clinical importance. On the basis of this information a new system of prognostic categorisation for patients receiving apparently curative surgery for rectal cancer has been developed, which is superior to the Dukes classification in that it can place many more patients into groups with clear prognostic implications.

Colonic Neoplasms↗

PubMed1992

[Continuous intra-arterial infusion chemotherapy in colorectal cancer patients with nonresectable metastatic liver cancer].

Five colorectal cancer patients with nonresectable metastatic liver cancer underwent continuous intraarterial chemotherapy in our institute from January to December 1991. Patients included four rectal cancers and one colonic cancer. 5-fluorouracil (5-FU) was infused continuously through an Infuse-A-Port; 360 mg/m2/day for one week after operation, and 180 mg/m2/day for the following three weeks. Since the fifth week after operation, two weeks without infusion and two weeks of infusion (180 mg/m2/day) were alternated as long as possible. Total periods of 5-FU infusion therapy were from one to 11 months and total doses of 5-FU ranged from 8,750 mg to 25,650 mg. Three patients showed partial response (PR) and two patients progressive disease (PD) (response rate; 60%). In three cases of PR, lengths of infusion therapy and total doses of 5-FU before PR was first observed was 8 weeks, 10,750 mg, 6 weeks, 9,250 mg, and 4 weeks, 8,750 mg, respectively. Four patients presented nausea, appetite loss or abdominal pain, which were considered to be side effects of 5-FU. In one of these four patients, infusion could not be continued because symptoms were so severe. However, catheter troubles were not noticed among all cases.

Colonic Neoplasms↗

PubMed1999

Possible beneficial effect of fish and fish n-3 polyunsaturated fatty acids in breast and colorectal cancer.

Breast and colorectal cancer are main causes of death in industrialized countries. In these cancers dietary factors appear to play beneficial or adverse roles. One of the possible beneficial factors may be fish intake or the n-3 polyunsaturated fatty acids from fish, as found in epidemiological and clinical studies. In population studies, high intake of fish during many years is associated with reduced risks of breast and colorectal cancer. Prospective and case-control studies either do not show an association between fish intake and cancer risks or show reduced risks at high fish intakes. In these studies, fish consumption may have been too low or may not reflect fish consumption over a longer period. In population, case-control, and prospective studies, fish and fish n-3 polyunsaturated fatty acids were not found to increase cancer risks. Clinical studies on markers of colorectal cancer indicate that fish n-3 polyunsaturated fatty acids may reduce cancer risk. In several studies in which the effect of fish consumption on cancer risk was investigated, meat and meat products were positively related to cancer risk, suggesting that cancer risks might be reduced more effectively when meat and meat products in meals are replaced by fish. In conclusion, the existing knowledge suggests that an increase in the consumption of fish and fish n-3 polyunsaturated fatty acids in industrialized countries may contribute to lower breast and colorectal cancer risks.

Animals↗

PubMed2002

Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis.

Familial adenomatous polyposis and hereditary non-polyposis colorectal cancer are dominantly inherited conditions with 100% and 80% life-time risk of developing colorectal cancer, respectively. The genetic mutations responsible for these two conditions lie in the adenomatous polyposis coli (APC) and mismatch repair genes. These same genes also play a key role in the formation of sporadic colorectal cancers, which arise on a background of a similar spectrum of mutations to the hereditary cancers. This article examines the genetic mechanisms underlying the hereditary colorectal cancers, as well as genetic predisposition to colorectal cancer in the general population in the absence of a clear-cut genetic syndrome. Colorectal cancer arises as the cumulative effect of multiple mutations within the cell, allowing it to escape growth and regulatory control mechanisms. This step-wise progression of mutations facilitates the histological transition from normal mucosa to adenoma to carcinoma. The latter part of this paper focuses on the key genetic events underlying this process and provides an overview of the genetic mechanisms responsible for colorectal tumorigenesis.

Adenoma↗

PubMed2000

Dendritic cell-based cancer immunotherapy: potential for treatment of colorectal cancer?

Human tumours including those of the gastrointestinal tract express a number of specific antigens that can be recognized by T cells, thus providing potential targets for cancer immunotherapy. Dendritic cells (DC) are rare leucocytes that are uniquely potent in their ability to capture, process and present antigens to T cells, and so selectively migrate through tissues to reach lymph nodes and spleen where initiation of immune responses takes place. Studies in murine tumour models have shown clearly that DC are capable of presenting tumour antigens to initiate tumour-specific cytotoxic T cell responses, and DC vaccination can induce anti-tumour activity against both primary tumours and pre-established tumour metastases. These findings together with the ability to culture sufficient numbers of DC from human bone marrow or blood progenitors have prompted the current major interest in their potential use in human tumour vaccination. Vaccine production involves harvesting autologous DC from cultured peripheral blood mononuclear cells in the presence of a cocktail of cytokines, ex vivo exposure of the DC to tumour antigens and return of pulsed DC to the patient to induce tumour immunity. Reports from Phase I/II clinical trials indicate that DC vaccines are safe with little or no side effect, and are capable of initiating antigen-specific T cell responses. Furthermore, defined tumour antigens are not necessarily required, which may make the process more applicable to human cancers, including many gastrointestinal cancers that lack well-characterized tumour-specific antigens. Additional trials of DC vaccination for a variety of human cancers including colorectal cancers are under way, and refinement of vaccine protocols and methods for targeting tumour antigens to DC in vivo are also being explored. There is reason to believe that DC-based vaccination could become an adjunct to current treatments for human cancers including colorectal cancer in the foreseeable future.

Clinical Trials as Topic↗

PubMed2005

Metastatic lymph node size and colorectal cancer prognosis.

BACKGROUND: Colorectal cancer patients with lymph node metastasis constitute a heterogeneous population with variable prognoses. In this study, my colleagues and I propose a simpler lymph node (LN) staging system for colorectal cancer. STUDY DESIGN: Four-hundred and twenty-three consecutive colorectal cancer patients were studied. Of these, 36 were excluded because another carcinoma was present. The remaining 387 patients entered the TNM staging analysis. In the survival analysis, 76 patients with distant metastasis were excluded and the remaining 311 patients (LN(-) = 204 and LN(+) = 107) were studied. The diameter of the largest metastatic LN (MLN) was measured on histopathological slides. After examination of various cutpoints and survival outcomes, patients with MLNs were classified into n1 (< or = 9 mm) and n2 (> or = 10 mm) groups, according to size of MLNs (n-stage). RESULTS: Using disease-free survival (DFS) and overall survival (OS) as outcomes, patients were separated into significant prognostic groups by MLN size (univariate, p < 0.0001) (5-year survival, DFS: n0 = 91.5%, n1 = 62.2%, and n2 = 34.4%; OS: n0 = 85.1%, n1 = 63.5%, and n2 = 42.5%) and International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) (N-stage) (univariate, p < 0.0001) (5-year survival, DFS: N0 = 91.5%, N1 = 60.5%, and N2 = 36.8%; OS: N0 = 85.1%, N1 = 65.3%, and N2 = 38.0%). But in patients with fewer than 15 LNs examined (n = 31), only the new nodal stage stratified patients into significant groups (OS: p = 0.003 and DFS: p = 0.001). Only the UICC/AJCC N-stage subcategories were further split into significant prognostic groups by MLN size (UICC/AJCC N1: DFS, p = 0.048 and OS, p = 0.11; N2: DFS, p = 0.04 and OS, p = 0.04). n-stage was an independent important factor both in the DFS and OS in multivariable analysis. CONCLUSIONS: MLN size is a strong prognostic variable in colorectal carcinoma. This new metric may help clinicians treating colorectal cancer patients, but additional studies are required before clinical application.

Adult↗

PubMed2004

Chemopreventive role of folic acid in colorectal cancer.

Mortality from colorectal cancer, a leading cause of death in the U.S.A. and other western countries, has remained unchanged over the past 45 years. Therefore, the search for strategies to prevent the development and progression of colorectal cancer has markedly intensified. Chemoprevention is one such strategy. Accumulating evidence suggests that folic acid, a water soluble vitamin, could be an effective chemopreventive agent for colorectal cancer. Results from several studies have demonstrated that a diet deficient in folic acid may be associated with an increased risk of colonic neoplasia, whereas dietary supplementation of this nutrient may be chemopreventive. Although the mechanisms by which folic acid exerts its chemopreventive role in colorectal carcinogenesis remain to be fully elucidated, supplemental folic acid has been shown to arrest the loss of heterozygosity (LOH) of the tumor suppressor gene DCC (deleted in colorectal cancer) and to stabilize its protein in normal appearing rectal mucosa of patients with colorectal adenomas. Data from in vitro studies utilizing colon cancer cell lines suggest that supplemental folic acid or its metabolite 5-methyltetrahydrofolate (5-MTF) attenuates the expression and activation of EGF-receptor (EGFR) as well as proliferation of cells. The folic acid mediated reduction of EGFR function could partly be the result of suppression of EGFR gene through increased methylation of CpG sequences within its promoter.

Animals↗

PubMed2004

The Quebec Association of Gastroenterology position paper on colorectal cancer screening - 2003.

Colorectal cancer is a leading cause of death and the third most common cancer in Canada. Evidence suggests that screening can reduce mortality rates and the cost effectiveness of a program compares favourably with initiatives for breast and cervical cancer. The objectives of the Association des gastro-entérologues du Québec Task Force were to determine the need for a policy on screening for colorectal cancer in Quebec, to evaluate the testing methods available and to propose one or more of these alternatives as part of a formal screening program, if indicated. Fecal occult blood testing (FOBT), endoscopy (including sigmoidoscopy and colonoscopy), barium enema and virtual colonoscopy were considered. Although most clinical efficacy data are available for FOBT and sigmoidoscopy, there are limitations to programs based on these strategies. FOBT has a high false positive rate and a low detection yield, and even a combination of these strategies will miss 24% of cancers. Colonoscopy is the best strategy to both detect and remove polyps and to diagnose colorectal cancer, with double contrast barium enema also being a sensitive detection method. The Task Force recommended the establishment, in Quebec, of a screening program with five- to 10-yearly double contrast barium enema or 10-yearly colonoscopy for individuals aged 50 years or older at low risk. The program should include outcome monitoring, public and professional education to increase awareness and promote compliance, and central coordination with other provincial programs. The program should be evaluated; specific billing codes for screening for colorectal cancer would help facilitate this. Formal feasibility, effectiveness and cost-effectiveness studies in Quebec are now warranted.

Barium Sulfate↗

PubMed2003

Microsatellite instability analysis and/or immunostaining for the diagnosis of hereditary nonpolyposis colorectal cancer?

Hereditary nonpolyposis colorectal cancer (HNPCC) represents 2-4% of colorectal cancers and is caused by a constitutional defect in a mismatch repair (MMR) gene, most commonly affecting the genes MLH1, MSH2, and MSH6. The MMR defect results in an increased cancer risk with the greatest lifetime risks for colorectal cancer and endometrial cancer. The HNPCC-associated tumor phenotype is generally characterized by microsatellite instability (MSI) and immunohistochemical loss of expression of the affected MMR protein. We have evaluated the information obtained from MSI analysis and immunostaining for MLH1, MSH2, and MSH6 in a series of 128 tumors from patients suspected of having HNPCC. A MSI-high pattern was present in 59 of 128 (46%) tumors. Loss of immunohistochemical expression for at least one of these MMR proteins was found in 54 of 59 (92%) evaluable MSI tumors. This loss affected MLH1 in 28, MSH2 in 22, and MSH6 in 21 tumors (with MSH6 as the only loss in 4 tumors). Five (8%) MSI-high tumors showed normal MMR protein expression. All 69 microsatellite stable or MSI-low tumors showed normal immunostaining for all three proteins. In 28 patients, all with MSI-H tumors, germ-line mutations of MLH1, MSH2, or MSH6 had been identified, and a corresponding immunohistochemical loss of MMR protein expression was identified in all these cases. In summary, immunostaining for the MMR proteins MLH1, MSH2, and MSH6 had a sensitivity of 92% and a specificity of 100% for detecting MMR-deficient tumors. MMR protein immunostaining facilitates mutation analysis in suspected HNPCC patients, since it pinpoints the mutated gene, but until the genetic background to the MSI tumors with retained MMR protein expression has been clarified, we suggest that MSI and MMR protein immunostaining should optimally be combined in clinical HNPCC analysis.

Adaptor Proteins, Signal Transducing↗