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PubMed2006

First- and second-line therapy of metastatic colorectal cancer.

In the USA, colorectal cancer is the fourth most prevalent cancer and is the second leading cause of cancer death after lung cancer. In 2006, 148,610 colorectal cancer cases are expected in the USA, with 55,170 deaths expected from this disease. After years of stagnation, the treatment of metastatic colorectal cancer has recently made dramatic advances. The previous standard of care, 5-fluorouracil, is the now the backbone of combination regimens with oxaliplatin or irinotecan. The addition of biological agents, such as the vascular endothelial growth factor inhibitor, bevacizumab, and the epidermal growth factor receptor inhibitors, cetuximab and panitumumab, have further enhanced the activity of conventional chemotherapy. These advances have increased the overall survival of advanced colorectal cancer patients, which was once 6 months with best supportive care, to over 2 years if all active agents are used in the course of the disease.

Antibodies, Monoclonal↗

PubMed2006

A patient's race/ethnicity does not explain the underuse of appropriate adjuvant therapy in colorectal cancer.

INTRODUCTION: To improve colorectal cancer outcomes, appropriate adjuvant therapy (chemotherapy, radiation therapy) should be given. Numerous studies have demonstrated underuse of adjuvant therapy in colorectal cancer. The current study examines variables associated with underuse of adjuvant therapy. METHODS: Three population-based databases were linked: California Cancer Registry, California Patient Discharge Database, 2000 Census. All colorectal cancer patients diagnosed from 1994 to 2001 were studied. Patient characteristics (age, gender, race/ethnicity, comorbidities, payer, diagnosis year, socioeconomic status) were used in five multivariate regression analyses to predict receipt of chemotherapy for Stage III colon cancer, and receipt of chemotherapy and radiation therapy for Stages II, III rectal cancer. RESULTS: The overall cohort was 18,649 Stage III colon cancer and Stages II, III rectal cancer patients. Mean age was 68.9 years, 50 percent male, 74 percent non-Hispanic white, 6 percent black, 11 percent Hispanic, 9 percent Asian, and 65 percent had no significant comorbid disease. Receipt of chemotherapy was 48 percent for Stage III colon cancer, 48 percent for Stage II rectal cancer, and 66 percent for Stage III rectal cancer. Receipt of radiation therapy was 52 percent for Stage II rectal cancer and 66 percent for Stage III rectal cancer. In all five models, low socioeconomic status predicted underuse of chemotherapy or radiation therapy (P < 0.016). Race/ethnicity was not statistically associated with underuse in any of the models. CONCLUSIONS: Most literature identifies race/ethnicity as the reason for disparate receipt of adjuvant therapy in colorectal cancer. Using a more robust database of three population-based sources, our analysis demonstrates that socioeconomic status is a more important predictor of (in)appropriate care than race/ethnicity. Explicit measures to improve care to the poor with colorectal cancer are needed.

Age Factors↗

PubMed2005

Association between subject factors and colorectal cancer screening participation in Ontario, Canada.

Colorectal cancer screening reduces colorectal cancer incidence and mortality. This population-based study was conducted to evaluate (i) the association between subject factors and colorectal screening participation and (ii) the lifetime prevalence of colorectal screening among the general population of Ontario, Canada. Population-based controls were recruited by the Ontario Familial Colorectal Cancer Registry during 1998-2000. The 1944 persons completed an epidemiologic questionnaire. Descriptive statistics were computed and step-wise multivariate logistic regression was used to estimate odds ratios and 95% confidence intervals. Overall, 23% of persons greater than 50 years of age reported ever having had colorectal cancer screening; 17% reported fecal occult blood test (FOBT), 6% sigmoidoscopy, and 4% colonoscopy. Family history of colorectal cancer, increased age, higher household income, and use of hormone replacement therapy (among women) were all significantly associated with ever having had colorectal cancer screening. The low prevalence of colorectal cancer screening among the target population suggests the need for an increased awareness of the public health importance of colorectal cancer screening.

Adult↗

PubMed1990

The genetics of colorectal cancer.

Two features of colorectal cancer have greatly aided the recent progress in understanding its genetics: firstly the majority of colorectal cancers arise from premalignant adenomatous polyps allowing the analysis of somatic genetic changes during tumorigenesis, and secondly there are several well defined inherited syndromes that predispose to colorectal cancer in an autosomal dominant manner. The familial polyposis gene has been mapped to chromosome 5q and loss of material on chromosome 5 shown in a large proportion of sporadic (non-familial) adenomas and carcinomas. Allele loss has also been found in a high proportion of colorectal cancers on chromosomes 17 and 18 and the respective genes involved identified as that coding for the oncoprotein p53 on 17p and the DCC ('deleted in colorectal carcinomas') gene on 18q. In addition activation of k-ras is found frequently in colorectal adenomas and carcinomas. The development of colorectal neoplasia is associated with the accumulation of genetic changes. Family studies of apparently sporadic colorectal cancer probands have shown an increased incidence of adenomas and carcinomas in first degree relatives. More recently pedigree studies have suggested that an inherited predisposition may be responsible for the majority of colorectal tumours.

Chromosome Aberrations↗

PubMed2006

Notoginseng enhances anti-cancer effect of 5-fluorouracil on human colorectal cancer cells.

PURPOSE: Panax notoginseng is a commonly used Chinese herb. Although a few studies have found that notoginseng shows anti-tumor effects, the effect of this herb on colorectal cancer cells has not been investigated. 5-Fluorouracil (5-FU) is a chemotherapeutic agent for the treatment of colorectal cancer that interferes with the growth of cancer cells. However, this compound has serious side effects at high doses. In this study, using HCT-116 human colorectal cancer cell line, we investigated the possible synergistic anti-cancer effects between notoginseng flower extract (NGF) and 5-FU on colon cancer cells. METHODS: The anti-proliferation activity of these modes of treatment was evaluated by MTS cell proliferation assay. Apoptotic effects were analyzed by using Hoechst 33258 staining and Annexin-V/PI staining assays. The anti-proliferation effects of four major single compounds from NGF, ginsenosides Rb1, Rb3, Rc and Rg3 were also analyzed. RESULTS: Both 5-FU and NGF inhibited proliferation of HCT-116 cells. With increasing doses of 5-FU, the anti-proliferation effect was slowly increased. The combined usage of 5-FU 5 microM and NGF 0.25 mg/ml, significantly increased the anti-proliferation effect (59.4 +/- 3.3%) compared with using the two medicines separately (5-FU 5 microM, 31.1 +/- 0.4%; NGF 0.25 mg/ml, 25.3 +/- 3.6%). Apoptotic analysis showed that at this concentration, 5-FU did not exert an apoptotic effect, while apoptotic cells induced by NGF were observed, suggesting that the anti-proliferation target(s) of NGF may be different from that of 5-FU, which is known to inhibit thymidilate synthase. CONCLUSIONS: This study demonstrates that NGF can enhance the anti-proliferation effect of 5-FU on HCT-116 human colorectal cancer cells and may decrease the dosage of 5-FU needed for colorectal cancer treatment.

Animals↗

PubMedDate not supplied

Dynamics of genetic instability in sporadic and familial colorectal cancer.

Genetic instability is a defining feature of human cancer. In colorectal cancer, two specific types of genetic instabilities have been identified: microsatellite instability (MIN) leads to a 1000-fold increase in the rate of subtle DNA changes, whereas chromosomal instability (CIN) enhances the rate at which gross chromosomal changes occur during cell division. In this paper, we develop a mathematical model for the dynamics of colon cancer initiation. We outline the processes and rate constants that determine the fraction of colon cancers where MIN or CIN mutations precede the inactivation of the first tumor suppressor gene. For a wide range of parameter values, we find support for the radical hypothesis that genetic instability initiates colonic tumorigenesis. We compare sporadic and hereditary forms of colorectal cancer.

Adenomatous Polyposis Coli↗

PubMed2004

The NOD2 3020insC mutation and the risk of colorectal cancer.

Several predispositions to colorectal cancer have been identified, but little is known about genetic susceptibilities to disease in older persons. Colorectal cancer is a risk in Crohn's disease and is believed to be associated with an inappropriate inflammatory response. Recently, the NOD2 gene has been associated with Crohn's disease, which further strengthens the notion that the inflammatory response plays a crucial role in this disease. Several mutations have been identified in the NOD2 gene, which appear with significantly higher frequency in patients with the disease. One such mutation (3020insC) is believed to be clearly causative because it results in a prematurely truncated protein with a predicted reduction in functional efficiency. In this report, we have examined the frequency of the 3020insC mutation in a series of 856 individuals including 556 patients with colorectal cancer. The frequency of the 3020insC mutation in a consecutive series of 250 non-hereditary nonpolyposis colorectal cancer patients >50 years of age was significantly elevated compared with the control population (odds ratio, 2.23; P = 0.0046). The results indicate that NOD2 may be a predisposing factor to colorectal cancer characterized by an older average age of disease onset in persons who do not harbor any other genetic predisposition to disease.

Adult↗

PubMed2001

Four novel MSH2 and MLH1 frameshift mutations and occurrence of a breast cancer phenocopy in hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations of genes encoding for proteins of the mismatch repair (MMR) machinery. The majority of mutations occur in the MLH1 and MSH2 genes, and consist of splice-site, frameshift and nonsense changes, leading to loss of protein function. In this study, we screened 7 HNPCC families for MLH1/MSH2 mutations. Sequence changes were identified in 5 families. Four alterations were novel 1- or 2-bp deletions or insertions causing a frameshift and appearance of premature stop codons (MLH1: c.597-598delGA, c.1520-1521insT; MSH2: c.1444delA, c.119delG). The four small insertions/ deletions were located within stretches of simple repeated sequences. By reviewing the HNPCC mutation database, we found that the majority of 1-2 bp frameshift mutations similarly affects simple repetitive stretches, pointing to DNA polymerase slippage during replication as the most likely source of such errors. We also evaluated microsatellite instability (MSI) in a breast carcinoma (BC) from an MLH1 mutation carrier. While a colon cancer from the same individual showed MSI, the BC specimen was MSI-negative, indicating that development of the latter tumor was unrelated to MMR impairment, despite presence of a constitutional MLH1 mutation. Hum Mutat 17:521, 2001.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Family history of colorectal adenomatous polyps and increased risk for colorectal cancer.

BACKGROUND: The risk for colorectal cancer among family members of patients with colorectal cancer is well established, but the risk among family members of patients with colorectal adenomas is less well established. OBJECTIVE: To examine the risk for colorectal cancer among first-degree relatives of patients with adenoma compared with that among first-degree relatives of controls without adenoma. DESIGN: Reconstructed cohort study. SETTING: Three university-based colonoscopy practices in New York City. PATIENTS: 1554 first-degree relatives of 244 patients with newly diagnosed adenomas and 2173 first-degree relatives of 362 endoscopically normal controls. MEASUREMENTS: Structured interviews were used to obtain family history. Adjusted relative risks (RR) were estimated from Cox proportional hazards regression models. RESULTS: The risk for colorectal cancer was elevated (RR, 1.74 [95% CI, 1.24 to 2.45]) among first-degree relatives of patients with newly diagnosed adenomas compared with the risk among first-degree relatives of controls. This increased risk was the same for parents (RR, 1.58 [CI, 1.07 to 2.34]) and siblings (RR, 1.58 [CI, 0.81 to 3.08]). First-degree relatives of patients with adenomas did not have elevated risk for other cancers. The risk for colorectal cancer among family members increased with decreasing age at diagnosis of adenoma in probands. Among first-degree relatives of patients who were 50 years of age or younger when the adenoma was diagnosed, the risk was more than four times greater (RR, 4.36 [CI, 2.24 to 8.51]) than that among first-degree relatives of patients who were older than 60 years of age when the adenoma was diagnosed. CONCLUSIONS: First-degree relatives of patients with newly diagnosed adenomas, particularly of patients who are 50 years of age or younger at diagnosis, are at increased risk for colorectal cancer and should undergo screening similar to that recommended for relatives of patients with colorectal cancer.

Adenomatous Polyposis Coli↗

PubMed2005

Stem cell factor (SCF) and interleukin 3 (IL-3) in the sera of patients with colorectal cancer.

For a long time markers that can detect a malignant cell transformation as early as possible have been sought. Substances which have been discovered are known as tumor markers. Stem cell factor (SCF) and interleukin 3 (IL-3) are members of a group of glycoprotein growth factors called hematopoietic cytokines (HCs). These factors take part in the regulation of developmental processes of hematopoietic progenitor cells and it was proved that HCs can be produced by different cancer cells, including colorectal cancer. The aim of this study was to investigate a potential role for SCF and IL-3 as tumor markers for colorectal cancer. We compared the serum levels of SCF and IL-3 in colorectal cancer patients with those in healthy subjects (control group) and commonly accepted tumor markers, such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). We defined the diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and receiver-operating characteristics (ROC) curve of tested substances. SCF and IL-3 were determined using enzyme-linked immunosorbent assay (ELISA). CEA and CA 19-9 were measured by microparticle enzyme immunoassay. The serum levels of HCs and tumor markers were investigated in 75 patients with colorectal cancer and in 40 healthy subjects. There were significant differences in the level of circulating SCF and IL-3 in the colorectal cancer patients compared to the control group. Moreover, the diagnostic sensitivity of SCF was higher than the sensitivity of CEA and CA 19-9. The SCF area under the ROC curve was larger than the IL-3 area but smaller than the CEA and CA 19-9 areas. The diagnostic specificities of cytokines were lower than those of tumor markers, but the combined use of cytokines and tumor markers increased the diagnostic values. The highest values of diagnostic parameters were observed for the combined use of SCF and CA 19-9. These results suggest a potential role for SCF and IL-3 as tumor markers for colorectal cancer, especially in combination with CEA or CA 19-9.

Adult↗

PubMed2004

High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases.

PURPOSE: Overexpression of PRL-3 has been implicated in colorectal cancer metastases. We investigated the significance of PRL-3 expression in the progression and development of colorectal cancer. EXPERIMENTAL DESIGN: We transfected PRL-3-specific small interfering RNA into human colon cancer DLD-1 cells and analyzed its effect on proliferation, motility, and hepatic colonization. Using an in situ hybridization method, we examined the levels of PRL-3 expression in both primary (177 cases) and metastatic (92 cases) human colorectal cancers and elucidated the relationships with clinicopathological parameters including the incidence of metachronous liver and/or lung metastasis after curative surgery for primary tumor. RESULTS: Transient down-regulation of PRL-3 expression in DLD-1 cells abrogated motility (in vitro) and hepatic colonization (in vivo), but no effect on the proliferation of these cells was observed. In human primary colorectal cancers, the frequency of up-regulated PRL-3 expression in cases with liver (84.4%) or lung (88.9%) metastasis was statistically higher than that in cases without either type of metastasis (liver, 35.9%; lung, 42.3%). In metastatic colorectal cancer lesions, high expression of PRL-3 was frequently detected (liver, 91.3%; lung, 100%). Interestingly, metachronous metastasis was observed more frequently in the cases with high PRL-3 expression (P < 0.0001). CONCLUSIONS: These results indicate that PRL-3 expression in colorectal cancers may contribute to the establishment of liver metastasis, particularly at the step in which cancer cells leave the circulation to extravasate into the liver tissue. In addition, PRL-3 is expected to be a promising biomarker for identifying colorectal cancer patients at high risk for distant metastases.

Aged↗

PubMed2005

Prognostic significance of MMP-1 and MMP-3 functional promoter polymorphisms in colorectal cancer.

PURPOSE: Matrix metalloproteinase (MMP) belongs to a large group of proteases capable of breaking essentially all components of the extracellular matrix. They are implicated in all steps of tumorogenesis, cancer invasion, and metastasis. Among them, metalloproteinase type 1 (MMP-1) is implicated in tumor invasion and metastasis in different types of cancers including colorectal cancer in which its expression was correlated with poor prognosis. A polymorphism in the promoter region of the MMP-1 gene leads to a variation of its level of transcription. STUDY DESIGN: MMP-1 -1607ins/delG and MMP-3 - 1612 ins/delA promoter polymorphisms were genotyped by multiplex PCR from 201 colorectal cancer patients. The median follow-up of patients was 30 months. The MMP genotypes were correlated to clinical outcome. RESULTS: Patients with the -1607insG/-1607insG MMP-1 genotype had significantly worse specific survival than the others in the whole series (P < 0.04), in stage I to III patients (P < 0.001), and in patients stage I and II (P < 0.01). In multivariate analysis, MMP-1-1607insG allele showed to be an independent poor prognostic factor after adjustment on stage, age, and the use of adjuvant chemotherapy. MMP-3 polymorphism was not associated with survival. CONCLUSIONS: In the subgroups of nondistant metatastic patients (stages I and II, and stages I-III), an inverse relation between the number of MMP-1-1607insG allele and survival was observed suggesting a gene dosage effect. Our results are consistent with the importance of MMP-1-1607ins/delG functional polymorphism in regulating transcription level and with the relationship between MMP-1 expression and cancer invasion, metastasis, and prognosis.

Adult↗

PubMed2005

Components of olive oil and chemoprevention of colorectal cancer.

Olive oil contains a vast range of substances such as monounsaturated free fatty acids (e.g., oleic acid), hydrocarbon squalene, tocopherols, aroma components, and phenolic compounds. Higher consumption of olive oil is considered the hallmark of the traditional Mediterranean diet, which has been associated with low incidence and prevalence of cancer, including colorectal cancer. The anticancer properties of olive oil have been attributed to its high levels of monounsaturated fatty acids, squalene, tocopherols, and phenolic compounds. Nevertheless, there is a growing interest in studying the role of olive oil phenolics in carcinogenesis. This review aims to provide an overview of the relationship between olive oil phenolics and colorectal cancer, in particular summarizing the epidemiologic, in vitro, cellular, and animal studies on antioxidant and anticarcinogenic effects of olive oil phenolics.

Animals↗

PubMed2002

Recent developments in colorectal cancer screening and prevention.

Colorectal cancer is a significant contributor to morbidity and mortality in the United States. Studies published in the early 1990s, showing that screening for colorectal cancer can reduce colorectal cancer-related mortality, led many organizations to recommend screening in asymptomatic, average-risk adults older than 50 years. Since then, however, national screening rates remain low. Several important studies published over the past four years have refined our understanding of existing screening tools and explored novel means of screening and prevention. The most important new developments, which are reviewed in this article, include the following: Additional trial results support the effectiveness of fecal occult blood testing in reducing the incidence of, and mortality from, colorectal cancer. New studies document the sensitivity of fecal occult blood testing, sigmoidoscopy, and double-contrast barium enema compared with colonoscopy. Cost-effectiveness models show that screening by any of several methods is cost-effective compared to no screening. Randomized trials show that calcium is effective but fiber is not effective in preventing reoccurrence of adenomatous polyps. Preliminary data suggest that nonsteroidal anti-inflammatory drugs may prevent adenomatous polyps and that DNA stool tests and virtual colonoscopy may show promise as screening tools. This new information provides further support for efforts to increase the use of colorectal cancer screening and prevention services in adults older than 50 years.

Adenoma↗

PubMed2005

Costs and cost effectiveness of a health care provider-directed intervention to promote colorectal cancer screening among Veterans.

PURPOSE: Colorectal cancer screening is underused, particularly in the Veterans Affairs (VA) population. In a randomized controlled trial, a health care provider-directed intervention that offered quarterly feedback to physicians on their patients' colorectal cancer screening rates led to a 9% increase in colorectal cancer screening rates among veterans. The objective of this secondary analysis was to assess the cost effectiveness of the colorectal cancer screening promotion intervention. METHODS: Providers in the intervention arm attended an educational workshop on colorectal cancer screening and received confidential feedback on individual and group-specific colorectal cancer screening rates. The primary end point was completion of colorectal cancer screening tests. Sensitivity analyses investigated cost-effectiveness estimates varying the data collection methods, costs of labor and technology, and the effectiveness of the intervention. RESULTS: Rates of colorectal cancer screening for the intervention versus control arms were 41.3% v 32.4%, respectively (P < .05). The incremental cost-effectiveness ratio was dollar 978 per additional veteran screened based on feedback reports generated from manual review of records. However, if feedback reports could be generated from information technology systems, sensitivity analyses indicate that the cost-effectiveness estimate would decrease to dollar 196 per additional veteran screened. CONCLUSION: An intervention based on quarterly feedback reports to physicians improved colorectal cancer screening rates at a VA medical center. This intervention would be cost effective if relevant data could be generated by existing information technology systems. Our findings may have broad applicability because a 2005 Medicare initiative will provide the VA electronic medical record system as a free benefit to all US physicians.

Aged↗

PubMed2003

Clinical implications of molecular diagnosis in hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer predisposition accounting for approximately 1%-5% of all colorectal cancers. Clinical management of HNPCC families is most challenging due to the following factors: (1) reduced penetrance of approximately 80%; (2) predisposition to cancer of the colorectum but also of the endometrium, urinary tract and small bowel; (3) broad inter- and intrafamilial heterogeneity; and (4) highly accelerated adenoma carcinoma sequence in the colorectum. To date, HNPCC may be defined either by the so-called Amsterdam I+II criteria or by detection of a mutation in one of the mismatch repair genes. Once the positive mutation has been identified, predictive testing of at-risk family members is available. Screening recommendations for clinically identified families, mutation carriers, and their unaffected at-risk relatives must be defined for clinical management. The question of prophylactic colectomy in HNPCC is also discussed.

Adenoma↗

PubMed2002

Seven novel MLH1 and MSH2 germline mutations in hereditary nonpolyposis colorectal cancer.

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most frequent hereditary form of colorectal cancer and is caused by germline mutations in mismatch repair (MMR) genes. The majority of mutations occur in MLH1 and MSH2. We report hereby seven novel germline mutations in these two genes (five in MLH1 and two in MSH2). All mutations have been found in families fulfilling criteria of the Bethesda guidelines and four of which also fulfilled the Amsterdam criteria. We identified three insertions or deletions of 1 bp leading to premature stop codons (MLH1: c.341delC, c.1413-1414insA; MSH2: c.1119delG) and three nonsense mutations (MLH1: c.67G>T [E23X], c.436C>T [Q146X]; MSH2: c.1857T>G [Y619X]). The corresponding tumors showed a high level of microsatellite instability (MSI-H) and a complete loss of expression of the affected protein. In addition, a missense mutation in MLH1 was identified (c.1984A>C [T662P]). The respective tumor also showed a high level of microsatellite instability but a reduced, rather then lost, expression of the MLH1-protein. This missense mutation was not found in 107 healthy control individuals and in 54 HNPCC patients.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Screening for colorectal cancer--United States, 1997.

Colorectal cancer is the second leading cause of cancer-related deaths in the United States. During 1999, approximately 129,400 new cases of colorectal cancer will be diagnosed, and 56,600 persons will die from the disease. In 1996, the U.S. Preventive Services Task Force (USPSTF) recommended the use of specific screening tests (i.e., annual fecal-occult blood testing [FOBT] and/or periodic flexible sigmoidoscopy for persons aged > or =50 years) to reduce colorectal cancer-related mortality. In 1997, the American Cancer Society and an interdisciplinary task force developed guidelines that recommend one test or a combination of several tests for colorectal cancer screening. To estimate the proportion of the U.S. population that received colorectal cancer screening tests, CDC analyzed data from the 1997 Behavioral Risk Factor Surveillance System (BRFSS) on the use of a home-administered blood stool test, or FOBT, and sigmoidoscopy/proctoscopy. This report summarizes the results of this analysis, which documents low rates of use of colorectal cancer screening tests.

Aged↗