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PubMed2001

New therapies, new directions: advances in the systemic treatment of metastatic colorectal cancer.

Colorectal cancer is the second leading cause of cancer death and it is clear that patients with metastatic disease have better quality of life and survival when given treatment. Despite four decades of experience of treating patients with fluorouracil, there remains considerable controversy about the optimum dose and scheduling, as well as biomodulation with leucovorin and methotrexate. However, irrespective of the dose and schedule, overall survival times are poor--about 1 year. Disappointingly, oral agents with similar mechanisms to fluorouracil do not improve survival rates in comparison with fluorouracil and leucovorin treatment. Irinotecan and oxaliplatin are newer agents that have improved the response rates for patients with metastatic disease when they are added to flurouracil and leucovorin. The combination of irinotecan, fluorouracil, and leucovorin has also improved overall survival. These are small advances in the fight against colorectal cancer, and further drug development is necessary.

Antineoplastic Agents↗

PubMedDate not supplied

The molecular basis of colorectal cancer.

Colorectal cancers, whether sporadic or hereditary, are caused by a defined set of molecular events. The genes and pathways involved in the earliest steps of tumorigenesis have crucial functions in the regulation of normal crypt homeostasis. Further insight into these pathways can lead to the development of useful prognostic indicators, and target preventive and therapeutic strategies in the management of colorectal cancer. Mutations in the APC/beta-catenin/Tcf-4 pathway lead to important changes in stem cell dynamics, before clinically identifiable lesions appear. Preventive strategies aimed at reversing these changes or therapeutic interventions targeting cell populations with these alterations should be most efficacious.

Adenoma↗

PubMed1995

[Determination of the activated proto-oncogene (Ki-ras) in feces. A new laboratory analysis for early diagnosis of colorectal cancer].

Colorectal cancer is one of the most common malignancies in Norway. Many cases of the disease are detected at a stage where surgery is unlikely to result in cure. Currently used screening tests based on faecal occult blood and other tumour markers are poor indicators of colorectal neoplasia. Multiple gene alterations are associated with colorectal carcinogenesis. Mutations in the Ki-ras oncogene occur in 50% of colorectal carcinomas and also in 50% of the precursor lesions, the adenomas. These mutations have proved to be detectable in the faeces of patients with colorectal tumours, but the techniques used so far have been impractical for screening purposes. We have developed a rapid and simple laboratory technique, based on the polymerase chain reaction, for detecting mutated Ki-ras in the faeces. In eight of 12 patients with mutated Ki-ras in adenomas or carcinomas we found the corresponding mutations in stool samples. Our results represent a significant progression towards a simple and effective DNA-based screening strategy for early detection of curable colorectal cancer.

Aged↗

PubMed1995

[Heredity and colorectal cancer].

Colorectal cancer is the second leading cause of death from malignancies in Western Countries. In spite of advances in treatment, little change in survival has been accomplished in last decades and this mandates greater importance to prevention and early detection. Although dietary factors have received primary attention familial clustering suggests that susceptibility to KCR is inherited. Hereditary colorectal cancer can arise on Familial Adenomatous Polyposis (HCC) or not on polyposis (HNPCC) and members of these families are at high risk of such neoplasias. Anyway, even in "sporadic" forms of KCR first-degree relatives have a 2 to 3-fold increased risk of the same cancer. The most desirable screening protocol would be a simple procedure involving only a blood test to identify gene defect by molecular biology techniques. Unfortunately, this is not practically possible, for lack of specific genetic alterations, out of FAP, and only the study of family history can enable targeted surveillance and cost-effective management strategies.

Adenomatous Polyposis Coli↗

PubMed2005

[Anemia and colorectal cancer].

Colorectal cancers are classically revealed by a low digestive bleeding, which can be occult or exteriorized. They commonly present anemia at the diagnosis leading to particular outcomes. Perioperative blood transfusions are frequently indicated for the treatment of localized tumors and for hepatic resection of metastatic lesions but transfusions seem to have a negative impact on prognosis by increasing infections and potentially recurrence. In this context, various strategies aim at limiting the transfusional risk (autologous transfusion, preoperative use of erythropoietin...). Anemia associated with advanced colorectal cancers provides the same interest as for any metastatic tumor, as quality of life of patients is correlated to the hemoglobin's level.

Anemia, Iron-Deficiency↗

PubMed1989

Detection and surveillance of colorectal cancer.

Colorectal cancer is the second most common cause of cancer in the United States. The overall mortality rate approaches 60%. However, the detection of early lesions results in a mortality rate of 20% or less. Therefore, if improvement in survival is to occur, increased efforts need to be focused not only on primary prevention but also on early detection of malignant lesions and the eradication of potentially malignant lesions. There is no universal consensus as to how this can be accomplished. The purpose of this article is to serve as a guideline, providing a practical basis for improving early detection and management of colorectal cancer and its precursors.

Adult↗

PubMed1995

Adjuvant chemotherapy for colorectal cancer.

Colorectal cancer is the second most common cancer in the Western world, and yet the survival after potentially curative excisional surgery has improved little over the last half century. Newer tumour prognostic markers are not superior to conventional Dukes' staging and there are currently no markers which predict response to chemotherapy. Adjuvant chemotherapy has had a chequered past, but recently a number of important prospective studies have demonstrated its proven benefit in patients with Dukes' stage C colorectal cancer. However, several issues still require clarification. (1) Do immunomodulators such as levamisole have a significant role in adjuvant chemotherapy? (2) Which patients derive most benefit from adjuvant chemotherapy? (3) Do prognostic markers have a role in predicting these patients? Approximately 30% of patients with Dukes' stage B cancers die of metastatic disease and the role of adjuvant chemotherapy in patients with these tumours seems worth exploring. Only a large randomised trial can give answers to these important questions. Such a trial would also encourage the widespread introduction of standard methods of surgical and pathological assessment.

Chemotherapy, Adjuvant↗

PubMed1985

Surveillance and early diagnosis of colorectal cancer.

Colorectal cancer is a major health problem in western countries such as the United States. The annual incidence of more than 130,000 new cases, and the annual mortality of more than 60,000 people justifies a consideration of efforts for its control. New concepts of risk, better understanding of the adenoma-adenocarcinoma natural history, and new screening and diagnostic technology have provided a basis for possible preventive approaches. Trials are in progress evaluating the fecal occult blood test and sigmoidoscopy screening tests, and colonoscopy as a diagnostic and surveillance test. Evaluation of data from the trials requires many considerations regarding bias and validity. Although the data from screening trials appear to be promising, they are still preliminary. In the interim, guidelines have been proposed for screening strategies related to average risk and high risk groups. Considerably more work will be required in order to provide the scientific basis for the control of large bowel cancer. In addition, efforts will have to be directed toward the effective communication of new concepts, data and techniques to the majority of physicians who interact with the at-risk population. Efforts will also have to be directed to the public at large to enhance their compliance with the approaches to increase their awareness of colorectal cancer as an important disease and to eliminate their misconceptions. Finally the cost effectiveness of various screening strategies will have to be examined once data indicates a benefit of such approaches.

Clinical Trials as Topic↗

PubMed2002

Surgery for colorectal cancer.

Colorectal cancer remains the second commonest cause of cancer death in North America and Western Europe. Surgery remains the mainstay of treatment. The aim of surgery should be to achieve cure and to avoid locoregional recurrence. The fixity of the primary tumour determines resectability, and the extent of spread determines ultimate survival. Patients with rectal cancer present a particular problem. There is good evidence that lower local recurrence rates may be achieved both by improvements in surgical technique and the use of adjuvant radiotherapy. The importance of adequate treatment of the circumferential tumour margin cannot be over-emphasised; meticulous attention is required to ensure an adequate circumferential excision. The lowest incidences of locoregional recurrence are reported by surgeons who perform total mesorectal excision. Anorectal function, sexual and urinary dysfunction may occur after rectal excision. Both postoperative and pre-operative radiotherapy can reduce the incidence of local recurrence. However, in view of the low recurrence rates obtained with TME alone, the role of adjuvant radiotherapy requires further evaluation. Several aspects of the surgical management of colorectal cancer, for example, the role of transanal local excision of selected rectal cancers and laparoscopic surgery, the management of obstructed cases and the role of follow-up remain to be defined clearly.

Aged↗

PubMed1991

Acetylator genotype-dependent expression of arylamine N-acetyltransferase in human colon cytosol from non-cancer and colorectal cancer patients.

Human epidemiological studies suggest an association between rapid acetylator phenotype and colorectal cancer. Acetylator genotype-dependent expression by the human colon of arylamine N-acetylation capacity, catalyzed by acetyl coenzyme A-dependent N-acetyltransferase(s) (EC 2.3.1.5) (NAT), may be an important risk factor in the initiation of colorectal cancer. Human colon cytosols from 48 fresh surgical samples were investigated for NAT activity toward p-aminobenzoic acid and the arylamine carcinogens 4-aminobiphenyl, 2-aminofluorene, and beta-naphthylamine. Apparent Vmax determinations of NAT activity toward these substrates indicated that 40 of these colons segregated into 3 distinct phenotypes. The distribution of the patients into rapid (5), intermediate (18), or slow (17) acetylators is a ratio that is not significantly different from the expected Hardy-Weinberg distribution of 3:16:21 (chi 2 = 2.206, P = 0.363). Significantly greater mean apparent Vmax levels were found in colons from rapid as compared to intermediate acetylators (1.5-3-fold) (P less than 0.001) and intermediate as compared to slow (2.5-3-fold) (P less than 0.005) acetylator phenotypes for the four arylamine substrates. Apparent Km determinations indicated that human colon NAT from rapid acetylators had a significantly lower affinity for the arylamine substrates (P less than 0.05) compared to intermediate or slow acetylator groups. No difference in apparent Km was detected for the cofactor acetyl coenzyme A between the three acetylator phenotypes. The colon samples were also tested for cytosolic N-hydroxy-2-acetylaminofluorene sulfotransferase activity and found to be monomorphically distributed for this enzyme activity. Of the 40 colon samples, 37 were from individuals of known pathology, 25 with colorectal cancer and 12 with no diagnosed neoplasia. Comparisons between mean apparent Vmax and mean apparent Km levels for each of the acetylator phenotypes indicated no significant differences between non-cancer and colorectal cancer patients. The distribution of rapid, intermediate, and slow acetylator phenotypes among the colon samples derived from colorectal cancer patients was precisely that predicted from published frequencies for the rapid and slow acetylator allele in Americans of African and European ancestry.

Acetylation↗

PubMed2004

Evidence-based update of chemotherapy options for metastatic colorectal cancer.

Colorectal carcinoma is one of the most common malignancies in the Western world. Although fluorouracil (5-FU) has been used for over 40 years, only in the last decade has its value been recognized in the treatment of advanced colorectal cancer. Early randomized studies explored the best possible doses and schedules of 5-FU and its modulators such as folinic acid or leucovorin (LV) in combination with respect to efficacy and side-effects. The development of oral fluoropyrimidines, in particular capecitabine, has made chemotherapy further accessible and acceptable. The introduction of newer cytotoxics irinotecan and oxaliplatin has achieved a significant improvement in survival rates with manageable toxicity. With appropriate selection of patients and proper sequencing of currently most efficient regimens, median survival durations of around 20 months can now be reached. Novel targeted therapies (bevacizumab, cetuximab and cyclooxygenase-2 (COX-2) inhibitors) in combination with most efficient chemotherapy regimens will probably push the median survival beyond the 2-year mark. The present article is an overview of most important studies that have substantially changed the approach to metastatic colorectal cancer and have given the patients and clinicians a wider range of options for treating this illness.

Antibodies, Monoclonal↗

PubMed2001

Microsatellite instability: application in hereditary non-polyposis colorectal cancer.

Colorectal cancer (CRC) is a significant cause of mortality in Western populations. About 15% of CRC patients report a family history of the disease. Studies on individuals with a genetic predisposition to CRC have been responsible for significant advances in the understanding of this disease. Thus, although developments in molecular biology have been mainly restricted to a minority of individuals with a hereditary background, information obtained from this group may affect the diagnosis and therapy of sporadic CRCs as well. Deficiency in the DNA mismatch repair (MMR) system results in microsatellite instability (MSI). Individuals from hereditary non-polyposis colorectal cancer (HNPCC) kindreds with germline mutations in genes involved in MMR may benefit from clinical screening programs. The higher frequency of MSI in HNPCC than in sporadic tumours suggests that involvement of MMR genes in sporadic adenomas may be uncommon. Consequently

Adult↗

PubMed2005

Novel therapeutics in colorectal cancer.

Colorectal cancer is an excellent tumor model for evaluating novel therapeutic strategies. Development of a mechanistic understanding of how this cancer develops, spreads, and grows allows a tailored approach to all stages of treatment: prevention, adjuvant treatment, and therapy of advanced disease. We focus on therapy in the advanced disease setting, although progress in this area could lend itself to treatment of early or premalignant disease. In the last 20 years, information has been generated about the intracellular pathways of tumor formation, invasion, and metastasis. As a result, specific molecular processes have been targeted for therapeutic intervention, including cell surface growth factor receptors, proliferation signaling, cell cycling, apo-ptosis, angiogenesis, and matrix metalloproteinases. We review the scientific rationale for recently developed novel therapeutics in colorectal cancer, and the results of clinical trials to date. We also suggest appropriate clinical settings for specific targets and outline future directions of research.

Angiogenesis Inhibitors↗

PubMed1986

Diagnosis and management of colorectal cancer.

Colorectal cancer is an important disease with high mortality. Clinical features are usually nonspecific and vary with the location of the tumor. Diagnosis depends on colonic investigations initiated by a high index of clinical suspicion. Rectal examination, sigmoidoscopy, air-contrast barium enema, and colonoscopy are the crucial diagnostic tools. Clinical judgment dictates the extent of work-up in individual symptomatic patients. Screening of asymptomatic middle-aged and elderly persons is widely advised but less widely practiced. More evidence is needed to clarify the value of screening, especially by occult blood testing. CEA testing is unsuitable for screening and of only limited value for monitoring patients with known colorectal cancer. Surgical resection is the mainstay of treatment. Radiotherapy is useful for palliation of rectal cancer and may delay postoperative tumor recurrence. Chemotherapy for disseminated disease generally gives disappointing results, since only a minority of tumors respond and survival benefit is marginal. Periodic colonic surveillance is important after tumor resection, primarily to detect premalignant new growths.

Adult↗

PubMed2004

Frequency of extra-colonic tumors in hereditary nonpolyposis colorectal cancer (HNPCC) and familial colorectal cancer (FCC) Brazilian families: An analysis by a Brazilian Hereditary Colorectal Cancer Institutional Registry.

UNLABELLED: The two main forms of hereditary colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Some families do not meet all the diagnostic criteria for HNPCC or FAP and are classified as familial colorectal cancer (FCC). Little information is available on the spectrum of tumors related to HNPCC and FCC in South America. OBJECTIVE: To describe the frequency of malignant tumors in a group of Brazilian families with HNPCC or FCC in an Institutional Hereditary Colorectal Cancer Registry. MATERIAL AND METHODS: The study included 61 families (29 HNPCC and 32 FCC) between January 1998 and June 2001. HNPCC families were clinically classified according to the Amsterdam Criteria I or II. FCC families were characterized by the presence of at least two individuals with CRC or extra-colonic tumors associated with the HNPCC spectrum, at least one of them being under 50 years of age. RESULTS: In the 29 families with HNPCC, 201 patients with cancer were identified among 1241 individuals (589 men and 652 women). Among the 201 patients 223 tumors were observed: 137 CRC (55 in men and 82 in women) and 86 extra-colonic (37 in men and 49 in women). In the 32 families with FCC, 146 patients with cancer were identified among 1053 individuals (505 men and 548 women); 158 tumors were observed in 146 patients, 75 CRC (33 in men and 42 in women) and 83 extra-colonic tumors (47 in men and 36 in women). The most frequent extra-colonic primary sites among the HNPCC families were: endometrium (26.5%) and breast (26.5%) (women), and stomach (35.1%) (men). Among the FCC families, the most common primary sites were: breast (27.8%) (women), and stomach (44.4%) (men). CONCLUSION: The high frequency of endometrial and gastric cancer found was expected, since these tumors are part of the HNPCC spectrum, but the high frequency of breast cancer requires further molecular investigation to determine a possible hereditary predisposition associated with hereditary CRC.

Adenomatous Polyposis Coli↗

PubMed2004

Autoimmune thyroid diseases in women with breast cancer and colorectal cancer.

The aim of the study was to compare the prevalence of autoimmune thyroid diseases in three groups of women (66 with breast cancer (CaB), 68 with colorectal cancer (CaC) and 49 without oncological diseases as a control group). Serum levels of thyroid-stimulating hormone (TSH), free thyroxin (fT4), antibodies to thyroglobulin (TGB-ab) and thyroperoxidase (TPO-ab) and tumor markers CEA, CA 15-3 and CA 19-9 were investigated in all subjects by using the chemiluminiscence method. In contrast to Graves' disease (no observed case), autoimmune thyroiditis was diagnosed in 24.2 % women with CaB (4.5 % euthyroid and 19.7 % with subclinical or overt hypothyroidism), compared to 16.7 % in women with CaC (2.0 % euthyroid and 14.7 % with subclinical or overt hypothyroidism) and 16.2 % controls (4.0 % euthyroid and 12.2 % with subclinical or overt hypothyroidism). Serum levels of TGB-ab were higher in the group with breast cancer as compared to those with colorectal cancer and the control group (medians: 35.80 vs. 31.75 vs. 27.70, p<0.001). Similarly, the percentage of positive TGB-ab and TPO-ab serum levels was higher in women with breast cancer as compared to those with colorectal cancer and the control group. The results of the study support the controversial theory that there is an increased prevalence of autoimmune thyroiditis in women with breast cancer.

Aged↗

PubMed2003

Value of histopathology in predicting microsatellite instability in hereditary nonpolyposis colorectal cancer and sporadic colorectal cancer.

Identification of colorectal carcinomas with high levels of DNA microsatellite instability (MSI-H) is important because of the suggested prognostic and therapeutic significance associated with MSI. The role of histology in identifying MSI-H colorectal carcinomas has been suggested by some studies but not confirmed by others. Furthermore, previous studies assumed that hereditary nonpolyposis colorectal cancer (HNPCC)-associated MSI-H tumors and sporadic MSI-H tumors have similar histology. This assumption, however, has been challenged by more recent studies. In this report, we first analyzed the value of various histologic features in predicting MSI-H in a series of 218 colorectal carcinomas containing mixed HNPCC and sporadic cases [77 tumors (35%) were MSI-H by polymerase chain reaction (PCR) method]. Then, we evaluated the various histologic features comparatively in two groups extracted from the 218 cases. Group A was composed of 84 tumors from 82 patients obtained based on a strong family history (HNPCC/HNPCC-like group) (male to female ratio, 42:40; age range, 23-80 years, median, 53.5 years). Thirty-one of the 84 tumors (41.7%) were MSI-H by PCR, and all 31 cases were HNPCC by Amsterdam criteria. Group B was composed of 109 patients with no family history of colorectal cancer or HNPCC-associated cancer, obtained from surgical clinics (sporadic group) (male to female ratio, 65:69; age range, 31-84 years, median, 65 years). Thirty-five of the 109 tumors (32.1%) were MSI-H by PCR. Our results showed that, overall, poor tumor differentiation, medullary type, mucinous type, signet-ring cell component, histologic heterogeneity, and increased tumor-infiltrating lymphocytes (TILs) were features more commonly seen in MSI-H tumors than in non-MSI-H tumors. Comparative analyses showed that the overall TIL count was significantly higher in HNPCC/HNPCC-like group, and mucinous type appeared to be more frequent in HNPCC MSI-H tumors than in sporadic MSI-H tumors. However, there was no significant difference in the odds ratio for predicting MSI-H status for any of the analyzed histologic features between HNPCC/HNPCC-like group and sporadic group, indicating that differences between HNPCC and sporadic MSI-H tumors did not significantly impact on the informative value of histology in predicting MSI in the two different clinical settings. TIL counts followed by histologic heterogeneity provided the greatest sensitivity and specificity in predicting MSI status in both HNPCC/HNPCC-like and sporadic cases. Using a stepwise logistic regression model, a formula was generated that could be used to calculate the probability of a colorectal carcinoma being MSI-H based on morphologic features.

Adaptor Proteins, Signal Transducing↗

PubMed2023

NLRP12 downregulates the Wnt/β-catenin pathway via interaction with STK38 to suppress colorectal cancer.

Colorectal cancer (CRC) at advanced stages is rarely curable, underscoring the importance of exploring the mechanism of CRC progression and invasion. NOD-like receptor family member NLRP12 was shown to suppress colorectal tumorigenesis, but the precise mechanism was unknown. Here, we demonstrate that invasive adenocarcinoma development in Nlrp12-deficient mice is associated with elevated expression of genes involved in proliferation, matrix degradation, and epithelial-mesenchymal transition. Signaling pathway analysis revealed higher activation of the Wnt/β-catenin pathway, but not NF-κB and MAPK pathways, in the Nlrp12-deficient tumors. Using Nlrp12-conditional knockout mice, we revealed that NLRP12 downregulates β-catenin activation in intestinal epithelial cells, thereby suppressing colorectal tumorigenesis. Consistent with this, Nlrp12-deficient intestinal organoids and CRC cells showed increased proliferation, accompanied by higher activation of β-catenin in vitro. With proteomic studies, we identified STK38 as an interacting partner of NLRP12 involved in the inhibition of phosphorylation of GSK3β, leading to the degradation of β-catenin. Consistently, the expression of NLRP12 was significantly reduced, while p-GSK3β and β-catenin were upregulated in mouse and human colorectal tumor tissues. In summary, NLRP12 is a potent negative regulator of the Wnt/β-catenin pathway, and the NLRP12/STK38/GSK3β signaling axis could be a promising therapeutic target for CRC.

Humans↗