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PubMed2002

Screening for colorectal cancer.

Colorectal cancer (CRC) causes 20 000 deaths per annum in the UK alone. Screening has been shown to reduce mortality but debate exists as to which approach to use. Direct visualization of the colorectum has the advantage that it detects lesions most effectively and is required at less frequent intervals, but the procedure is invasive and at present too costly for screening purposes. Faecal occult blood measurement, despite its limitations, is currently the recommended screening method, with follow-up of positive tests by colonoscopy or other visualization techniques. This strategy has been shown to reduce mortality from CRC by about 20% and screening trials directed towards individuals in the over 50 years age group are underway in the UK and elsewhere. Future developments in CRC screening include colorectal visualization by computed colonography -- a less-invasive alternative to colonoscopy. Developments in stool analysis are also occurring. Examination of faecal samples for cellular products derived from neoplasms (e.g. calprotectin) may prove more sensitive and specific than faecal occult blood measurements. In addition, detection of altered DNA in faeces is being investigated by molecular biology techniques. Using a multi-target assay panel to detect point mutations and other neoplasia-associated DNA abnormalities may be an effective strategy for CRC screening in the future.

Biomarkers, Tumor↗

PubMed2002

Prognosis and response to therapy in colorectal cancer.

Colorectal cancer is Europe's second biggest cancer killer. Yet despite advances in knowledge and changes in chemotherapy practice, we have not seen great strides in improved survival. Histopathological staging is at present the most accurate prognostic factor for survival and recurrence. Improvements in staging have led to the recognition of the importance of the circumferential resection margin (CRM) and how the quality of surgery influences local recurrence rates. Further refinements in staging and increasing knowledge of tumour biology will have a large contribution to play in the future.

Colorectal Neoplasms↗

PubMed2002

The role of genomic instabilities in affecting treatment responses of colorectal cancer.

Colorectal cancer is one of the most common tumors worldwide. The knowledge gained on its biology and molecular changes is helping us to choose the best chemotherapeutic treatment. Two different pathways, i.e. the chromosomal and microsatellite instabilities, give the same result but with totally different biological behaviors. In fact, the response to treatment with 5-FU or platinum compounds is dramatically different in both settings. In the future, the use of these compounds should require molecular testing of the specimen prior to treatment.

Antineoplastic Agents↗

PubMed1999

Aberrant methylation of p16INK4a in anatomic and gender-specific subtypes of sporadic colorectal cancer.

Colorectal cancer (CRC) occurring in the proximal colon and among women may represent a distinct subtype of the disease. In the present study of 120 sporadic CRCs, we used methylation-specific PCR to test whether methylation of the CpG island in the 5' region of the p16INK4a tumor suppressor gene was associated with anatomical location, gender, or other clinicopathological characteristics. Overall, 18.3% of the tumors had detectable p16INK4a methylation. A marked preponderance of methylated tumors occurred within the proximal colon; cancers occurring proximal to the sigmoid colon were 13.1 times more likely to contain methylated p16INK4a compared with distal tumors. In addition, female patients were 8.8 times more likely than males to have methylation-positive cancers, and p16INK4a methylation was also associated with poorly differentiated tumors. The localization of tumors with p16INK4a methylation within the proximal colon and among female patients specifically adds to a growing database of molecular alterations that define important subtypes of sporadic CRC. The potentially reversible nature of CpG methylation may provide novel therapeutic opportunities for this increasing subtype of the disease, which, due to anatomical location, presents a great challenge for early detection.

Aged↗

PubMed2004

Capecitabine: the new generation of fluoropyrimidines in colorectal cancer.

Colorectal cancer is the second leading cause of cancer death in the USA and fluoropyrimidines have been the mainstay of treatment for over 40 years. Currently, capecitabine is the only orally available fluoropyrimidine approved for treatment in the USA. As a single agent it has demonstrated activity and equivalence to 5-fluorouracil (5-FU) intravenous administration via the Mayo Clinic regimen, in both the metastatic and adjuvant settings. Ongoing clinical trials are evaluating the efficacy of capecitabine in combination with oxaliplatin and irinotecan as more convenient substitutes for infusional 5-FU in the 5-FU/leucovorin/oxaliplatin and 5-FU/irinotecan regimens.

Antimetabolites, Antineoplastic↗

PubMed2006

[Adjuvant treatment of colorectal cancer].

Colorectal cancer is a real national healthy problem because of high frequency and high rate of mortality. Folfox4 is the new standard treatment since publication of Mosaic' results. Irinotecan associated with 5 fluorouracil (5FU) and leucovorin (LV) failed to demonstrate superiority over LV modulated 5FU. Oral fluoropyrimidines (capecitabine or UFT + LV) are an effective alternative to intravenous 5FU and LV. In stage II colon cancer, treatment strategies are more debated. Some data suggest that chemotherapy is not mandatory for stage II tumors low risk (T3N0 without risk factors). For stage II tumors with high risk factors (T4 or bowel obstruction, perforation, poorly differenciated tumor or, < 10 examined lymphs nodes), Folfox4 and fluoropyrimidine (oral and LV5FU2) should be candidate as adjuvant treatment. Now studies evaluate the role of bevacizumab (Avant, NSABP C08) and cetuximab (Petacc 8 and NCCTG-N0147) in combination with Folfox4 in stage III tumors.

Age Factors↗

PubMedDate not supplied

Role of colonoscopy in colorectal cancer.

Colorectal cancer (CRC) represents the third most common malignancy throughout the world. Little or no improvement in survival has been effectively achieved in the last 50 years. Extensive epidemiological and genetic data are able to identify more precisely definite risk-groups so screening and early diagnosis can be more frequently accomplished. CRC is best detected by colonoscopy, which allows sampling for histologic diagnosis. Colonoscopy is the gold standard for detection of small and premalignant lesions, although it is not cost-effective for screening average-risk population. Colonoscopic polypectomy and mucosal resection constitute curative treatment for selective cases of invasive CRC. Similarly, alternative trans-colonoscopic treatment can be offered for adequate palliation, thus avoiding surgery.

Colonic Polyps↗

PubMed2002

Models of screening program for colorectal cancer.

Colorectal cancer is one of the most frequent neoplasms in western countries, with an estimated 400,000 deaths per year throughout the world. The results of treatment vary widely, depending on the extent of the disease. In particular, the disease stage at diagnosis by the Dukes' modified classification is significantly correlated with prognosis. Colonoscopic polypectomy substantially reduces CRC incidence in comparison to that expected in the general population. These results are of particular relevance considering that people with adenomas are at increased risk for CRC. These observations strengthen the concept of effective population screening in view of the fact that adenomatous polyps are the most frequent neoplastic outcome of screening. Today we have new opportunities for CRC secondary prevention and it is time to start public awareness campaigns and involve gastroenterologists and general practitioners in a common effort.

Colonic Polyps↗

PubMed2001

Long lasting p53-specific T cell memory responses in the absence of anti-p53 antibodies in patients with resected primary colorectal cancer.

Colorectal carcinoma is commonly associated with mutation and overexpression of p53, making this antigen a potential target for immune intervention. We analyzed humoral and proliferative immunity against p53 in the blood of patients with resected primary colorectal cancer. The majority of these patients displayed anti-p53 T helper (Th) immunity in the absence of measurable p53 specific antibody levels. The Th responses were long-lasting since they could be detected up to several years after resection of the primary tumor. In a number of cases the Th responses were highly sensitive, reflected by the recognition of naturally processed p53 protein. Our data argue that boosting of these responses in patients with minimal residual disease through p53-specific vaccination, may be employed for improving the chance of disease-free survival of these patients.

Aged↗

PubMedDate not supplied

Current trends in screening and secondary prevention of colorectal cancer.

Colorectal cancer is one of the most frequent neoplasms in Western countries with an estimated 400,000 deaths per year worldwide. Several randomized studies have demonstrated that screening programs with FOBT (Fecal Occult Blood Test) reduce mortality from 18 to 33%, whereas case-control and cohort studies with endoscopy have shown a mortality reduction ranging from 60 to 76%. The target population for secondary prevention is men and women aged more than 50 years and younger subjects in case first-degree relatives are affected or the family pedigree raises the suspicion of a genetic syndrome. This report summarizes the results of different screening strategies for average risk patients (FOBT, anamnestic risk questionnaire, sigmoidoscopy, colonoscopy and virtual colonoscopy) and the surveillance protocols applicable to high-risk patients, particularly for hereditary syndromes such as HNPCC and FAP.

Colonography, Computed Tomographic↗

PubMed1996

Evidence for the involvement of the Wnt 2 gene in human colorectal cancer.

Colorectal cancer (CRC) is one of the most frequent cancers in humans. It develops via a multistage process involving alterations of both protooncogenes and tumor suppressor genes. In the present report we determined the level of expression of several Wnt genes in CRC by RT-PCR and direct sequencing. While Wnt-1 was not detectably expressed in any colonic tissues, Wnt-5a gene was efficiently expressed both in nontumorous as well as in colonic tumor tissues. In contrast, the Wnt-2 gene, which was expressed at low levels in normal colon, exhibited overexpression in all tumor tissue samples at the different Dukes' stages of CRC progression, including premalignant polyps and liver metastases. Overexpression of the Wnt-2 gene occurred also in other digestive neoplasms such as gastric and esophageal carcinomas, as well as in diverticulitis associated with stenosis or pseudo-tumor.

Base Sequence↗

PubMed2002

Controversy: PPARgamma as a target for treatment of colorectal cancer.

Colorectal cancer (CRC) represents a significant cause of morbidity and mortality worldwide. Recently, ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) have exhibited promise in the treatment of CRC. For example, activation of PPARgamma reduces the proliferation of cultured CRC cells grown in vitro or in vivo using the nude mouse xenograft model of tumor growth. Furthermore, agonists of the receptor also reduce the development of preneoplastic lesions in a model of carcinogen-induced CRC in rats. However, ligands for the receptor paradoxically enhance intestinal adenoma formation in another murine model of intestinal polyposis, the APC(Min) mice. These disparate results may be due to the inherent limitations of the APC(Min) mouse as a model for humans with CRC. Finally, genetic studies identifying loss of function mutations of PPARgamma in human CRC specimens strongly suggest a tumor suppressive role for the receptor during the development of CRC.

Animals↗

PubMed1999

Detection and significance of minimal residual disease in colorectal cancer.

Colorectal cancer (CRC) is one of the most common causes of cancer death in the developed world. Although the primary treatment for CRC is surgical, disease relapse due to minimal residual disease (MRD) following apparently curative surgery occurs in up to fifty percent of patients. Most patients who develop overt metastases beyond the regional lymph nodes eventually die of the disease. At present adjuvant chemotherapy is used to improve survival in patients with metastases to regional lymph nodes demonstrated by routine histopathology with no other evidence of spread. The ability to identify metastatic disease at an earlier stage could be of considerable benefit in directing adjuvant therapy to patients at high risk of relapse who are not identified by current methods. Several techniques have been developed for the detection of MRD, including immunohistochemical and molecular methods, however their role in clinical practise is not yet established. The purpose of this paper is to review these techniques and their potential clinical use in the management of CRC.

Colorectal Neoplasms↗

PubMedDate not supplied

Treatment of advanced colorectal cancer.

Colorectal cancer is one of the most chemotherapy-resistant human malignancies. After 30 years of intensive research, 5-fluorouracil (5-FU) remains the most frequently used drug. The expected response rate is of about 15% without any proven benefit in survival. One of the combination most investigated recently has been methyl CCNU, 5-FU, vincristine and streptozotocine (MOF-S). It has shown a response rate of 30-40% but only little benefit in survival. Although cisplatin (CDDP) is inactive as a single agent, the combination of 5-FU and cisplatin (CDDP) might still be of interest when CDDP is fractionated over 3 to 5 days and 5-FU given as a continuous infusion. Local treatment using the intra-arterial and the intraportal route gives rather high response rates, but has not shown any benefit in survival. Biochemical modulation using allopurinol, methotrexate and leucovorin has raised considerable interest, but at the present time no major benefit in survival has been disclosed.

Allopurinol↗

PubMed2006

Human neutrophil peptides 1, 2 and 3 are biochemical markers for metastatic colorectal cancer.

Colorectal cancer (CRC) patients have increased levels of human neutrophil peptides 1-3 (HNP1-3) in tumour tissue and plasma. The aim is to study whether the amount of HNP1-3 in tumour and plasma from CRC patients correlate with Dukes' stages A-D. The amount of HNP1-3 in tumour tissue, normal colonic mucosa, and plasma was determined with mass spectrometry. Plasma levels of HNP1-3 were determined with enzyme-linked immuno-sorbent assay (ELISA). The amount of HNP1-3 determined with mass spectrometry was increased in tumours compared to normal colonic tissue in CRC patients in Dukes' stage A-D, whereas HNP1-3 in plasma was only elevated in Dukes' stage D compared to healthy individuals. HNP1-3 plasma concentration determined with ELISA was increased in Dukes' stages C and D, but not in A and B. It is concluded that HNP1-3 is a potential marker for prognostic assessment, surveillance of patients, and monitoring chemotherapy in CRC patients with advanced disease.

Adult↗

PubMed2004

Diagnostic application of hMLH1 methylation in hereditary non-polyposis colorectal cancer.

Colorectal cancer (CRC) due to mismatch repair (MMR) defect has distinct characteristics among unselected CRCs. These CRCs are biologically less aggressive and, thus, showing better prognosis but less sensitive to the 5FU-based chemotherapy. CRCs with MMR defect derive from both hereditary and sporadic reasons. Germline inactivation of MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2) underlies the hereditary CRC with MMR defect (Lynch syndrome) and epigenetic silencing of hMLH1 gene causes the sporadic CRC with MMR defect. Hereditary and sporadic CRC with MMR defect can be detectable by microsatellite instability (MSI) test or immunohistochemical analysis among general CRCs. Lynch syndrome can be diagnosed by the clinical criteria or by genetic test to detect pathogenic germline mutations in MMR genes. However, both clinical criteria and genetic test are inadequate for the diagnosis of Lynch syndrome. Since genetic test for the diagnosis of the Lynch syndrome is expensive and not always identify pathogenic germline mutations, effective and inexpensive screening program is desirable. Here we propose a possible application of methylation test combined with MSI or pathological analysis as an effective and a cost-saving new strategy for screening of Lynch syndrome.

Adaptor Proteins, Signal Transducing↗

PubMed2003

[Inhibitors of epidermal growth factor receptor and colorectal cancer].

Colorectal cancers (CRC) express the epidermal growth factor receptor (EGF-R), a type I transmembrane receptor with tyrosine kinase activity. EGF-R signaling inhibition is a promising target for cancer therapy. ZD1839 (Iressa, AstraZeneca) and OSI-774 (Tarceva, Roche) are small molecular weight molecules with selective and reversible tyrosine kinase inhibition properties directed to EGF-R. Orally administered, these molecules induce sustained tumor stabilizations in previously treated metastatic CRC patients. The most frequent treatment-related toxicities are fatigue, diarrhea and acne-like follicular rash. The addition in the clinic of 5-FU, lOHP or CPT-11 to ZD1839 or OSI-774 does not seem to increase the own toxicity of each cytotoxic agents. Cetuximab (Erbitux, Merck) is an intravenously administered humanized monoclonal antibody which bind with high affinity with the extracellular domain of the EGF-R. The most frequent treatment-related toxicities are diarrhea, fatigue, nausea and cutaneous toxicity (allergic or acne-like follicular rashes, folliculitis). Most, if not all of these adverse events are mild. Partial responses were observed with cetuximab either alone (RR: 10%) or in combination with CPT-11 (RR: 22%) in patients with CPT-11 refractory advanced CRC which expressed EGF-R. The combination of cetuximab to folinic acid, 5-FU and CPT-11 seems tolerable at the cost of a slight increase of severe diarrhea and neutropenia. Finally, the promising activity of these EGF-R inhibitors has to be confirmed throughout randomized studies.

Antineoplastic Agents↗

PubMed2003

[Chemotherapy for colorectal cancers].

Colorectal Cancer (CRC) is the most frequent digestive cancer in France and a major public health problem. The benefits of adjuvant chemotherapy after curative resection of Stage III CRC has been clearly demonstrated. For metastatic CRC, palliative chemotherapy allows an improvement in survival duration and quality of life compared with symptomatic treatment. 5-FU/Leucovorin chemotherapy (Mayo Clinic protocol and LV5FU2) is the standard adjuvant therapy. The addition of irinotecan (FOLFIRI) or oxyplatin (FOLFOX) to this regimen may improve response in palliative situations. These two regimens have shown their superiority to 5FU/Leucovorin in both tumor response and survival. A good objective response to palliative chemotherapy may allow for a secondary resection of hepatic metastases as part of a multidisciplinary approach. Current studies aim to define: 1) optimal treatment strategies (which drug protocols? in what order?) as they apply to tumor spread, drug toxicity profiles, the general state of the patient, and the desired therapeutic effect; 2) evaluation of new drugs and novel therapeutic approaches. Despite notable progress, the prognosis still remains grim with a survival of only 40% at 5 years. Any improvement in results will require not only an improvement in chemotherapy but also an improvement in methods of early diagnosis (systematic mass screening) which would permit the diagnosis of CRC at earlier stages where curative resection is feasible.

Antimetabolites, Antineoplastic↗