Metastatic colorectal cancer

Opinion statement Despite advances in screening procedures and the use of adjuvant therapy, approximately 50% of patients with colorectal cancer eventually will develop metastatic disease. Long-term disease-free survival can be achieved in 25% to 40% of selected patients who undergo resection of liver or lung metastases. For all other patients, treatment is palliative. For decades, 5-fluorouracil was the only available drug for colorectal cancer; hence, numerous trials were performed that used various administration schedules and modulating agents to improve therapeutic efficacy. The addition of leucovorin to 5-FU improves response but not survival. Infusion schedules alter the toxicity profile but have a negligible impact on survival. Irinotecan was the first new drug to demonstrate activity in colorectal cancer. It was used initially in the second-line setting, where it was shown to improve quality of life and survival over best supportive care or infusional 5-FU. Recently, irinotecan has been incorporated into the front-line treatment of metastatic colorectal cancer in combination with 5-FU and leucovorin; this combination improves survival by approximately 3 months. Careful patient selection and adherence to strict dose adjustments are essential to prevent significant toxicity when patients are treated on this regimen. The oral fluoropyrimidine capecitabine recently has been approved for the front-line treatment of patients with colorectal cancer who are not appropriate candidates for combination therapy. Oxaliplatin, a novel DACH (diaminocyclohexane) platinum with definite activity in colorectal cancer, is approved for this disease in Europe and is undergoing phase III clinical trials in the United States. Other drugs with potential activity in colorectal cancer include raltitrexed, pemetrexed disodium, and the epothilone analog BMS-247550 (Bristol-Myers Squibb, New York, NY). Novel cytostatics with promising activity in colorectal cancer are being evaluated in clinical trials, including epidermal growth factor receptor inhibitors, such as IMC-C225 (Imclone Systems, New York, NY) and ZD1839 (AstraZeneca, London, UK), angiogenesis inhibitors such as bevacizumab and SU5416 (Sugen, San Francisco, CA), and vaccines such as CEAVac (Titan Pharmaceuticals, San Francisco, CA). For those patients whose disease is localized to the liver, there also is an emerging role for local therapies, including cryosurgery, radiofrequency ablation, and hepatic artery infusional chemotherapy, and resection. The emergence of these new drugs and new interventional modalities has allowed physicians who treat colorectal cancer to move beyond 5-FU.     

Metastatic colorectal cancer

Metastatic colorectal cancer remains a public-health issue on a global scale. With development of a new generation of cytotoxic agents, survival has improved for patients with metastatic disease. How to maximize the benefit of chemotherapy with acceptable toxicity remains incompletely answered. Hepatic resection can provide a significant hope for long term survival, and a subset of patients might benefit from perioperative approaches. More recently, specific molecular processes have been targeted for therapeutic interventions, and encouraging results have been achieved using inhibitors of the Epidermal Growth Factor Receptor and the Vascular Endothelial Growth Factor.     

Laparoscopic colorectal cancer surgery

Colorectal cancer remains the second most common cause of cancer death in the USA and western Europe, with more than 34,000 new cases per year in the UK alone. Annual expenditure is in excess of £300 million, required for surgical, adjuvant and palliative treatment. Laparoscopic colorectal surgery has yet to gain the widespread support observed with gallbladder surgery. Randomized controlled trials are ongoing, evaluating the short- and long-term risks and benefits of laparoscopic versus conventional open surgery. Although long-term results are awaited, there is evidence of short-term benefits and no obvious evidence of laparoscopic techniques conferring any additional harm in terms of tumor recurrence or disease-free survival. This review explores at the likely benefits and areas of continued concern. Information resources provide a background to colorectal cancer for nonclinicians and new strategies and a 5-year view are presented.     

Palliation of colorectal cancer

Patients with advanced incurable colorectal cancer (CRC) face a grim prognosis. The goal of palliative intervention is directed at alleviating disease-related symptoms and improving quality of life. The provision of optimal palliative care for these patients is a compound and demanding process. This dilemma becomes more challenging when patients with advanced metastatic colorectal disease present with an incurable and asymptomatic primary lesion. Treatment options are numerous and include a variety of surgical and nonsurgical interventions. Most data regarding the role of surgery in palliation of CRC are from retrospective, nonrandomized case series. Surgical resection may provide good palliation of symptoms and prevent future tumor-related complications. Metal stents are also able to provide good palliative relief of obstruction and should be used when appropriate. The best palliative care will often require a multidisciplinary approach that involves input from surgical and nonsurgical teams, where treatment plans will be made in accordance with the wishes of the patient and family with a goal of decreasing morbidity and a focus on quality of life.     

Inherited colorectal cancer syndromes

Colorectal cancer is the most common gastrointestinal malignancy and the second leading cause of cancer death in both men and women in the United States. Most colorectal cancer cases diagnosed annually are due to sporadic events, but up to 5% are attributed to known monogenic disorders including Lynch syndrome, familial adenomatous polyposis, MYH-associated polyposis, and the rare hamartomatous polyposis syndromes. These inherited colorectal cancer syndromes confer a markedly increased risk for the development of multiple cancers, and predictive genetic testing is available to identify mutation carriers and at-risk family members. Through personalized strategies for diagnosis and management, a substantial reduction in morbidity and mortality has been appreciated among patients at highest risk for the development of colorectal cancer.     

Screening of colorectal cancer

Cost-effectiveness analyses have shown that the cost per year of life saved by screening with any of the tests recommended is reasonable by US standards. Although the specific results vary among analyses, in general the marginal cost-effectiveness of this screening is less than $25,000 per year of life saved. Screening for CRC was among the highest ranked services in an analysis of the value of preventive services based on the burden of disease prevented and cost-effectiveness. Although the up-front costs vary by screening modality, the long-term cost-effectiveness is similar across screening tests, so that decisions about which options to include--in the long run and from the perspective of society--do not need to be affected heavily by costs. Costs increase out of proportion to benefits with shorter intervals between screening examinations. Screening has provided great opportunities. Screening can prevent CRC by polypectomy and find early-stage cancers for treatment with less morbidity. Screening can reduce the burden of treating advanced cancers and can identify families at increased risk. Screening also has provided a better understanding of the biology of CRC. Screening for CRC should be part of a complete prevention program that includes a healthy lifestyle and familial risk assessment. Individuals with increased familial risk require special screening approaches, whereas individuals with average risk can have more standard screening. The average-risk individuals can be stratified further into persons who require intensive follow-up and persons who require less intensive or no follow-up at all. We are beginning to learn how to apply screening and surveillance approaches based on risk stratification for a more cost-effective approach to conserve resources and reduce complications and costs. Chemoprevention can be added to the program when substantial benefit of agents has been demonstrated. We have a better understanding of the biology of CRC and the technology to intervene in that biology to make a difference in the lives of many people. We have the concepts and technology to reduce substantially the mortality for CRC and even prevent it entirely. Newer screening tests or others yet to be developed may, with time, replace the modern options. Screening should take place with the tests currently available and not wait until something better comes along. In this way, needless suffering and loss of life can be avoided for this leading cause of cancer death. Screening may become even more successful if the promise of new technologies is confirmed and they enter clinical practice. In the last analysis, the best test is the one that gets done and gets done immediately.     

Immunotherapy for colorectal cancer

There have been significant improvements in the diagnosis and treatment of colorectal cancer over the past 15 years. However, some 30% of patients with colorectal cancer have disseminated disease at presentation, and furthermore, 50% of patients initially believed to be cured by surgery subsequently relapse and die of the disease. Novel treatment concepts based on understanding the molecular signatures that separate tumor from normal epithelium, such as immunotherapy, are aimed at abolishing microscopic residual disease post standard treatment. The authors provide an overview of progress in the development of specific and nonspecific immunotherapies and explain why definition of end-points and early translation of immunotherapy into the adjuvant field are key to effective use of such agents in the clinical setting.     

Immunotherapy for colorectal cancer

Immunologic approaches to therapy for colorectal cancer have evolved substantially. In the past, patients were treated with nonspecific immune stimulants such as bacillus Calmette-Guérin (BCG). The current focus lies in targeting tumor-associated antigens. This is done either through passive immune therapy, with antibodies targeted directly to tumor cells, or by active immune therapy through vaccination with tumor cells, tumor cell lysates, peptides, carbohydrates, gene constructs encoding proteins, or anti-idiotype antibodies that mimic tumor-associated antigens. These different approaches to immunotherapy are reviewed.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

脂肪因子与结直肠癌

脂联素、瘦素、网膜素、内脂素均为脂肪组织细胞分泌的脂肪因子,与肥胖、胰岛素抵抗密切相关.研究发现上述脂肪因子也与结直肠癌的发生发展密切相关,有望成为结直肠癌临床诊断以及预后判断的生物学标志物.目前关于脂肪因子如何诱发结直肠癌的机制尚不清楚,仍需开展深入的研究.     

Panitumumab in colorectal cancer

The combination of chemotherapy and targeted therapies is rapidly becoming the standard of care in the treatment of metastatic colorectal cancer. Panitumumab (formerly ABX-EGF) is a fully human antibody developed to target the human epidermal growth factor receptor (EGFR/HER-1), which is expressed in up to 75% of patients with colorectal cancer. As a fully human antibody, panitumumab can be administered without any premedication and few infusion reactions have been reported. It has recently been approved in the USA for the treatment of colorectal cancer as a single agent in the salvage setting. Ongoing studies are being performed to determine whether the addition of panitumumab to standard treatment for metastatic colorectal cancer will improve the survival of these patients.     

Biomarkers in colorectal cancer

Systemic therapies available for treatment of colorectal cancer have increased in recent years, leading to improved clinical outcomes. However, a significant proportion of patients fail to derive meaningful benefits, whereas others suffer from unacceptable toxicities. Therefore, not only does the search for novel and effective anticancer agents continue, there is also a pressing need to optimise the use of all treatments in the therapeutic armamentarium. In addition to knowledge gleaned from well-designed and relevant clinical trials, increasing effort is being invested into biomarkers. The identification and implementation of validated biomarkers has the potential to further our understanding of the biology of colorectal cancer and also to greatly improve the efficiency with which cancer treatments are administered.     

Screening for colorectal cancer

This review will comprise a general overview of colorectal cancer (CRC) screening. We will cover the impact of CRC, CRC risk factors, screening modalities, and guideline recommendations for screening in average-risk and high-risk individuals. Based on this data, we will summarize our approach to CRC screening.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

遗传性非息肉病性结直肠癌

Hereditary non-polyposis colorectal cancer(HNPCC) is an autosomal-dominantly inherited disease which is associated with germline mutations in mismatch repair(MMR) genes and microsatellite instability (MSI). As an important clinical subtype of colorectal cancer, HNPCC is accounting for 5%～15% of colorectal cancer. It' s focus research of colon cancer and hereditary tumor currently because of the special genetic etiopathogenisis and the prominent clinical pathology characteristic.     

二甲双胍与结直肠癌

二甲双胍是治疗2型糖尿病的一线用药,除发挥降糖作用外,还具有抑制结直肠癌等肿瘤细胞增殖的作用。近年来大量证据表明二甲双胍能降低结直肠癌等肿瘤的发病风险及死亡率,其机制主要包括激活单磷酸腺苷活化的蛋白激酶通路,干扰细胞周期,改善胰岛素抵抗,抑制炎症反应,杀伤结直肠癌干细胞等。