Review article: colorectal cancer chemotherapy

Colorectal cancer is a leading cause of cancer death world-wide. There have been important advances in the chemotherapeutic management of colorectal cancer as a result of a deliberate collaborative process of well-designed clinical trials. From the earlier standard of 5-fluorouracil-based therapy alone, the recent availability of newer agents, including capecitabine, irinotecan and oxaliplatin, has significantly expanded the options available for the management of patients with advanced colorectal cancer, with consequent improvements in survival. For patients with resected, high-risk, localized disease, adjuvant systemic chemotherapy improves survival. The identification of new chemotherapy regimens, the use of predictive testing and the integration of novel targeted therapies with cytotoxic chemotherapies are areas of active clinical investigation. A review of the chemotherapeutic management of colorectal cancer is presented.     

Review article: current treatment and optimal patient management in pancreatic cancer

This review analyses the current state of knowledge and understanding concerning the optimum treatment and therapeutic management of patients who suffer from pancreatic cancer. It outlines recent advances in scientific understanding and assesses their potential future value to clinicians in confronting this disease. Despite a significant expansion in scientific knowledge relating to factors underlying the early development of pancreatic carcinoma, the clinician continues to be restricted to a severely limited therapeutic armoury for this disease. Local therapies (surgery and radiation) are inevitably of limited value in the face of a disease that is normally encountered at a stage where metastasis is already highly developed. Despite such limitations, however, surgery performed in specialist units may be of value for 10–20% of patients, with a 5-year survival rate in such units of between 10 and 24%. This may be improved even further by appropriate use of adjuvant treatment. The advanced stage of the disease when normally encountered emphasizes the potential value of systemic treatment in this therapeutic area. Unfortunately systemic treatment (chemotherapy) has been found to be ineffective to date in significantly extending survival, with a low rate and duration of remission being identified in most trials. The challenge for both the health service and the pharmaceutical industry is to harness recent and future developments in scientific knowledge to the practical benefit of clinicians. Where cure is possible it should be vigorously pursued; where it is not, in this field above all others, clinicians have a duty of care. To achieve this it is necessary to abandon the therapeutic nihilism that has characterized the attitudes of clinicians towards this disease in the past. It is time that such nihilism was replaced by a recognition of the challenges and the opportunities available to clinicians in enhancing the quantity and quality of life available to patients. The dictum of ‘curing whenever possible but caring always’ should be the future therapeutic philosophy used to guide clinicians in this important and rapidly changing therapeutic area.     

Review article: Population screening for colorectal cancer

Colorectal cancer is a common cancer and common cause of death. The mortality rate from colorectal cancer can be reduced by identification and removal of cancer precursors, adenomas, or by detection of cancer at an earlier stage. Pilot screening programmes have demonstrated decreased colorectal cancer mortality; as a result many countries are developing colorectal cancer screening programmes. The most common modalities being evaluated are faecal occult blood testing, flexible sigmoidoscopy and colonoscopy. Implementation of screening tests has been hampered by cost, invasiveness, availability of resources and patient acceptance. New technologies such at computed tomographic colonography and stool screening for molecular markers of neoplasia are in development as potential minimally invasive tools. This review considers who should be screened, which test to use and how often to screen.     

Review article: current practice and future perspectives in detection and diagnosis of pancreatic cancer

Pancreatic cancer is the tenth most prevalent malignancy and the fifth most common cause of cancer death in the developed world. Less than 10% of patients survive for more than 1 year following diagnosis and the 5-year survival rate (0.4%) is the lowest of any cancer. The poor prognosis associated with this diagnosis led in the past to therapeutic nihilism on the part of clinicians who were all too aware of the limitations of their available therapeutic strategies. Breaking this therapeutic impasse requires a significant expansion in the knowledge of clinicians concerning the pathogenesis and behaviour of pan- creatic cancer. Recent advances in the scientific understanding of the aetiology of pancreatic cancer has facilitated progress towards the development of promising and innovative approaches to the early detection and diagnosis of pancreatic cancer. While acknowledging that pancreatic cancer will continue to present significant challenges to both scientists and clinicians in the foreseeable future, it is becoming increasingly clear that recent advances in our scientific knowledge base holds the potential to significantly improve prognosis for patients. The challenge facing both scientists and clinicians is how best to translate such promising scientific advances into survival and quality of life benefits to patients.     

Review article: benefits and risks of chemotherapy in elderly patients with metastatic colorectal cancer

Background  Although metastatic colorectal cancer (mCRC) is largely a disease of older individuals, our understanding of disease processes and their optimal treatment has been gained through trials with populations largely confined to younger individuals.
Aim  To identify through a review issues specific to geriatric patients with mCRC (physiological changes associated with aging, burden of coexisting illnesses, altered drug pharmacokinetics and functional impairment) and assess challenges to elderly patients posed by malignancy and exposure to cytotoxic medication.
Methods  Our literature search for indexed articles published between 2000 and May 2008 employed terms including irinotecan, oxaliplatin, elderly, mCRC, targeted agents and biologicals.
Results  Underrepresentation of older patients in clinical trials makes it difficult to extrapolate findings to older age groups. However, some trials have demonstrated that elderly patients can achieve survival benefits and toxicity comparable to younger patients, although dosage modifications may be required.
Conclusions  Currently, benefits with pharmacological therapy are suggested but not proven in the elderly population. Although concurrent illnesses and disabilities can complicate treatment decision making, chronological age alone should not disqualify these patients with mCRC from receiving optimal treatment similar to that offered to their younger cohorts.     

Review article: gastrin and colorectal cancer

The polypeptide hormone gastrin was identified nearly a hundred years ago and its role in the regulation of acid secretion is well established. Gastrin also acts as a growth factor and is trophic for the normal gastric oxyntic mucosa. This growth promoting action has led to the extensive investigation of its role in carcinogenesis, in particular colorectal neoplasia. The relationship between gastrin and colorectal adenocarcinoma has been subject to controversy, however the findings from several recent studies have resulted in a clearer understanding of the mechanism of action of gastrin in this is common cancer. The majority of colorectal cancers produce their own gastrin, which may act in an autocrine manner. The tumour cells also express gastrin/CCKB receptors (and/or a combination of isoforms) which mediate the proliferative action. This locally produced gastrin gives rise to a small increase in systemic gastrin levels. Autocrine gastrin may also have a role in tumour development, as expression occurs early in the adenoma-carcinoma sequence. In addition, several studies using animal models have shown that systemic hypergastrinaemia promotes the proliferation of both normal and neoplastic colonic epithelium. Hyperproliferative colonic epithelium in the presence of hypergastrinaemia has been recorded in humans and a well-designed epidemiological study has demonstrated an increased incidence of colorectal cancer. Gastrin is a potential therapeutic target in the treatment of colorectal cancer and several approaches have been assessed. Receptor antagonists and antisecretory agents have been demonstrated to be ineffectual. Novel methods of inhibition, including the use of anti-gastrin antibodies, are currently being evaluated.     

Review article: chemoprevention of colorectal cancer

Colorectal cancer is a disease with a high mortality at present, due to the late stage at which many cases present. Attention is therefore focusing on preventative strategies for colorectal cancer given that polyps appear to be identifiable and treatable precursor lesions of this disease. Endoscopic polypectomy has been shown to reduce the incidence of colorectal cancer and there is a good case for endoscopic screening of the general population. However, this will require a large amount of manpower and resources and its success will also depend on the overall compliance of the population. Epidemiological studies have shown that individuals reporting a regular intake of aspirin and other non-steroidal anti-inflammatory drugs have a reduced risk of developing colorectal polyps and cancer. Similarly, a number of natural substances, such as calcium and folate, when supplemented regularly in the diet, have also been linked to a possible decreased incidence of colorectal cancer. This has led to the concept of using such agents to reduce the number of cases of colorectal cancer. In this article, we review the current evidence for the use of these and other agents for the chemoprevention of colorectal cancer, together with theories as to their possible mechanisms of action.     

Review article: pancreatic renin-angiotensin systems in health and disease

Aliment Pharmacol Ther 2011; 34: 840–852

Summary

Background In addition to the circulating (endocrine) renin–angiotensin system (RAS), local renin–angiotensin systems are now known to exist in diverse cells and tissues. Amongst these, pancreatic renin–angiotensin systems have recently been identified and may play roles in the physiological regulation of pancreatic function, as well as being implicated in the pathogenesis of pancreatic diseases including diabetes, pancreatitis and pancreatic cancer. Aim To review and summarise current knowledge of pancreatic renin–angiotensin systems. Methods We performed an extensive PubMed, Medline and online review of all relevant literature. Results Pancreatic RAS appear to play various roles in the regulation of pancreatic physiology and pathophysiology. Ang II may play a role in the development of pancreatic ductal adenocarcinoma, via stimulation of angiogenesis and prevention of chemotherapy toxicity, as well as in the initiation and propagation of acute pancreatitis (AP); whereas, RAS antagonism is capable of preventing new‐onset diabetes and improving glycaemic control in diabetic patients. Current evidence for the roles of pancreatic RAS is largely based upon cell and animal models, whilst definitive evidence from human studies remains lacking. Conclusions The therapeutic potential for RAS antagonism, using cheap and widely available agents, and may be untapped and such roles are worthy of active investigation in diverse pancreatic disease states.     

Review article: faecal occult blood testing for colorectal cancer

Major health organizations recommend colorectal cancer screening using faecal occult blood tests, sigmoidoscopy or both for patients 50 years of age or older who are at average risk for colorectal cancer. However, no specific recommendations have been made regarding choice of test from among the tests currently or soon to be available. Therefore, to aid clinicians in rationally choosing a particular test for faecal occult blood, published data are reviewed regarding the performance characteristics, strengths and weaknesses of the various faecal occult blood tests. New studies suggest that immunochemical tests (e.g. HemeSelect) or a combination of sensitive guaiac tests and immunochemical tests (e.g. Hemoccult Sensa and HemeSelect) are the most sensitive, specific tests for detecting colorectal carcinoma and colorectal polyps ≥ 1 cm.     

Review article: immune suppression and colorectal cancer

BACKGROUND: Advances in immunology and molecular biology have shown that colorectal cancer is potentially immunogenic and that host immune responses influence survival. However, immune surveillance and activation is frequently ineffective in preventing and/or controlling tumour growth. AIM: To discuss potential ways in which colorectal cancer induces immune suppression, its effect upon prognosis and avenues for therapeutic development. METHOD: A literature review was undertaken for evidence of colorectal cancer-induced immune suppression using PubMed and Medline searches. Further studies were identified from the reference lists of identified papers. RESULTS: Immune suppression occurs at a molecular and cellular level and can result in a shift from cellular to humoral immunity. Several mechanisms for immune suppression have been described affecting innate and adaptive immunity with suppression linked to poorer clinical outcome. CONCLUSIONS: Colorectal cancer causes direct inhibition of the host's immune response with a detrimental effect upon prognosis. Immunotherapy offers a therapeutic strategy to counteract these effects with promising results seen particularly in precancerous conditions and early tumours. This review strongly suggests that immunotherapy should be incorporated into adjuvant therapeutic trials for stage 2 tumours and be considered as adjuvant treatment in conjunction with standard chemotherapy regimes for advanced disease.     

Review article: the prevention of colorectal cancer

Colorectal cancer is a leading cause of cancer mortality in the industrialized world. Survival remains poor because most cases are diagnosed at an advanced stage. It is a preventable disease as colorectal cancers usually develop slowly from an identifiable precursor lesion, the adenoma. The existing strategies for colorectal cancer prevention include dietary prevention, chemoprevention and endoscopic intervention. The exact relationship between diet, particularly fibre, and colorectal cancer remains unclear, with the most recent studies suggesting that dietary fibre may not decrease colorectal cancer risk as previously thought. Non-steroidal anti-inflammatory drugs have been shown to have a protective effect against colorectal cancer, but the adverse effect profile of the non COX-2 selective drugs, particularly the risk of gastrointestinal haemorrhage, precludes their widespread use. There is increasing evidence that colorectal cancer incidence and mortality can be decreased from endoscopic polypectomy and early detection of cancer. Faecal occult blood testing in the general population ('average-risk') has been shown in randomized trials to decrease mortality from colorectal cancer by 15--33%. Long-term results of randomized trials of the effectiveness of flexible sigmoidoscopy and colonoscopy screening in the general population are awaited. Targeting high risk individuals may also be an effective and efficient way to decrease the colorectal cancer burden. As many as 15--30% of colorectal cases may be due to hereditary factors. Individuals with one or two direct relatives affected are at moderate risk for colorectal cancer (empirical lifetime mortality from colorectal cancer approximately 10%) and approximately 2--3% of cases arise in individuals harbouring highly penetrant autosomal dominant mutations, which puts them at high-risk for colorectal cancer. Surveillance colonoscopy is offered to individuals at moderate and high risk for colorectal cancer.     

Review article: gastric cancer and Helicobacter pylori

Gastric cancer is the second commonest cause of death from malignancy in the world. Its pathogenesis is comparatively well understood and its aetiology multifactorial. Non-cardia gastric cancer usually arises in a stomach that has been inflamed over a long period and where atrophy and intestinal metaplasia have supervened. The commonest cause of gastric inflammation is infection with Helicobacter pylori. Colonization with this organism increases the relative risk of developing this cancer by about six [Helicobacter and Cancer Collaborative Group. Gut 2001; 49: 347-53]. Its likelihood increases with the severity and extent of the gastritis. Severity is influenced by the virulence of the infecting organism, the genetics of the host, bile reflux, dietary factors and the presence of hypochlorhydria which influences the extent, as well as the severity, of the inflammation. The only predisposing factor which can easily be manipulated is H. pylori infection, which can be successfully treated in 80-90% of cases using a 1-week therapeutic regimen.     

Review article: genetic testing and counselling for hereditary colorectal cancer

Colorectal cancer is the second leading cause of cancer death, after lung cancer, in the USA. The great majority (80%) of patients with colorectal cancer have sporadic disease with no evidence of having inherited the disorder. In the remaining 20%, a potentially definable genetic component exists. With the discovery of gene mutations related to hereditary colorectal cancer, risk assessment based on genetic test results is now feasible. The following review focuses on the two well-described colorectal cancer genetic syndromes-familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, the process of genetic counselling, currently available genetic tests, and indications for their use.     

Review article: nutrition, obesity and colorectal cancer

Background  The age-adjusted incidence of colorectal cancer is higher in prosperous industrialized countries than elsewhere. Dietary factors may account for 75% of sporadic colorectal cancer in the west, but the mechanisms remain obscure.
Aim  To review evidence for the effects of overweight and obesity, physical activity and specific dietary components on colorectal neoplasia.
Methods  English language papers cited on MEDLINE, obtained using search terms related to colorectal cancer, physical activity and body mass and specific food components were reviewed.
Results  There is evidence for adverse effects of overweight and obesity and protective effects of high physical activity against colon, but not for rectal cancer. These effects may reflect metabolic stress and chronic low-grade inflammation. There are also modest adverse effects of red and processed meat. There is evidence for protective effects of dietary fibre, but for fruits and vegetables the evidence remains weak and inconclusive. There is some evidence for protective effects of n -3 polyunsaturated fatty acids from fish, some micronutrients and possibly phytochemicals. The effects of many dietary constituents may depend upon genetic polymorphisms affecting a variety of genes.
Conclusion  Further research should focus particularly on the effects of insulin-resistance, impaired glucose tolerance and chronic low-grade inflammation on the colonic mucosa.     

Review article: anorexia and cachexia in gastrointestinal cancer

In patients with gastrointestinal malignancies, i.e. cancers of the stomach, colon, liver, biliary tract or pancreas, progressive undernutrition can be regularly observed during the course of illness. Undernutrition significantly affects the patients' quality of life, morbidity and survival. Pathogenetically, two different causes are relevant in the development of undernutrition in patients with gastrointestinal cancer. One cause is reduced nutritional intake. This condition is referred to as anorexia and can be worsened by the side effects of cancer therapy. The other cause is the release of endogenous transmitters and/or other products of the tumour leading to the cachexia syndrome, which is characterized by loss of body weight, negative nitrogen balance and fatigue. Cancer anorexia and cancer cachexia may have synergistic negative effects in affecting the patients' status. In this review, current nutritional support strategies with respect to different clinically relevant situations are described. An algorithm of the treatment strategies, including dietetic counselling, oral supplements, enteral and parenteral nutritional support is given. One focus is the approach of nutrition-focused patient care, which shows promising results. In addition, the possibilities of pharmacological intervention are discussed.     

Conventional chemotherapy of advanced pancreatic cancer

The vast majority of patients with pancreatic cancer present with locally advanced unresectable or metastatic disease, and in this setting only a palliative treatment can be offered. Single-agent gemcitabine has been considered the standard chemotherapy for patients with advanced pancreatic cancer since the results of a pivotal phase III trial showing superior clinical benefit compared to bolus 5-fluorouracil were published in 1997. In recent years, many randomized trials have attempted to improve results obtained with gemcitabine exploring a different schedule (fixed dose rate) of its administration, or testing the addition of one or more drugs to gemcitabine. Unfortunately, none of these trials produced a statistically significant and clinically relevant improvement in overall survival compared to the standard. A randomized phase III trial has recently shown a survival advantage using a combination of more drugs (FOLFIRINOX: irinotecan, oxaliplatin, folinic acid and 5-fluorouracil) compared to single-agent gemcitabine, suggesting that regimens without gemcitabine can be successfully used in patients with advanced pancreatic cancer. FOLFIRINOX was associated with worse toxicity than gemcitabine, and the available data suggest that this regimen may be considered for patients with metastatic pancreatic cancer who are fit enough to withstand potential side effects. The best option for these patients remains the enrolment in prospective clinical trials. Improvements in the treatment of the advanced disease will possibly derive from new combinations or from new drugs, but certainly from a better knowledge of the multiple molecular pathways implicated in pancreatic carcinogenesis and in invasion and metastasis.